FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Nafi, SNM Generali, D Kramer-Marek, G Gijsen, M Strina, C Cappelletti, M Andreis, D Haider, S Li, JL Bridges, E Capala, J Ioannis, R Harris, AL Kong, A AF Nafi, Siti Norasikin Mohd Generali, Daniele Kramer-Marek, Gabriela Gijsen, Merel Strina, Carla Cappelletti, Mariarosa Andreis, Daniele Haider, Syed Li, Ji-Liang Bridges, Esther Capala, Jacek Ioannis, Roxanis Harris, Adrian L. Kong, Anthony TI Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer SO ONCOTARGET LA English DT Article DE breast cancer; HER4; HER2; trastuzumab; resistance ID RECEPTOR TYROSINE KINASE; GAMMA SECRETASE INHIBITORS; MESSENGER-RNA EXPRESSION; ERBB4 ISOFORM; INTRACELLULAR DOMAIN; ESTROGEN-RECEPTOR; PROGNOSTIC VALUE; MAMMARY-GLAND; IN-VIVO; CELLS AB The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a y-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. C1 [Nafi, Siti Norasikin Mohd; Gijsen, Merel; Kong, Anthony] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Epidermal Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England. [Haider, Syed; Li, Ji-Liang; Bridges, Esther; Harris, Adrian L.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England. [Capala, Jacek] NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Generali, Daniele; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele] AI Inst Ospitalieri Cremona, UO Multidisciplinare Patol Mammaria, US Terapia Mol & Farmacogenom, Cremona, Italy. [Ioannis, Roxanis] Oxford Univ Hosp, Dept Cellular Pathol, Oxford, England. [Ioannis, Roxanis] Oxford Biomed Res Ctr, Oxford, England. [Kramer-Marek, Gabriela] Inst Canc Res, Div Radiotherapy & Imaging, Sutton, Surrey, England. RP Kong, A (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Epidermal Growth Factor Grp,Dept Oncol, Oxford OX3 9DU, England. EM anthony.kong@oncology.ox.ac.uk RI Mohd Nafi, Siti Norasikin/M-4548-2015; Andreis, Daniele/J-8333-2016; OI Mohd Nafi, Siti Norasikin/0000-0002-0642-0909; Andreis, Daniele/0000-0001-6686-5662; Harris, Adrian/0000-0003-1376-8409 NR 54 TC 14 Z9 14 U1 1 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 15 PY 2014 VL 5 IS 15 BP 5934 EP 5949 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ0EQ UT WOS:000347919500008 ER PT J AU Matthews, CE Cohen, SS Fowke, JH Han, XJ Xiao, Q Buchowski, MS Hargreaves, MK Signorello, LB Blot, WJ AF Matthews, Charles E. Cohen, Sarah S. Fowke, Jay H. Han, Xijing Xiao, Qian Buchowski, Maciej S. Hargreaves, Margaret K. Signorello, Lisa B. Blot, William J. TI Physical Activity, Sedentary Behavior, and Cause-Specific Mortality in Black and White Adults in the Southern Community Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE blacks; cancer; exercise; prevention; sedentary behavior ID ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; US ADULTS; AFRICAN-AMERICANS; SITTING TIME; QUESTIONNAIRE; RISK; WOMEN; POPULATION; EXERCISE AB There is limited evidence demonstrating the benefits of physical activity with regard to mortality risk or the harms associated with sedentary behavior in black adults, so we examined the relationships between these health behaviors and cause-specific mortality in a prospective study that had a large proportion of black adults. Participants (40-79 years of age) enrolled in the Southern Community Cohort Study between 2002 and 2009 (n = 63,308) were prospectively followed over 6.4 years, and 3,613 and 1,394 deaths occurred in blacks and whites, respectively. Black adults who reported the highest overall physical activity level (= 32.3 metabolic equivalent-hours/day vs. <9.7 metabolic equivalent-hours/day) had lower risks of death from all causes (hazard ratio (HR) = 0.76. 95% confidence interval (CI): 0.69, 0.85), cardiovascular disease (HR = 0.81, 95% CI: 0.67, 0.98), and cancer (HR = 0.76, 95% CI: 0.62, 0.94). In whites, a higher physical activity level was associated with a lower risk of death from all causes (HR = 0.76, 95% CI: 0.64, 0.90) and cardiovascular disease (HR = 0.69, 95% CI: 0.49, 0.99) but not cancer (HR = 0.95, 95% CI: 0.67, 1.34). Spending more time being sedentary (>12 hours/day vs. <5.76 hours/day) was associated with a 20%-25% increased risk of all-cause mortality in blacks and whites. Blacks who reported the most time spent being sedentary (= 10.5 hours/day) and lowest level of physical activity (<12.6 metabolic equivalent-hours/day) had a greater risk of death (HR = 1.47, 95% CI: 1.25, 1.71). Our study provides evidence that suggests that health promotion efforts to increase physical activity level and decrease sedentary time could help reduce mortality risk in black adults. C1 [Matthews, Charles E.; Xiao, Qian] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Rockville, MD USA. [Cohen, Sarah S.] EpidStat Inst, Ann Arbor, MI USA. [Fowke, Jay H.; Buchowski, Maciej S.; Blot, William J.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Fowke, Jay H.; Buchowski, Maciej S.; Blot, William J.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Han, Xijing; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Hargreaves, Margaret K.] Meharry Med Coll, Dept Internal Med, Nashville, TN 37208 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. RP Matthews, CE (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E340,MSC 9704, Bethesda, MD 20892 USA. EM charles.matthews2@nih.gov RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Buchowski, Maciej/0000-0002-0566-1743 FU National Cancer Institute at the National Institutes of Health [R01 CA92447]; American Recovery and Reinvestment Act [3R01 CA092447-08S1]; National Institutes of Health [5P60 DK20593-24, 5U01 CA114641-05] FX The Southern Community Cohort Study is funded by grant R01 CA92447 from the National Cancer Institute at the National Institutes of Health, including special allocations from the American Recovery and Reinvestment Act (grant 3R01 CA092447-08S1). Partial support for M. K. H. was provided by National Institutes of Health grants 5P60 DK20593-24 and 5U01 CA114641-05. NR 36 TC 17 Z9 17 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2014 VL 180 IS 4 BP 394 EP 405 DI 10.1093/aje/kwu142 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AQ7XD UT WOS:000343032100008 PM 25086052 ER PT J AU Wang, WH Zhang, CB Lin, DH Wang, LJ Graves, JP Zeldin, DC Capdevila, JH AF Wang, Wen-Hui Zhang, Chengbiao Lin, Dao-Hong Wang, Lijun Graves, Joan P. Zeldin, Darryl C. Capdevila, Jorge H. TI Cyp2c44 epoxygenase in the collecting duct is essential for the high K+ intake-induced antihypertensive effect SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE epoxyeicosatrienoic acid; epithelial Na+ channel; renal sodium excretion; hypertension; cytochrome P-450, family 2, subfamily c, polypeptide 44 ID EPITHELIAL SODIUM-CHANNEL; SALT-SENSITIVE HYPERTENSION; ARACHIDONIC-ACID EPOXYGENASE; THICK ASCENDING LIMB; DIETARY POTASSIUM; LIDDLES SYNDROME; APICAL MEMBRANE; BLOOD-PRESSURE; RENAL INJURY; NA CHANNELS AB Cytochrome P-450, family 2, subfamily c, polypeptide 44 (Cyp2c44) epoxygenase metabolizes arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) in kidney and vascular tissues. In the present study, we used real-time quantitative PCR techniques to examine the effect of high salt or high K+ (HK) intake on the expression of Cyp2c44, a major Cyp2c epoxygenase in the mouse kidney. We detected Cyp2c44 in the proximal convoluted tubule, thick ascending limb, distal convoluted tubule (DCT)/connecting tubule (CNT), and collecting duct (CD). A high-salt diet increased the expression of Cyp2c44 in the thick ascending limb and DCT/CNT but not in the proximal convoluted tubule and CD. In contrast, an increase in dietary K+ intake augmented Cyp2c44 expression only in the DCT/CNT and CD. Neither high salt nor HK intake had a significant effect on the blood pressure (BP) of wild-type mice. However, HK but not high salt intake increased BP in CD-specific, Cyp2c44 conditional knockout (KO) mice. Amiloride, an epithelial Na+ channel (ENaC) inhibitor, normalized the BP of KO mice fed HK diets, suggesting that lack of Cyp2c44 in the CD enhances ENaC activity and increases Na+ absorption in KO mice fed HK diets. This notion was supported by metabolic cage experiments demonstrating that renal Na+ excretion was compromised in KO mice fed HK diets. Also, patch-clamp experiments demonstrated that 11,12-EET, a major Cyp2c44 product, but not AA inhibited ENaC activity in the cortical CD of KO mice. We conclude that Cyp2c44 in the CD is required for preventing the excessive Na+ absorption induced by HK intake by inhibition of ENaC and facilitating renal Na+ excretion. C1 [Wang, Wen-Hui; Zhang, Chengbiao; Lin, Dao-Hong; Wang, Lijun] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA. [Graves, Joan P.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. [Capdevila, Jorge H.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Wang, WH (reprint author), New York Med Coll, Dept Pharmacol, 15 Dana Rd, Valhalla, NY 10595 USA. EM Wenhui_wang@nymc.edu FU National Institutes of Health (NIH) [DK-38226, P01-HL-34300]; Intramural Research Program of the NIH under NIH [Z01-ES-025034] FX The work was supported by National Institutes of Health (NIH) Grant DK-38226 (to J. H. Capdevila) and P01-HL-34300 (W.-H. Wang). This work was also supported, in part, by the Intramural Research Program of the NIH under NIH Grant Z01-ES-025034 (to D. C. Zeldin). NR 44 TC 6 Z9 6 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG 15 PY 2014 VL 307 IS 4 BP F453 EP F460 DI 10.1152/ajprenal.00123.2014 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AO1PN UT WOS:000341085600010 PM 24966089 ER PT J AU Philip, PA Chansky, K LeBlanc, M Rubinstein, L Seymour, L Ivy, SP Alberts, SR Catalano, PJ Crowley, J AF Philip, Philip A. Chansky, Kari LeBlanc, Michael Rubinstein, Lawrence Seymour, Lesley Ivy, S. Percy Alberts, Steven R. Catalano, Paul J. Crowley, John TI Historical Controls for Metastatic Pancreatic Cancer: Benchmarks for Planning and Analyzing Single-Arm Phase II Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; GEMCITABINE; COMBINATION; ADENOCARCINOMA; METAANALYSIS; CARCINOMA; SURVIVAL; BENEFIT AB We compiled and analyzed a database of cooperative group trials in advanced pancreatic cancer to develop historical benchmarks for overall survival (OS) and progression-free survival (PFS). Such benchmarks are essential for evaluating new therapies in a single-arm setting. The analysis included patients with untreated metastatic pancreatic cancer receiving regimens that included gemcitabine, between 1995 and 2005. Prognostic baseline factors were selected by their significance in Cox regression analysis. Outlier trial arms were identified by comparing individual 6-month OS and PFS rates against the entire group. The dataset selected for the generation of OS and PFS benchmarks was then tested for intertrial arm variability using a logistic-normal model with the selected baseline prognostic factors as fixed effects and the individual trial arm as a random effect. A total of 1,132 cases from eight trials qualified. Performance status and sex were independently significant for OS, and performance status was prognostic for PFS. Outcomes for one trial (NCCTG-034A) were significantly different from the other trial arms. When this trial was excluded, the remaining trial arms were homogeneous for OS and PFS outcomes after adjusting for performance status and sex. Benchmark values for 6-month OS and PFS are reported along with a method for using these values in future study design and analysis. The benchmark survival values were generated from a dataset that was homogeneous between trials. The benchmarks can be used to enable single-arm phase II trials using a gemcitabine platform, especially under certain circumstances. Such circumstances might be when a randomized control arm is not practically feasible, an early signal of activity of an experimental agent is being explored such as in expansion cohorts of phase I studies, and in patients who are not candidates for combination cytotoxic therapy. (C) 2014 AACR. C1 [Philip, Philip A.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. [Chansky, Kari; Crowley, John] Canc Res & Biostat, Seattle, WA 98101 USA. [LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Rubinstein, Lawrence; Ivy, S. Percy] NCI, Bethesda, MD 20892 USA. [Alberts, Steven R.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Catalano, Paul J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Seymour, Lesley] NCIC Clin Trials Grp, Kingston, ON, Canada. RP Chansky, K (reprint author), Canc Res & Biostat, 1730 Minor Ave,Suite 1900, Seattle, WA 98101 USA. EM karic@crab.org FU NCI of the NIH [U10CA038926] FX This work was supported by the NCI of the NIH under award number U10CA038926 (to J. Crowley). NR 25 TC 4 Z9 4 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 AUG 15 PY 2014 VL 20 IS 16 BP 4176 EP 4185 DI 10.1158/1078-0432.CCR-13-2024 PG 10 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100002 PM 24914040 ER PT J AU Khanna, C Fan, TM Gorlick, R Helman, LJ Kleinerman, ES Adamson, PC Houghton, PJ Tap, WD Welch, DR Steeg, PS Merlino, G Sorensen, PHB Meltzer, P Kirsch, DG Janeway, KA Weigel, B Randall, L Withrow, SJ Paoloni, M Kaplan, R Teicher, BA Seibel, NL Smith, M Uren, A Patel, SR Trent, J Savage, SA Mirabello, L Reinke, D Barkaukas, DA Krailo, M Bernstein, M AF Khanna, Chand Fan, Timothy M. Gorlick, Richard Helman, Lee J. Kleinerman, Eugenie S. Adamson, Peter C. Houghton, Peter J. Tap, William D. Welch, Danny R. Steeg, Patricia S. Merlino, Glenn Sorensen, Poul H. B. Meltzer, Paul Kirsch, David G. Janeway, Katherine A. Weigel, Brenda Randall, Lor Withrow, Stephen J. Paoloni, Melissa Kaplan, Rosandra Teicher, Beverly A. Seibel, Nita L. Smith, Malcolm Ueren, Aykut Patel, Shreyaskumar R. Trent, Jeffrey Savage, Sharon A. Mirabello, Lisa Reinke, Denise Barkaukas, Donald A. Krailo, Mark Bernstein, Mark TI Toward a Drug Development Path That Targets Metastatic Progression in Osteosarcoma SO CLINICAL CANCER RESEARCH LA English DT Article ID LIPOSOMAL MURAMYL TRIPEPTIDE; COLONY-STIMULATING FACTOR; CHILDRENS ONCOLOGY GROUP; CANCER METASTASIS; BREAST-CANCER; TUMORICIDAL PROPERTIES; THERAPEUTIC TARGET; LUNG METASTASES; TUMOR-CELLS; BONE-MARROW AB Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting. (C) 2014 AACR. C1 [Khanna, Chand] NIH, Mol Oncol Sect, Bethesda, MD 20892 USA. [Kaplan, Rosandra] NIH, Tumor Microenvironm Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Paoloni, Melissa] NIH, Comparat Oncol Program, Bethesda, MD 20892 USA. [Seibel, Nita L.] NIH, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Savage, Sharon A.] NIH, Clin Genet Branch, Bethesda, MD 20892 USA. [Mirabello, Lisa] NIH, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Steeg, Patricia S.] NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Merlino, Glenn] NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Meltzer, Paul] NIH, Genet Branch, Bethesda, MD 20892 USA. [Teicher, Beverly A.] NIH, Mol Pharmacol Branch, Bethesda, MD 20892 USA. [Khanna, Chand; Helman, Lee J.; Steeg, Patricia S.; Merlino, Glenn; Meltzer, Paul; Paoloni, Melissa; Kaplan, Rosandra; Teicher, Beverly A.; Seibel, Nita L.; Savage, Sharon A.; Mirabello, Lisa] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Khanna, Chand; Helman, Lee J.; Steeg, Patricia S.; Merlino, Glenn; Meltzer, Paul; Paoloni, Melissa; Kaplan, Rosandra; Teicher, Beverly A.; Seibel, Nita L.; Smith, Malcolm; Savage, Sharon A.; Mirabello, Lisa] NCI, NIH, Bethesda, MD 20892 USA. [Fan, Timothy M.] Univ Illinois, Dept Vet Clin Med, Urbana, IL USA. [Gorlick, Richard] Yeshiva Univ, Albert Einstein Coll Med, Dept Pediat & Mol Pharmacol, Bronx, NY USA. [Gorlick, Richard] Childrens Hosp Montefiore, Dept Pediat, Div Hematol Oncol, Bronx, NY USA. [Tap, William D.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Sarcoma Oncol Melanoma & Sarcoma Serv, New York, NY USA. [Kleinerman, Eugenie S.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Patel, Shreyaskumar R.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Res Inst, Ctr Childhood Canc, Columbus, OH USA. [Welch, Danny R.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Kirsch, David G.] Duke Univ, Med Ctr, Durham, NC USA. [Janeway, Katherine A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Janeway, Katherine A.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Weigel, Brenda] Univ Minnesota, Dept Pediat, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Randall, Lor] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Randall, Lor] Univ Utah, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Withrow, Stephen J.] Colorado State Univ, Flint Anim Canc Ctr, Ft Collins, CO 80523 USA. [Ueren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Ueren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Biochem, Washington, DC 20007 USA. [Ueren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Mol & Cellular Biol, Washington, DC 20007 USA. [Trent, Jeffrey] Translat Genom Res Inst TGen, Phoenix, AZ USA. [Reinke, Denise] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Barkaukas, Donald A.] QuadW COG Childhood Sarcoma Biostat & Annotat, Childrens Oncol Grp, Monrovia, CA USA. [Krailo, Mark] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Sorensen, Poul H. B.] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada. [Sorensen, Poul H. B.] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Bernstein, Mark] Dalhousie Univ, Dept Pediat, IWK Hlth Ctr, Halifax, NS, Canada. RP Fan, TM (reprint author), Univ Illinois, Dept Vet Clin Med, Urbana, IL 61802 USA. EM t-fan@illinois.edu RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU National Cancer Institute, NIH, Bethesda, Maryland; Chair's Grant [U10 CA98543]; Human Specimen Banking Grant of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, Maryland [U24 CA114766]; WWWW (QuadW) Foundation, Inc. FX This research was supported by the Intramural Research Program of the National Cancer Institute, NIH, Bethesda, Maryland. This research also was supported by the Chair's Grant U10 CA98543 and Human Specimen Banking Grant U24 CA114766 of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Additional support for research was provided by a grant from the WWWW (QuadW) Foundation, Inc. (www.QuadW.org) to the Children's Oncology Group. NR 63 TC 32 Z9 33 U1 5 U2 24 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 AUG 15 PY 2014 VL 20 IS 16 BP 4200 EP 4209 DI 10.1158/1078-0432.CCR-13-2574 PG 10 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100005 PM 24803583 ER PT J AU Paller, CJ Bradbury, PA Ivy, SP Seymour, L LoRusso, PM Baker, L Rubinstein, L Huang, E Collyar, D Groshen, S Reeves, S Ellis, LM Sargent, DJ Rosner, GL LeBlanc, ML Ratain, MJ AF Paller, Channing J. Bradbury, Penelope A. Ivy, S. Percy Seymour, Lesley LoRusso, Patricia M. Baker, Laurence Rubinstein, Larry Huang, Erich Collyar, Deborah Groshen, Susan Reeves, Steven Ellis, Lee M. Sargent, Daniel J. Rosner, Gary L. LeBlanc, Michael L. Ratain, Mark J. TI Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee SO CLINICAL CANCER RESEARCH LA English DT Review ID CELL LUNG-CANCER; CHRONIC MYELOID-LEUKEMIA; FACTOR TYROSINE KINASES; DOSE-ESCALATION; COLORECTAL-CANCER; SOLID TUMORS; IMATINIB MESYLATE; ADVANCED MELANOMA; MALIGNANT GLIOMA; PLUS ERLOTINIB AB Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). (C) 2014 AACR. C1 [Paller, Channing J.; Rosner, Gary L.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Ivy, S. Percy; Rubinstein, Larry; Huang, Erich; Reeves, Steven] NCI, Bethesda, MD 20892 USA. [LoRusso, Patricia M.] Karmanos Canc Inst, Detroit, MI USA. [Baker, Laurence] Univ Michigan, Ann Arbor, MI 48109 USA. [Collyar, Deborah] Patient Advocates Res, Danville, PA USA. [Groshen, Susan] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Ellis, Lee M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sargent, Daniel J.] Mayo Clin, Rochester, MN USA. [LeBlanc, Michael L.] Fred Hutchinson Canc Res Ctr, Canc Res & Biostat, Seattle, WA 98104 USA. [Ratain, Mark J.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Bradbury, Penelope A.; Seymour, Lesley] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. RP Ratain, MJ (reprint author), Univ Chicago Med, MC2115,5841 South Maryland St, Chicago, IL 60637 USA. EM mratain@medicine.bsd.uchicago.edu FU Cancer Care Ontario Research Chair in Experimental Therapeutics FX P.A. Bradbury was supported by a Cancer Care Ontario Research Chair in Experimental Therapeutics. NR 67 TC 13 Z9 13 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4210 EP 4217 DI 10.1158/1078-0432.CCR-14-0521 PG 8 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100006 PM 25125258 ER PT J AU Shah, N Wang, JJ Selich-Anderson, J Graham, G Siddiqui, H Li, X Khan, J Toretsky, J AF Shah, Nilay Wang, Jianjun Selich-Anderson, Julia Graham, Garrett Siddiqui, Hasan Li, Xin Khan, Javed Toretsky, Jeffrey TI PBX1 Is a Favorable Prognostic Biomarker as It Modulates 13-cis Retinoic Acid-Mediated Differentiation in Neuroblastoma SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL-LINES; GENE-EXPRESSION; NEURONAL DIFFERENTIATION; N-MYC; PRE-B; 4S NEUROBLASTOMA; RISK; PROTEINS; CLASSIFICATION; MORPHOLOGY AB Purpose: Neuroblastoma is an embryonic childhood cancer with high mortality. 13-cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance and the normal differentiation pathway are poorly understood. Three-amino-acid loop extension (TALE) family genes are master regulators of differentiation. Because retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma. Experimental Design: We evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13-cisRA treatment, identifying genes whose expression correlates with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by qRT-PCR, and three independent clinical cohort microarray datasets. Results: We confirmed that induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in neuroblastoma cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA-dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histologic neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts. Conclusions: PBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors. (C)2014 AACR. C1 [Shah, Nilay; Selich-Anderson, Julia; Siddiqui, Hasan] Nationwide Childrens Hosp, Res Inst, Ctr Childhood Canc & Blood Dis, Columbus, OH 43205 USA. [Shah, Nilay; Selich-Anderson, Julia; Siddiqui, Hasan] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Wang, Jianjun; Khan, Javed] NCI, Oncogen Sect, Adv Technol Ctr, Pediat Oncol Branch,Ctr Canc Res,NIH, Gaithersburg, MD USA. [Graham, Garrett; Toretsky, Jeffrey] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC USA. [Li, Xin] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC USA. RP Shah, N (reprint author), Nationwide Childrens Hosp, 700 Childrens Dr,RBII WA4023, Columbus, OH 43205 USA. EM nshahnb@gmail.com RI Khan, Javed/P-9157-2014; Shah, Nilay/H-9988-2013; Shah, Nilay/E-4925-2015; OI Khan, Javed/0000-0002-5858-0488; Shah, Nilay/0000-0002-8906-6844; Graham, Garrett/0000-0002-1097-0962 FU NCH Internal Fund [187213]; Burroughs Wellcome Clinical Scientist in Translational Research; NIH [R01CA133662, R01CA138212, RC4CA156509]; Conquer Cancer Foundation Young Investigator Award FX This study was supported by Conquer Cancer Foundation Young Investigator Award and NCH Internal Fund 187213 (to N. Shah), Burroughs Wellcome Clinical Scientist in Translational Research, and NIH grants R01CA133662, R01CA138212, and RC4CA156509 (to J. Khan). NR 49 TC 4 Z9 4 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4400 EP 4412 DI 10.1158/1078-0432.CCR-13-1486 PG 13 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100023 PM 24947929 ER PT J AU Philpott, CC AF Philpott, Caroline C. TI Pumping iron SO ELIFE LA English DT Editorial Material ID EHLERS-DANLOS-SYNDROME; ZINC-TRANSPORTER; DROSOPHILA-MELANOGASTER; UPTAKE SYSTEM; PROTEIN; ENCODES; ZIP13; YEAST C1 Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 8 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 15 PY 2014 VL 3 AR e03997 DI 10.7554/eLife.03997 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AO3RN UT WOS:000341252600002 PM 25128012 ER PT J AU Terajima, M Perdivara, I Sricholpech, M Deguchi, Y Pleshko, N Tomer, KB Yamauchi, M AF Terajima, Masahiko Perdivara, Irina Sricholpech, Marnisa Deguchi, Yoshizumi Pleshko, Nancy Tomer, Kenneth B. Yamauchi, Mitsuo TI Glycosylation and Cross-linking in Bone Type I Collagen SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POSTTRANSLATIONAL MODIFICATIONS; LYSYL HYDROXYLASE; OSTEOGENESIS IMPERFECTA; EHRLICH CHROMOGEN; ARTICULAR-CARTILAGE; MOLECULAR PACKING; FIBRILS; IDENTIFICATION; PROTEIN; FIBRILLOGENESIS AB Fibrillar type I collagen is the major organic component in bone, providing a stable template for mineralization. During collagen biosynthesis, specific hydroxylysine residues become glycosylated in the form of galactosyl- and glucosylgalactosylhydroxylysine. Furthermore, key glycosylated hydroxylysine residues, alpha 1/2-87, are involved in covalent intermolecular cross-linking. Although cross-linking is crucial for the stability and mineralization of collagen, the biological function of glycosylation in cross-linking is not well understood. In this study, we quantitatively characterized glycosylation of non-cross-linked and cross-linked peptides by biochemical and nanoscale liquid chromatography-high resolution tandem mass spectrometric analyses. The results showed that glycosylation of non-crosslinked hydroxylysine is different from that involved in cross-linking. Among the cross-linked species involving alpha 1/2-87, divalent cross-links were glycosylated with both mono- and disaccharides, whereas the mature, trivalent cross-links were primarily monoglycosylated. Markedly diminished diglycosylation in trivalent cross-links at this locus was also confirmed in type II collagen. The data, together with our recent report (Sricholpech, M., Perdivara, I., Yokoyama, M., Nagaoka, H., Terajima, M., Tomer, K. B., and Yamauchi, M. (2012) Lysyl hydroxylase 3-mediated glucosylation in type I collagen: molecular loci and biological significance. J. Biol. Chem. 287, 22998-23009), indicate that the extent and pattern of glycosylation may regulate cross-link maturation in fibrillar collagen. C1 [Terajima, Masahiko; Deguchi, Yoshizumi; Yamauchi, Mitsuo] Univ N Carolina, North Carolina Oral Hlth Inst, Sch Dent, Chapel Hill, NC 27599 USA. [Perdivara, Irina; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Sricholpech, Marnisa] Srinakharinwirot Univ, Fac Dent, Dept Oral Surg & Oral Med, Bangkok 10110, Thailand. [Pleshko, Nancy] Temple Univ, Dept Bioengn, Tissue Imaging & Spect Lab, Philadelphia, PA 19122 USA. RP Yamauchi, M (reprint author), Univ N Carolina, North Carolina Oral Hlth Inst, 385 S Columbia St, Chapel Hill, NC 27599 USA. EM yamauchm@dentistry.unc.edu FU National Institutes of Health [DE020909, AR060978]; National Institutes of Health, NIEHS [ES050171] FX This work was supported, in whole or in part, by National Institutes of Health Grants DE020909 and AR060978 (to M. Y.) and the Intramural Research Program of National Institutes of Health, NIEHS, Project ES050171 (to K. B. T.). NR 52 TC 15 Z9 15 U1 5 U2 19 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 15 PY 2014 VL 289 IS 33 BP 22636 EP 22647 DI 10.1074/jbc.M113.528513 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO0QV UT WOS:000341017200010 PM 24958722 ER PT J AU Thorborn, G Ploquin, MJ Eksmond, U Pike, R Bayer, W Dittmer, U Hasenkrug, KJ Pepper, M Kassiotis, G AF Thorborn, Georgina Ploquin, Mickael J. Eksmond, Urszula Pike, Rebecca Bayer, Wibke Dittmer, Ulf Hasenkrug, Kim J. Pepper, Marion Kassiotis, George TI Clonotypic Composition of the CD4(+) T Cell Response to a Vectored Retroviral Antigen Is Determined by Its Speed SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; IN-VIVO; REPERTOIRE DIVERSITY; IMMUNE-RESPONSE; SIGNAL STRENGTH; VIRUS-INFECTION; VIRAL VECTORS; HIV-1 VACCINE; MICE LACKING; IFN-GAMMA AB The mechanisms whereby different vaccines may expand distinct Ag-specific T cell clonotypes or induce disparate degrees of protection are incompletely understood. We found that several delivery modes of a model retroviral Ag, including natural infection, preferentially expanded initially rare high-avidity CD4(+) T cell clonotypes, known to mediate protection. In contrast, the same Ag vectored by human adenovirus serotype 5 induced clonotypic expansion irrespective of avidity, eliciting a predominantly low-avidity response. Nonselective clonotypic expansion was caused by relatively weak adenovirus serotype 5-vectored Ag presentation and was reproduced by replication-attenuated retroviral vaccines. Mechanistically, the potency of Ag presentation determined the speed and, consequently, completion of the CD4(+) T cell response. Whereas faster completion retained the initial advantage of high-avidity clonotypes, slower completion permitted uninhibited accumulation of low-avidity clonotypes. These results highlighted the importance of Ag presentation patterns in determining the clonotypic composition of vaccine-induced T cell responses and ultimately the efficacy of vaccination. C1 [Thorborn, Georgina; Ploquin, Mickael J.; Eksmond, Urszula; Pike, Rebecca; Kassiotis, George] Natl Inst Med Res, MRC, Div Immunoregulat, London NW7 1AA, England. [Bayer, Wibke; Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, D-45147 Essen, Germany. [Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Pepper, Marion] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Kassiotis, George] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Med, London W2 1PG, England. RP Kassiotis, G (reprint author), Natl Inst Med Res, MRC, Div Immunoregulat, London NW7 1AA, England. EM gkassio@nimr.mrc.ac.uk FU Medical Research Council (United Kingdom) [U117581330] FX This work was supported by Medical Research Council (United Kingdom) Grant U117581330. NR 64 TC 4 Z9 4 U1 1 U2 5 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 2014 VL 193 IS 4 BP 1567 EP 1577 DI 10.4049/jimmunol.1400667 PG 11 WC Immunology SC Immunology GA AO2HK UT WOS:000341139300008 PM 25000983 ER PT J AU Wang, HS Yan, M Sun, JF Jain, S Yoshimi, R Abolfath, SM Ozato, K Coleman, WG Ng, AP Metcalf, D DiRago, L Nutt, SL Morse, HC AF Wang, Hongsheng Yan, Ming Sun, Jiafang Jain, Shweta Yoshimi, Ryusuke Abolfath, Sanaz Momben Ozato, Keiko Coleman, William G., Jr. Ng, Ashley P. Metcalf, Donald DiRago, Ladina Nutt, Stephen L. Morse, Herbert C., III TI A Reporter Mouse Reveals Lineage-Specific and Heterogeneous Expression of IRF8 during Lymphoid and Myeloid Cell Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEQUENCE-BINDING-PROTEIN; CD8-ALPHA(+) DENDRITIC CELLS; CRITICAL TRANSCRIPTION FACTOR; IFN REGULATORY FACTOR-8; BONE-MARROW; B-CELL; IN-VIVO; HEMATOPOIETIC PROGENITORS; DEFICIENT MICE; PRECURSORS AB The IFN regulatory factor family member 8 (IRF8) regulates differentiation of lymphoid and myeloid lineage cells by promoting or suppressing lineage-specific genes. How IRF8 promotes hematopoietic progenitors to commit to one lineage while preventing the development of alternative lineages is not known. In this study, we report an IRF8-EGFP fusion protein reporter mouse that revealed previously unrecognized patterns of IRF8 expression. Differentiation of hematopoietic stem cells into oligopotent progenitors is associated with progressive increases in IRF8-EGFP expression. However, significant induction of IRF8-EGFP is found in granulocyte-myeloid progenitors and the common lymphoid progenitors but not the megakaryocytic-erythroid progenitors. Surprisingly, IRF8-EGFP identifies three subsets of the seemingly homogeneous granulocyte-myeloid progenitors with an intermediate level of expression of EGFP defining bipotent progenitors that differentiation into either EGFP(hi) monocytic progenitors or EGFP(lo) granulocytic progenitors. Also surprisingly, IRF8-EGFP revealed a highly heterogeneous pre-pro-B population with a fluorescence intensity ranging from background to 4 orders above background. Interestingly, IRF8-EGFP readily distinguishes true B cell committed (EGFP(int)) from those that are noncommitted. Moreover, dendritic cell progenitors expressed extremely high levels of IRF8-EGFP. Taken together, the IRF8-EGFP reporter revealed previously unrecognized subsets with distinct developmental potentials in phenotypically well-defined oligopotent progenitors, providing new insights into the dynamic heterogeneity of developing hematopoietic progenitors. C1 [Wang, Hongsheng; Sun, Jiafang; Jain, Shweta; Abolfath, Sanaz Momben; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Yan, Ming; Coleman, William G., Jr.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Yoshimi, Ryusuke] Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Yokohama, Kanagawa 2360004, Japan. [Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Ng, Ashley P.; Metcalf, Donald; DiRago, Ladina; Nutt, Stephen L.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Ng, Ashley P.; Metcalf, Donald; Nutt, Stephen L.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. RP Morse, HC (reprint author), NIAID, NIH, 5640 Fishers Lane, Rockville, MD 20852 USA. EM wanghongs@niaid.nih.gov; hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705; Yoshimi, Ryusuke/0000-0002-3945-307X; Nutt, Stephen/0000-0002-0020-6637 FU National Institutes of Health's National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; Australian National Health and Medical Research Council [1016647, 361646]; Cancer Council of Victoria; Cure Cancer Australia/Leukaemia Foundation Australia; Victorian State Government Operational Infrastructure; Australian Research Council FX This work was supported by the Intramural Research Program of the National Institutes of Health's National Institute of Allergy and Infectious Diseases (to H.W., J.S., S.J., S.M.A., and H.C.M.), the National Institute of Child Health and Human Development (to R.Y. and K.O.), and the National Institute of Diabetes and Digestive and Kidney Diseases (to M.Y. and W.G.C.). A.P.N., L.D., and D.M. were supported by Program Grant 1016647 and Independent Research Institutes Infrastructure Support Scheme Grant 361646 from the Australian National Health and Medical Research Council. This work was also supported by the Carden fellowship (to D.M.) from the Cancer Council of Victoria, a Cure Cancer Australia/Leukaemia Foundation Australia postdoctoral fellowship and a Lions fellowship from the Cancer Council of Victoria (to A.P.N.), and the Victorian State Government Operational Infrastructure. S.L.N. was supported by an Australian Research Council Future fellowship. NR 63 TC 21 Z9 21 U1 0 U2 2 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 2014 VL 193 IS 4 BP 1766 EP 1777 DI 10.4049/jimmunol.1301939 PG 12 WC Immunology SC Immunology GA AO2HK UT WOS:000341139300028 PM 25024380 ER PT J AU Darrah, PA Bolton, DL Lackner, AA Kaushal, D Aye, PP Mehra, S Blanchard, JL Didier, PJ Roy, CJ Rao, SS Hokey, DA Scanga, CA Sizemore, DR Sadoff, JC Roederer, M Seder, RA AF Darrah, Patricia A. Bolton, Diane L. Lackner, Andrew A. Kaushal, Deepak Aye, Pyone Pyone Mehra, Smriti Blanchard, James L. Didier, Peter J. Roy, Chad J. Rao, Srinivas S. Hokey, David A. Scanga, Charles A. Sizemore, Donata R. Sadoff, Jerald C. Roederer, Mario Seder, Robert A. TI Aerosol Vaccination with AERAS-402 Elicits Robust Cellular Immune Responses in the Lungs of Rhesus Macaques but Fails To Protect against High-Dose Mycobacterium tuberculosis Challenge SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BACILLUS-CALMETTE-GUERIN; NONHUMAN PRIMATE MODEL; CD8(+) T-CELLS; RECOMBINANT ADENOVIRUS VECTORS; VACCINIA VIRUS ANKARA; PULMONARY TUBERCULOSIS; BOVIS BCG; POLYFUNCTIONAL CD4(+); MUCOSAL IMMUNIZATION; GENETIC IMMUNIZATION AB Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag-specific CD4 and CD8 T cells in the lung. The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans. In this study, we used an aerosol vaccination strategy to administer AERAS-402, a replication-defective recombinant adenovirus (rAd) type 35 expressing Mycobacterium tuberculosis Ags Ag85A, Ag85B, and TB10.4, in bacillus Calmette-Guerin (BCG)-primed or unprimed rhesus macaques. Immunization with BCG generated low purified protein derivative-specific CD4 T cell responses in blood and bronchoalveolar lavage. In contrast, aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific CD4 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-gamma, as well as TNF and IL-2. Such responses induced by BCG, AERAS-402, or both failed to confer overall protection following challenge with 275 CFUs M. tuberculosis Erdman, although vaccine-induced responses associated with reduced pathology were observed in some animals. Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge. Overall, our data suggest that a high M. tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model. However, the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens, alternative rAd serotypes with enhanced immunogenicity, and a physiological challenge dose may achieve protection against M. tuberculosis. C1 [Darrah, Patricia A.; Bolton, Diane L.; Rao, Srinivas S.; Roederer, Mario; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Lackner, Andrew A.; Kaushal, Deepak; Aye, Pyone Pyone; Mehra, Smriti; Blanchard, James L.; Didier, Peter J.; Roy, Chad J.] Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Hokey, David A.; Scanga, Charles A.; Sizemore, Donata R.; Sadoff, Jerald C.] Aeras, Rockville, MD 20850 USA. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr MSC 3025,Bldg 40,Room 3512, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov FU Aeras; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [P51RR000164, P51OD011104] FX This work was supported in part by Aeras as well as by the intramural research program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health and by National Institutes of Health Grants P51RR000164 and P51OD011104 to the Tulane National Primate Research Center. NR 100 TC 23 Z9 23 U1 2 U2 9 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 2014 VL 193 IS 4 BP 1799 EP 1811 DI 10.4049/jimmunol.1400676 PG 13 WC Immunology SC Immunology GA AO2HK UT WOS:000341139300031 PM 25024382 ER PT J AU Tabor, KM Bergeron, SA Horstick, EJ Jordan, DC Aho, V Porkka-Heiskanen, T Haspel, G Burgess, HA AF Tabor, Kathryn M. Bergeron, Sadie A. Horstick, Eric J. Jordan, Diana C. Aho, Vilma Porkka-Heiskanen, Tarja Haspel, Gal Burgess, Harold A. TI Direct activation of the Mauthner cell by electric field pulses drives ultrarapid escape responses SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE escape response; Mauthner cell; electric pulse; nitroreductase; SCN5 ID ESCHERICHIA-COLI-NITROREDUCTASE; RETICULOSPINAL COMMAND NEURON; CARDIAC SODIUM-CHANNELS; LARVAL ZEBRAFISH; STARTLE RESPONSE; GOLDFISH; FISH; BRAIN; BEHAVIOR; AXON AB Rapid escape swims in fish are initiated by the Mauthner cells, giant reticulospinal neurons with unique specializations for swift responses. The Mauthner cells directly activate motoneurons and facilitate predator detection by integrating acoustic, mechanosensory, and visual stimuli. In addition, larval fish show well-coordinated escape responses when exposed to electric field pulses (EFPs). Sensitization of the Mauthner cell by genetic overexpression of the voltage-gated sodium channel SCN5 increased EFP responsiveness, whereas Mauthner ablation with an engineered variant of nitroreductase with increased activity (epNTR) eliminated the response. The reaction time to EFPs is extremely short, with many responses initiated within 2 ms of the EFP. Large neurons, such as Mauthner cells, show heightened sensitivity to extracellular voltage gradients. We therefore tested whether the rapid response to EFPs was due to direct activation of the Mauthner cells, bypassing delays imposed by stimulus detection and transmission by sensory cells. Consistent with this, calcium imaging indicated that EFPs robustly activated the Mauthner cell but only rarely fired other reticulospinal neurons. Further supporting this idea, pharmacological blockade of synaptic transmission in zebrafish did not affect Mauthner cell activity in response to EFPs. Moreover, Mauthner cells transgenically expressing a tetrodotoxin (TTX)-resistant voltage-gated sodium channel retained responses to EFPs despite TTX suppression of action potentials in the rest of the brain. We propose that EFPs directly activate Mauthner cells because of their large size, thereby driving ultrarapid escape responses in fish. C1 [Tabor, Kathryn M.; Bergeron, Sadie A.; Horstick, Eric J.; Jordan, Diana C.; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD USA. [Aho, Vilma; Porkka-Heiskanen, Tarja] Univ Helsinki, Inst Biomed, Helsinki, Finland. RP Burgess, HA (reprint author), Bldg 6B,Rm 3B308,6 Ctr Dr, Bethesda, MD 20892 USA. EM burgessha@mail.nih.gov RI Burgess, Harold/B-8474-2015; OI Stenberg, Tarja/0000-0003-1843-7625; Burgess, Harold/0000-0003-1966-7801; Haspel, Gal/0000-0001-6701-697X; Bergeron, Sadie/0000-0002-1238-8730; Jordan, Diana C/0000-0001-9469-9358 FU National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development. NR 66 TC 10 Z9 10 U1 0 U2 15 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG 15 PY 2014 VL 112 IS 4 BP 834 EP 844 DI 10.1152/jn.00228.2014 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AN8FR UT WOS:000340839300009 PM 24848468 ER PT J AU Reale, M Kamal, MA Patruno, A Costantini, E D'Angelo, C Pesce, M Greig, NH AF Reale, Marcella Kamal, Mohammad A. Patruno, Antonia Costantini, Erica D'Angelo, Chiara Pesce, Miko Greig, Nigel H. TI Neuronal Cellular Responses to Extremely Low Frequency Electromagnetic Field Exposure: Implications Regarding Oxidative Stress and Neurodegeneration SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; AMYOTROPHIC-LATERAL-SCLEROSIS; REMITTING MULTIPLE-SCLEROSIS; PRO-INFLAMMATORY CYTOKINES; ALZHEIMERS-DISEASE; HUNTINGTONS-DISEASE; NEUROBLASTOMA-CELLS; PARKINSONS-DISEASE; LEARN MODEL; NEUROGENESIS AB Neurodegenerative diseases comprise both hereditary and sporadic conditions characterized by an identifying progressive nervous system dysfunction and distinctive neuopathophysiology. The majority are of non-familial etiology and hence environmental factors and lifestyle play key roles in their pathogenesis. The extensive use of and ever increasing worldwide demand for electricity has stimulated societal and scientific interest on the environmental exposure to low frequency electromagnetic fields (EMFs) on human health. Epidemiological studies suggest a positive association between 50/60-Hz power transmission fields and leukemia or lymphoma development. Consequent to the association between EMFs and induction of oxidative stress, concerns relating to development of neurodegenerative diseases, such as Alzheimer disease (AD), have been voiced as the brain consumes the greatest fraction of oxygen and is particularly vulnerable to oxidative stress. Exposure to extremely low frequency (ELF)-EMFs are reported to alter animal behavior and modulate biological variables, including gene expression, regulation of cell survival, promotion of cellular differentiation, and changes in cerebral blood flow in aged AD transgenic mice. Alterations in inflammatory responses have also been reported, but how these actions impact human health remains unknown. We hence evaluated the effects of an electromagnetic wave (magnetic field intensity 1mT; frequency, 50-Hz) on a well-characterized immortalized neuronal cell model, human SH-SY5Y cells. ELF-EMF exposure elevated the expession of NOS and O-2(-), which were countered by compensatory changes in antioxidant catylase (CAT) activity and enzymatic kinetic parameters related to CYP-450 and CAT activity. Actions of ELF-EMFs on cytokine gene expression were additionally evaluated and found rapidly modified. Confronted with co-exposure to H2O2-induced oxidative stress, ELF-EMF proved not as well counteracted and resulted in a decline in CAT activity and a rise in O-2(-) levels. Together these studies support the further evaluation of ELF-EMF exposure in cellular and in vivo preclinical models to define mechanisms potentially impacted in humans. C1 [Reale, Marcella; Costantini, Erica; D'Angelo, Chiara] Univ G dAnnunzio, Dept Expt & Clin Sci, Chieti, Italy. [Kamal, Mohammad A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah 21413, Saudi Arabia. [Patruno, Antonia; Pesce, Miko] Univ G dAnnunzio, Dept Med & Aging Sci, Chieti, Italy. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Reale, M (reprint author), Univ G dAnnunzio, Dept Expt & Clin Sci, Chieti, Italy. EM mreale@unich.it; greign@grc.nia.nih.gov OI D'ANGELO, Chiara/0000-0002-1477-0706; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU Italian MIUR; King Fahd Medical Research Center, King Abdulaziz University; National Institute on Aging, National Institutes of Health FX This work was supported by grants from the Italian MIUR to M. R. and A. P., the King Fahd Medical Research Center, King Abdulaziz University for M. A. K., and the Intramural Research Program, National Institute on Aging, National Institutes of Health for N. H. G. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 15 Z9 16 U1 3 U2 31 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 15 PY 2014 VL 9 IS 8 AR e104973 DI 10.1371/journal.pone.0104973 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8UD UT WOS:000340879300067 PM 25127118 ER PT J AU Seitz, AE Younes, N Steiner, CA Prevots, DR AF Seitz, Amy E. Younes, Naji Steiner, Claudia A. Prevots, D. Rebecca TI Incidence and Trends of Blastomycosis-Associated Hospitalizations in the United States SO PLOS ONE LA English DT Article ID ENDEMIC FUNGAL-INFECTIONS; PULMONARY BLASTOMYCOSIS; GEOGRAPHIC-DISTRIBUTION; PRACTICE GUIDELINES; OLDER PERSONS; WISCONSIN; OUTBREAK; DERMATITIDIS; MANAGEMENT; TENNESSEE AB We used the State Inpatient Databases from the United States Agency for Healthcare Research and Quality to provide state-specific age-adjusted blastomycosis-associated hospitalization incidence throughout the entire United States. Among the 46 states studied, states within the Mississippi and Ohio River valleys had the highest age-adjusted hospitalization incidence. Specifically, Wisconsin had the highest age-adjusted hospitalization incidence (2.9 hospitalizations per 100,000 person-years). Trends were studied in the five highest hospitalization incidence states. From 2000 to 2011, blastomycosis-associated hospitalizations increased significantly in Illinois and Kentucky with an average annual increase of 4.4% and 8.4%, respectively. Trends varied significantly by state. Overall, 64% of blastomycosis-associated hospitalizations were among men and the median age at hospitalization was 53 years. This analysis provides a complete epidemiologic description of blastomycosis-associated hospitalizations throughout the endemic area in the United States. C1 [Seitz, Amy E.; Prevots, D. Rebecca] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Seitz, Amy E.; Younes, Naji] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Epidemiol & Biostat, Washington, DC USA. [Steiner, Claudia A.] US Agcy Healthcare Res & Qual, Healthcare Cost Utilizat Project, Rockville, MD USA. RP Seitz, AE (reprint author), NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM seitza@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This Research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 15 PY 2014 VL 9 IS 8 AR e105466 DI 10.1371/journal.pone.0105466 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN8UD UT WOS:000340879300112 PM 25126839 ER PT J AU Roetker, NS Chen, LY Heckbert, SR Nazarian, S Soliman, EZ Bluemke, DA Lima, JAC Alonso, A AF Roetker, Nicholas S. Chen, Lin Y. Heckbert, Susan R. Nazarian, Saman Soliman, Elsayed Z. Bluemke, David A. Lima, Joao A. C. Alonso, Alvaro TI Relation of Systolic, Diastolic, and Pulse Pressures and Aortic Distensibility With Atrial Fibrillation (from the Multi-Ethnic Study of Atherosclerosis) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BLOOD-PRESSURE; RISK-FACTORS; CARDIOVASCULAR RISK; ONSET; HYPERTENSION AB Previous research suggests that elevated pulse pressure (PP) is a risk factor for atrial fibrillation (AF) independently of mean arterial pressure (MAP). PP may serve as an indirect measure of aortic stiffness (reduced distensibility), but whether directly measured aortic distensibility is related to risk for AF has not yet been studied. This analysis included 6,630 participants aged 45 to 84 years from the Multi-Ethnic Study of Atherosclerosis. At baseline, blood pressure and other relevant covariates were measured using standardized protocols. Magnetic resonance imaging-based aortic distensibility was measured in 3,441 participants. Incident AF was identified from hospitalization discharge codes and Medicare claims. Multivariate Cox models were used to estimate the association of blood pressure components and aortic distensibility with AF risk. During a mean follow-up of 7.8 years, 307 AF events (137 among those with aortic distensibility measurements) were identified. In multivariate-adjusted models simultaneously including MAP and PP, each 1-SD increase in PP was associated with a 29% increased risk of AF (95% confidence interval 5% to 59%, p = 0.02), with MAP not being associated with increased AF risk. Overall, aortic distensibility was not consistently associated with AF risk: after removing outliers, each 1-SD increase in aortic distensibility was associated with a 9% increased risk of AF (95% confidence interval -22% to 51%, p = 0.63). In conclusion, in this large community-based cohort, we found that PP, but not MAP or aortic distensibility, was a significant risk factor for AF, emphasizing the importance of PP when assessing the risk for developing AF. Our results cast doubt on the clinical utility of aortic distensibility as a predictor for the development of AF. (C) 2014 Elsevier Inc. All rights reserved. C1 [Roetker, Nicholas S.; Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Chen, Lin Y.] Univ Minnesota, Sch Med, Dept Med, Div Cardiovasc, Minneapolis, MN 55455 USA. [Heckbert, Susan R.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Nazarian, Saman; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Soliman, Elsayed Z.] Wake Forest Sch Sci, Epidemiol Cardiol Res Ctr, Div Publ Hlth Sci, Winston Salem, NC USA. [Bluemke, David A.] Natl Inst Hlth, Bethesda, MD USA. RP Alonso, A (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. EM alonso@umn.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources, Bethesda, Maryland [UL1-TR-000040, UL1-RR-025005] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland and by grants UL1-TR-000040 and UL1-RR-025005 from National Center for Research Resources, Bethesda, Maryland. NR 17 TC 9 Z9 9 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2014 VL 114 IS 4 BP 587 EP 592 DI 10.1016/j.amjcard.2014.05.041 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN2UX UT WOS:000340442600014 PM 24996553 ER PT J AU Ryu, H Seo, S Cho, SH Kim, HS Jung, A Kang, DW Son, K Cui, M Hong, SH Sharma, PK Choi, S Blumberg, PM Frank-Foltyn, R Bahrenberg, G Stockhausen, H Schiene, K Christoph, T Frormann, S Lee, J AF Ryu, HyungChul Seo, Sejin Cho, Seong-Hee Kim, Ho Shin Jung, Aeran Kang, Dong Wook Son, Karam Cui, Minghua Hong, Sun-Hye Sharma, Pankaz Kumar Choi, Sun Blumberg, Peter M. Frank-Foltyn, Robert Bahrenberg, Gregor Stockhausen, Hannelore Schiene, Klaus Christoph, Thomas Frormann, Sven Lee, Jeewoo TI 2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonist; Capsaicin; Resiniferatoxin; Molecular modeling ID CAPSAICIN RECEPTORS; ANALGESICS; TARGET AB A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Ryu, HyungChul; Seo, Sejin; Cho, Seong-Hee; Kim, Ho Shin; Jung, Aeran; Kang, Dong Wook; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. [Son, Karam; Cui, Minghua; Hong, Sun-Hye; Sharma, Pankaz Kumar; Choi, Sun] Ewha Womans Univ, Natl Leading Res Lab Mol Modeling & Drug Design, Coll Pharm, Sch Pharmaceut Sci, Seoul 120750, South Korea. [Son, Karam; Cui, Minghua; Hong, Sun-Hye; Sharma, Pankaz Kumar; Choi, Sun] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Schiene, Klaus; Christoph, Thomas; Frormann, Sven] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. [Kang, Dong Wook] Catholic Univ Deagu, Coll Hlth & Med Sci, Dept Pharmaceut Sci & Technol, Gyongsan 712702, Gyeongsangbuk D, South Korea. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Research Grants from Grunenthal, Germany; National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; National Leading Research Lab (NLRL) program, Republic of Korea [2011-0028885]; Intramural Research Program of NIH, Center for Cancer Research, NCI, USA [Z1A BC 005270] FX This research was supported by Research Grants from Grunenthal, Germany, Grants from the National Research Foundation of Korea (NRF) (R11-2007-107-02001-0), Grants from the National Leading Research Lab (NLRL) program (2011-0028885), Republic of Korea and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI, USA (Project Z1A BC 005270). NR 21 TC 6 Z9 6 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2014 VL 24 IS 16 BP 4039 EP 4043 DI 10.1016/j.bmcl.2014.05.074 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AN4NX UT WOS:000340565900071 PM 24948568 ER PT J AU Ryu, H Seo, S Kim, MS Kim, MY Kim, HS Ann, J Tran, PT Hoang, VH Byun, J Cui, MH Son, K Sharma, PK Choi, S Blumberg, PM Frank-Foltyn, R Bahrenberg, G Koegel, BY Christoph, T Frormann, S Lee, J AF Ryu, HyungChul Seo, Sejin Kim, Myeong Seop Kim, Mi-Yeon Kim, Ho Shin Ann, Jihyae Phuong-Thao Tran Van-Hai Hoang Byun, Jieun Cui, Minghua Son, Karam Sharma, Pankaz Kumar Choi, Sun Blumberg, Peter M. Frank-Foltyn, Robert Bahrenberg, Gregor Koegel, Babette-Yvonne Christoph, Thomas Frormann, Sven Lee, Jeewoo TI 2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonist; Capsaicin; Resiniferatoxin; Molecular modeling ID CAPSAICIN RECEPTORS; ANALGESICS; TARGET AB A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Ryu, HyungChul; Seo, Sejin; Kim, Myeong Seop; Kim, Mi-Yeon; Kim, Ho Shin; Ann, Jihyae; Phuong-Thao Tran; Van-Hai Hoang; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. [Byun, Jieun; Cui, Minghua; Son, Karam; Sharma, Pankaz Kumar; Choi, Sun] Ewha Womans Univ, Natl Leading Res Lab Mol Modeling & Drug Design, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 120750, South Korea. [Byun, Jieun; Cui, Minghua; Son, Karam; Sharma, Pankaz Kumar; Choi, Sun] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank-Foltyn, Robert; Bahrenberg, Gregor; Koegel, Babette-Yvonne; Christoph, Thomas; Frormann, Sven] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Research Grants from Grunenthal, Germany; National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; National Leading Research Lab (NLRL) program, Republic of Korea [2011-0028885]; Intramural Research Program of NIH, Center for Cancer Research, NCI, USA [Z1A BC 005270] FX We greatly acknowledge Elke Schumacher and Franz-Josef Butz for technical assistance in CCI and Cap hypothermia studies, resp. This research was supported by Research Grants from Grunenthal, Germany, Grants from the National Research Foundation of Korea (NRF) (R11-2007-107-02001-0), Grants from the National Leading Research Lab (NLRL) program (2011-0028885), Republic of Korea, and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270), USA. NR 22 TC 8 Z9 8 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2014 VL 24 IS 16 BP 4044 EP 4047 DI 10.1016/j.bmcl.2014.05.072 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AN4NX UT WOS:000340565900072 PM 25011915 ER PT J AU Kamal, AK Majeed, F Pasha, O Rehman, H Islam, M Azam, I Ilyas, MS Hussain, M Masood, K Ahmed, B Nazir, S Sajjad, Z Kasner, SE AF Kamal, Ayeesha Kamran Majeed, Farzin Pasha, Omrana Rehman, Hasan Islam, Muhammad Azam, Iqbal Ilyas, Muhammad Saleem Hussain, Munawar Masood, Kamran Ahmed, Bilal Nazir, Sumaira Sajjad, Zafar Kasner, Scott E. TI Clinical, lifestyle, socioeconomic determinants and rate of asymptomatic intracranial atherosclerosis in stroke free Pakistanis SO BMC NEUROLOGY LA English DT Article DE Intracranial atherosclerosis; Stroke; Asymptomatic; Developing countries; Prevention; Sociodemographic risk factors; Epidemiology ID TRANSIENT ISCHEMIC ATTACK; COMMUNITY-HEALTH WORKERS; SMOKELESS TOBACCO USE; HIGH-RISK PATIENTS; CEREBROVASCULAR-DISEASE; ARTERIAL-STENOSIS; SEX-DIFFERENCES; DIETARY PATTERNS; RANDOMIZED-TRIAL; CEREBRAL INFARCTION AB Background: Intracranial Atherosclerotic Disease (ICAD) is the most frequent etiology of stroke with high prevalence among Asians. Despite this, early determinants of ICAD have not been described from this region. Methods: The study is an analytical prospective cross-sectional study of 200 adults from Radiology Departments of two diagnostic centers in Karachi. Eligible participants confirmed the absence of stroke symptoms via the Questionnaire for Verifying Stroke Free Status (QVSFS) and underwent an interview covering medical, socio demographic, lifestyle and anthropometric evaluation using locally validated and standardized definitions. Magnetic Resonance Images (MRI) were centrally reviewed to detect ICAD using the criterion used in the Warfarin-Aspirin Symptomatic Intracranial Disease study. The risk factors associated with asymptomatic ICAD are reported along with prevalence ratios. Results: Of the 200 participants, ICAD was found in 34.5% (n = 69) of the participants. Mean age was 37.1 (S. D 15.1) years with 62% younger than 45 years. Self-reported hypertension was found in 26.5% subjects, diabetes in 9%, dyslipidemia in 5% and depression in 60%. Smokeless tobacco (Adjusted PR 3.27 (1.07-6.05)), Western diet, high socioeconomic status (Adjusted PR 2.26 (1.99-5.62)) and dyslipidemia (Adjusted PR 1.88 (1.25-2.21)) had significant associations with ICAD after multivariable analysis. Age, gender, diabetes, hypertension, depression and physical activity did not have a significant association. Conclusion: ICAD was found on MRI in one in three asymptomatic Pakistanis and was associated with modifiable risks. Initiatives targeting primary prevention may be able to decrease the burden of disease caused by stroke due to ICAD. C1 [Kamal, Ayeesha Kamran] Natl Inst Hlth, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv, Karachi, Pakistan. [Kamal, Ayeesha Kamran; Majeed, Farzin; Rehman, Hasan; Nazir, Sumaira; Sajjad, Zafar] Aga Khan Univ, Karachi, Pakistan. [Majeed, Farzin; Rehman, Hasan; Nazir, Sumaira] Natl Inst Hlth, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Karachi, Pakistan. [Pasha, Omrana] Aga Khan Univ, Epidemiol & Biostat Program, Karachi, Pakistan. [Islam, Muhammad; Azam, Iqbal] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Ilyas, Muhammad Saleem] Dow Univ Hlth Sci, Karachi, Pakistan. [Hussain, Munawar; Masood, Kamran] Dow Univ Hlth Sci, Dow Inst Radiol, Karachi, Pakistan. [Ahmed, Bilal] Aga Khan Univ, Dept Med, Karachi, Pakistan. [Kasner, Scott E.] Univ Penn, Comprehens Stroke Ctr, Div Stroke & Neurointens Care, Philadelphia, PA 19104 USA. RP Kamal, AK (reprint author), Natl Inst Hlth, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU Fogarty International Center, National Institutes of Health; Fogarty International Center [D43TW008660]; National Institute of Neurologic Disorders and Stroke FX Dr. Ayeesha Kamran Kamal is the co-director and recipient of grant entitled The International Cerebrovascular Translational Clinical Research Training Program (Fogarty International Center, National Institutes of Health). Dr. Farzin Majeed is a neurovascular research fellow whose mentored research practicum training is funded by Award Number D43TW008660 from the Fogarty International Center and the National Institute of Neurologic Disorders and Stroke. NR 81 TC 2 Z9 2 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD AUG 15 PY 2014 VL 14 AR 155 DI 10.1186/s12883-014-0155-6 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA AN5OY UT WOS:000340642300001 PM 25124284 ER PT J AU Pappo, AS Vassal, G Crowley, JJ Bolejack, V Hogendoorn, PCW Chugh, R Ladanyi, M Grippo, JF Dall, G Staddon, AP Chawla, SP Maki, RG Araujo, DM Geoerger, B Ganjoo, K Marina, N Blay, JY Schuetze, SM Chow, WA Helman, LJ AF Pappo, Alberto S. Vassal, Gilles Crowley, John J. Bolejack, Vanessa Hogendoorn, Pancras C. W. Chugh, Rashmi Ladanyi, Marc Grippo, Joseph F. Dall, Georgina Staddon, Arthur P. Chawla, Sant P. Maki, Robert G. Araujo, Dejka M. Geoerger, Birgit Ganjoo, Kristen Marina, Neyssa Blay, Jean-Yves Schuetze, Scott M. Chow, Warren A. Helman, Lee J. TI A Phase 2 Trial of R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor-1 Receptor (IGF-1R), in Patients With Recurrent or Refractory Rhabdomyosarcoma, Osteosarcoma, Synovial Sarcoma, and Other Soft Tissue Sarcomas Results of a Sarcoma Alliance for Research Through Collaboration Study SO CANCER LA English DT Article DE sarcoma; IGF-1R; SARC; insulin-like growth factor ID ADVANCED SOLID TUMORS; EWING SARCOMA; OPEN-LABEL; CANCER; MECHANISMS; CIXUTUMUMAB; RESISTANCE; INHIBITOR; THERAPY; FAMILY AB BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS: Eligibility criteria included age >= 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeksx4 and every 12 weeks thereafter. RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n=38), RMS (n=36), SS (n=23), and other sarcomas (n=66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a >= 50% decrease in tumor size that lasted for < 4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted. (C) 2014 American Cancer Society. C1 [Pappo, Alberto S.] St Jude Childrens Res Hosp, Solid Tumor Div, Memphis, TN 38105 USA. [Vassal, Gilles; Geoerger, Birgit] Inst Gustave Roussy, Villejuif, France. [Crowley, John J.; Bolejack, Vanessa] Canc Res & Biostat, Seattle, WA USA. [Hogendoorn, Pancras C. W.] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Chugh, Rashmi] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Mol Diagnost Serv, New York, NY 10021 USA. [Grippo, Joseph F.; Dall, Georgina] Hoffmann LaRoche, Basel, Switzerland. [Staddon, Arthur P.] Abramson Canc Ctr, Penn Hematol Oncol, Philadelphia, PA USA. [Chawla, Sant P.] Sarcoma Oncol Ctr, Santa Monica, CA USA. [Maki, Robert G.] Mt Sinai Med Ctr, Dept Med, New York, NY 10029 USA. [Araujo, Dejka M.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Ganjoo, Kristen] Stanford Univ, Med Ctr, Sch Med, Stanford, CA 94305 USA. [Marina, Neyssa] Stanford Univ, Dept Pediat, Stanford Canc Ctr, Stanford, CA 94305 USA. [Blay, Jean-Yves] Ctr Leon Berard, Dept Med Oncol, F-69373 Lyon, France. [Schuetze, Scott M.] Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Chow, Warren A.] City Hope Natl Med Ctr, Lab Warren A Chow, Duarte, CA 91010 USA. [Helman, Lee J.] NIH, Mol Oncol Sect, Bethesda, MD 20892 USA. RP Pappo, AS (reprint author), St Jude Hosp, St Jude Childrens Res Hosp, Solid Tumor Div, 262 Danny Thomas Pl,Mail Stop 260, Memphis, TN 38105 USA. EM alberto.pappo@stjude.org RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU F. Hoffman-LaRoche; Sarcoma Alliance for Research FX This study was supported by F. Hoffman-LaRoche. Dr. Maki was supported by a grant from F. Hoffman-LaRoche. Dr. Chow was supported by a grant from the Sarcoma Alliance for Research through Collaboration. NR 43 TC 36 Z9 38 U1 0 U2 10 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 2014 VL 120 IS 16 BP 2448 EP 2456 DI 10.1002/cncr.28728 PG 9 WC Oncology SC Oncology GA AN3DB UT WOS:000340464100011 PM 24797726 ER PT J AU Smith, MA Altekruse, SF Adamson, PC Reaman, GH Seibel, NL AF Smith, Malcolm A. Altekruse, Sean F. Adamson, Peter C. Reaman, Gregory H. Seibel, Nita L. TI Declining Childhood and Adolescent Cancer Mortality SO CANCER LA English DT Article DE childhood cancer; adolescents; childhood leukemia; mortality rates; childhood solid tumors ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDRENS ONCOLOGY GROUP; IMPROVES EVENT-FREE; ARSENIC TRIOXIDE; CLINICAL-TRIALS; HISTONE H3.3; YOUNG-ADULTS; SURVIVAL; GLIOBLASTOMA; MUTATIONS AB BACKGROUND: To evaluate whether progress continues in identifying more effective treatments for children and adolescents with cancer, the authors examined both overall and disease-specific childhood cancer mortality rates for the United States, focusing on data from 2000 to 2010. METHODS: Age-adjusted US mortality trends from 1975 to 2010 were estimated using joinpoint regression analysis. Analyses of annual percentage change (APC) were performed on the same diagnostic groupings for the period restricted to 2000 through 2010 for groupings ages < 20 years, < 15 years, and 15 to 19 years. RESULTS: After a plateau in mortality rates during 1998 to 2002 (APC, 0.3%), the annual decline in childhood cancer mortality from 2002 to 2010 (APC, -2.4%) was similar to that observed from 1975 to 1998 (APC, -2.7%). Statistically significant declines in mortality rates from 2000 to 2010 were noted for acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, central nervous system cancers, and gonadal cancers. From 2000 to 2010, the rates of decline in mortality for the group ages 15 to 19 years generally were equal to or greater than the rates of decline for the group ages birth to 14 years. Improvements in treatment since 1975 resulted > 45,000 cancer deaths averted through 2010. CONCLUSIONS: Cancer mortality for both children and adolescents declined from 2000 to 2010, with significant declines observed for multiple cancer types. However, greater than 1900 cancer deaths still occur each year among children and adolescents in the United States, and many survivors experience long-term effects that limit their quality of life. Continued research directed toward identifying more effective treatments that produce fewer long-term sequelae is critical to address these remaining challenges. Published 2014. C1 [Smith, Malcolm A.; Seibel, Nita L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Altekruse, Sean F.] NCI, Surveillance Res Program, Bethesda, MD 20892 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Dept Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Reaman, Gregory H.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, 9609 Med Ctr Dr,RM 5-W414,MSC 9737, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov FU National Cancer Institute [U10CA98543] FX This work was supported by a grant from the National Cancer Institute (U10CA98543) to Dr. Adamson. NR 33 TC 53 Z9 58 U1 0 U2 11 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 2014 VL 120 IS 16 BP 2497 EP 2506 DI 10.1002/cncr.28748 PG 10 WC Oncology SC Oncology GA AN3DB UT WOS:000340464100017 PM 24853691 ER PT J AU Lee, NC Wong, FL Jamison, PM Jones, SF Galaska, L Brady, KT Wethers, B Stokes-Townsend, GA AF Lee, Nancy C. Wong, Faye L. Jamison, Patricia M. Jones, Sandra F. Galaska, Louise Brady, Kevin T. Wethers, Barbara Stokes-Townsend, George-Ann TI Implementation of the National Breast and Cervical Cancer Early Detection Program SO CANCER LA English DT Article DE cancer prevention; cancer screening program; National Breast and Cervical Cancer Early Detection Program; breast cancer; cervical cancer; screening ID FORCE RECOMMENDATION STATEMENT; MEDICALLY UNDERSERVED WOMEN; SCREENING-PROGRAM; SERVICES; TIMELINESS; PREVENTION; INITIATION; DIAGNOSIS AB In 1990, Congress passed the Breast and Cervical Cancer Mortality Prevention Act because of increases in the number of low-income and uninsured women being diagnosed with breast cancer. This act authorized the Centers for Disease Control and Prevention (CDC) to establish the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) to provide high-quality and timely breast and cervical cancer screening and diagnostic services to low-income, uninsured women. The program started in 1991, and, in 1993, Congress amended the act to allow the CDC to fund American Indian and Alaska Native tribes and tribal organizations. By 1996, the program was providing cancer screening across the United States. To ensure appropriate delivery and monitoring of services, the program adopted detailed policies on program management, evidence-based guidelines for clinical services, a systematized clinical data system to track service quality, and key partnerships that expand the program's reach. The NBCCEDP currently funds 67 programs, including all 50 states, the District of Columbia, 5 US territories, and 11 tribes or tribal organizations. Published 2014. This article is a U. S. Government work and is in the public domain in the USA. C1 [Lee, Nancy C.] US Dept HHS, Off Womens Hlth, Off Assistant Secretary Hlth, Washington, DC USA. [Wong, Faye L.; Jones, Sandra F.; Wethers, Barbara; Stokes-Townsend, George-Ann] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA 30341 USA. [Jamison, Patricia M.] NCI, Surveillance Epidemiol & End Results Program, NIH, Rockville, MD USA. [Brady, Kevin T.] Ctr Dis Control & Prevent, Div Global HIV AIDS, Atlanta, GA 30341 USA. RP Wong, FL (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Highway NE,Mailstop F76, Atlanta, GA 30341 USA. EM fwong@cdc.gov FU US Centers for Disease Control and Prevention (CDC), an Agency of the Department of Health and Human Services [200-2012-M-52408 00002] FX This Supplement edition of Cancer has been sponsored by the US Centers for Disease Control and Prevention (CDC), an Agency of the Department of Health and Human Services, under the Contract #200-2012-M-52408 00002. NR 32 TC 17 Z9 17 U1 1 U2 7 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 2014 VL 120 IS 16 SU S BP 2540 EP 2548 DI 10.1002/cncr.28820 PG 9 WC Oncology SC Oncology GA AN3DW UT WOS:000340466300002 PM 25099896 ER PT J AU Yi, F Ball, J Stoll, KE Satpute, VC Mitchell, SM Pauli, JL Holloway, BB Johnston, AD Nathanson, NM Deisseroth, K Gerber, DJ Tonegawa, S Lawrence, JJ AF Yi, Feng Ball, Jackson Stoll, Kurt E. Satpute, Vaishali C. Mitchell, Samantha M. Pauli, Jordan L. Holloway, Benjamin B. Johnston, April D. Nathanson, Neil M. Deisseroth, Karl Gerber, David J. Tonegawa, Susumu Lawrence, J. Josh TI Direct excitation of parvalbumin-positive interneurons by M-1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID HIPPOCAMPAL CA1 INTERNEURONS; METABOTROPIC GLUTAMATE RECEPTORS; FIELD POTENTIAL OSCILLATIONS; STRATUM-ORIENS INTERNEURONS; PROTEIN-COUPLED RECEPTORS; LONG-TERM POTENTIATION; GAMMA-OSCILLATIONS; CHOLINERGIC MODULATION; WORKING-MEMORY; GABAERGIC INTERNEURONS AB Parvalbumin-containing (PV) neurons, a major class of GABAergic interneurons, are essential circuit elements of learning networks. As levels of acetylcholine rise during active learning tasks, PV neurons become increasingly engaged in network dynamics. Conversely, impairment of either cholinergic or PV interneuron function induces learning deficits. Here, we examined PV interneurons in hippocampus (HC) and prefrontal cortex (PFC) and their modulation by muscarinic acetylcholine receptors (mAChRs). HC PV cells, visualized by crossing PV-CRE mice with Rosa26YFP mice, were anatomically identified as basket cells and PV bistratified cells in the stratum pyramidale; in stratum oriens, HC PV cells were electrophysiologically distinct from somatostatin-containing cells. With glutamatergic transmission pharmacologically blocked, mAChR activation enhanced PV cell excitability in both CA1 HC and PFC; however, CA1 HC PV cells exhibited a stronger postsynaptic depolarization than PFC PV cells. To delete M-1 mAChRs genetically from PV interneurons, we created PV-M-1 knockout mice by crossing PV-CRE and floxed M-1 mice. The elimination of M-1 mAChRs from PV cells diminished M-1 mAChR immunoreactivity and muscarinic excitation of HC PV cells. Selective cholinergic activation of HC PV interneurons using Designer Receptors Exclusively Activated by Designer Drugs technology enhanced the frequency and amplitude of inhibitory synaptic currents in CA1 pyramidal cells. Finally, relative to wild-type controls, PV-M-1 knockout mice exhibited impaired novel object recognition and, to a lesser extent, impaired spatial working memory, but reference memory remained intact. Therefore, the direct activation of M-1 mAChRs on PV cells contributes to some forms of learning and memory. C1 [Yi, Feng; Ball, Jackson; Stoll, Kurt E.; Satpute, Vaishali C.; Mitchell, Samantha M.; Pauli, Jordan L.; Holloway, Benjamin B.; Johnston, April D.; Lawrence, J. Josh] Univ Montana, COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. [Yi, Feng; Ball, Jackson; Stoll, Kurt E.; Satpute, Vaishali C.; Mitchell, Samantha M.; Pauli, Jordan L.; Holloway, Benjamin B.; Lawrence, J. Josh] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Satpute, Vaishali C.] Univ Montana, Grad Program Neurosci, Missoula, MT 59812 USA. [Mitchell, Samantha M.] Univ Montana, Davidson Honors Coll, Missoula, MT 59812 USA. [Nathanson, Neil M.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Gerber, David J.; Tonegawa, Susumu] MIT, Howard Hughes Med Inst, RIKEN MIT Neurosci Res Ctr, Picower Inst Learning & Memory,Dept Biol, Cambridge, MA 02139 USA. [Gerber, David J.; Tonegawa, Susumu] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Lawrence, JJ (reprint author), Univ Montana, Dept Biomed & Pharmaceut Sci, COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. EM josh.lawrence@umontana.edu OI Satpute Janve, Vaishali/0000-0001-8828-3540 FU National Institutes of Health [R01 NS069689]; National Center for Research Resources [P20RR015583]; Epilepsy Foundation; Alzheimer's Association; NSF EPSCOR; University of Montana Small Grants Program; Montana Space Grant Consortium; COBRE CSFN Pilot Grant [P20RR015583]; NSFEPSCOR; [P20RR017670]; [P20GM10356] FX We are grateful for financial support from National Institutes of Health grant R01 NS069689 (J.J.L.), National Center for Research Resources grant P20RR015583 (J.J.L., J.B. and V. C. S.), the Epilepsy Foundation (J.J.L.), the Alzheimer's Association (J.J.L.), NSF EPSCOR (K. E. S.), the University of Montana Small Grants Program (J.J.L. and K. E. S.) and the Montana Space Grant Consortium (S. M. M.). AnyMaze equipment was purchased with a COBRE CSFN Pilot Grant to Loretta Bolyard (P20RR015583), a Montana Space Grant Consortium grant (S. M. M.) and NSFEPSCOR(K. E. S.). P20RR015583, P20RR017670 and P20GM10356 grants supported core facilities. NR 143 TC 23 Z9 24 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 15 PY 2014 VL 592 IS 16 BP 3463 EP 3494 DI 10.1113/jphysiol.2014.275453 PG 32 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AN4ZS UT WOS:000340599200014 PM 24879872 ER PT J AU Romero, R Dey, SK Fisher, SJ AF Romero, Roberto Dey, Sudhansu K. Fisher, Susan J. TI Preterm labor: One syndrome, many causes SO SCIENCE LA English DT Review ID MATERNAL ANTIFETAL REJECTION; FETAL MEMBRANE RUPTURE; SYSTEMATIC ANALYSIS; INTRAAMNIOTIC INFECTION; INTRAUTERINE INFECTION; INFLAMMATORY RESPONSE; EXTRACELLULAR-MATRIX; PREMATURE RUPTURE; IDENTIFY PATIENTS; GENE-EXPRESSION AB Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment. C1 [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Detroit Med Ctr, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Perinatal Inst, Cincinnati, OH 45229 USA. [Fisher, Susan J.] Univ Calif San Francisco, Dept Anat, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Fisher, Susan J.] Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. EM romeror@mail.nih.gov FU Division of Intramural Research of the Eunice Kennedy Shriver NICHD, NIH/Department of Health and Human Services; NIH [HD068524, DA06668]; March of Dimes [21-FY12-127, 22-FY14-470]; [R37 HD076253]; [U54 HD055764] FX The authors regret that, because of page limitations, the contributions of many investigators to the study of parturition could not be credited in this article. The authors thank S. Curtis for editing the manuscript. The work of R. R. is supported by the Division of Intramural Research of the Eunice Kennedy Shriver NICHD, NIH/Department of Health and Human Services. Studies from S.K.D.'s lab were supported in part by grants from the NIH (HD068524 and DA06668) and March of Dimes (21-FY12-127 and 22-FY14-470). The work of S. F. is supported by R37 HD076253 and U54 HD055764. We thank M. Gormley for assistance preparing the figures. NR 73 TC 203 Z9 213 U1 13 U2 74 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 15 PY 2014 VL 345 IS 6198 BP 760 EP 765 DI 10.1126/science.1251816 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN4XM UT WOS:000340593100033 PM 25124429 ER PT J AU Seeher, S Carlson, BA Miniard, AC Wirth, EK Mahdi, Y Hatfield, DL Driscoll, DM Schweizer, U AF Seeher, Sandra Carlson, Bradley A. Miniard, Angela C. Wirth, Eva K. Mahdi, Yassin Hatfield, Dolph L. Driscoll, Donna M. Schweizer, Ulrich TI Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice SO BIOCHEMICAL JOURNAL LA English DT Article DE cholinergic; glutathione peroxidase; neurodegeneration; parvalbumin; redox; selenium ID PROGRESSIVE CEREBELLOCEREBRAL ATROPHY; NEUROLOGICAL DYSFUNCTION; THIOREDOXIN REDUCTASE; SELENIUM DEFICIENCY; NEUROTROPHIC FACTOR; SELENOCYSTEINE; GENE; MUTATIONS; INTERNEURONS; SEIZURES AB Secisbp2 [SECTS (selenocystdine insertion sequence)-binding protein 2] binds to SECTS elements located in the 3'-UTR region of eukaryotic selenoprotein mRNAs. It facilitates the incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2(fl/fl)) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA([Ser]Sec). This allowed us to study the development of cortical PV (parvalbumin)+ interneurons, which are completely lost in tRNA([Ser]Sec) mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus and striatum. In Situ hybridization for Gad67 (glutamic acid decarboxylase 67) confirmed the reduction of GABAergic (where GABA is gamma-aminobutyric acid) interneurons. Because of the obvious movement phenotype involving a broad dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49 % respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68 %. Our observations demonstrate that several classes of striatal intemeurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations. C1 [Seeher, Sandra; Mahdi, Yassin; Schweizer, Ulrich] Univ Bonn, Inst Biochem & Mol Biol, D-53115 Bonn, Germany. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Mouse Canc Genet Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Miniard, Angela C.; Driscoll, Donna M.] Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. [Wirth, Eva K.] Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. RP Schweizer, U (reprint author), Univ Bonn, Inst Biochem & Mol Biol, Nussallee 11, D-53115 Bonn, Germany. EM uschweiz@uni-bonn.de OI Wirth, Eva Katrin/0000-0002-0491-9941; Schweizer, Ulrich/0000-0003-1380-4780 FU Deutsche Forschungsgemeinschaft [Schw914/2-1]; National Institutes of Health [R01DK085391] FX This work was supported by the Deutsche Forschungsgemeinschaft [grant number Schw914/2-1 (to U.S.)] and the National Institutes of Health [grant number R01DK085391 (to D.M.D.)]. NR 39 TC 13 Z9 13 U1 1 U2 2 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 2014 VL 462 BP 67 EP 75 DI 10.1042/BJ20140423 PN 1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM9RG UT WOS:000340218100006 PM 24844465 ER PT J AU Hao, H Veleri, S Sun, B Kim, DS Keeley, PW Kim, JW Yang, HJ Yadav, SP Manjunath, SH Sood, R Liu, P Reese, BE Swaroop, A AF Hao, Hong Veleri, Shobi Sun, Bo Kim, Douglas S. Keeley, Patrick W. Kim, Jung-Woong Yang, Hyun-Jin Yadav, Sharda P. Manjunath, Souparnika H. Sood, Raman Liu, Paul Reese, Benjamin E. Swaroop, Anand TI Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL SO HUMAN MOLECULAR GENETICS LA English DT Article ID NRL(-/-) MOUSE RETINA; MAMMALIAN ODORANT RECEPTORS; IN-VIVO; DIFFERENTIATION FACTOR; FUNCTIONAL EXPRESSION; CONE PHOTORECEPTORS; GENE-EXPRESSION; LEUCINE-ZIPPER; MESSENGER-RNA; CELL-FATE AB The Maf-family leucine zipper transcription factor NRL is essential for rod photoreceptor development and functional maintenance in the mammalian retina. Mutations in NRL are associated with human retinopathies, and loss of Nrl in mice leads to a cone-only retina with the complete absence of rods. Among the highly down-regulated genes in the Nrl(-/-) retina, we identified receptor expression enhancing protein 6 (Reep6), which encodes a member of a family of proteins involved in shaping of membrane tubules and transport of G-protein coupled receptors. Here, we demonstrate the expression of a novel Reep6 isoform (termed Reep6.1) in the retina by exon-specific Taqman assay and rapid analysis of complementary deoxyribonucleic acid (cDNA) ends (5'-RACE). The REEP6.1 protein includes 27 additional amino acids encoded by exon 5 and is specifically expressed in rod photoreceptors of developing and mature retina. Chromatin immunoprecipitation assay identified NRL binding within the Reep6 intron 1. Reporter assays in cultured cells and transfections in retinal explants mapped an intronic enhancer sequence that mediated NRL-directed Reep6.1 expression. We also demonstrate that knockdown of Reep6 in mouse and zebrafish resulted in death of retinal cells. Our studies implicate REEP6.1 as a key functional target of NRL-centered transcriptional regulatory network in rod photoreceptors. C1 [Hao, Hong; Veleri, Shobi; Sun, Bo; Kim, Douglas S.; Kim, Jung-Woong; Yang, Hyun-Jin; Yadav, Sharda P.; Manjunath, Souparnika H.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Kim, Douglas S.] Howard Hughes Med Inst, Ashburn, VA USA. [Keeley, Patrick W.; Reese, Benjamin E.] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. [Keeley, Patrick W.] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. [Reese, Benjamin E.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Sood, Raman; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Sood, Raman; Liu, Paul] NHGRI, Zebrafish Core, NIH, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute, National Institutes of Health; National Human Genome Research Institute, National Institutes of Health; NIH [EY019968] FX These studies were supported by intramural research programs of the National Eye Institute and National Human Genome Research Institute, National Institutes of Health, and by NIH extramural support (EY019968). NR 72 TC 7 Z9 9 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2014 VL 23 IS 16 BP 4260 EP 4271 DI 10.1093/hmg/ddu143 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AM7SX UT WOS:000340070100006 PM 24691551 ER PT J AU Castellsague, X Naud, P Chow, SN Wheeler, CM Germar, MJV Lehtinen, M Paavonen, J Jaisamrarn, U Garland, SM Salmeron, J Apter, D Kitchener, H Teixeira, JC Skinner, SR Limson, G Szarewski, A Romanowski, B Aoki, FY Schwarz, TF Poppe, WAJ Bosch, FX de Carvalho, NS Peters, K Tjalma, WAA Safaeian, M Raillard, A Descamps, D Struyf, F Dubin, G Rosillon, D Baril, L AF Castellsague, Xavier Naud, Paulo Chow, Song-Nan Wheeler, Cosette M. Germar, Maria Julieta V. Lehtinen, Matti Paavonen, Jorma Jaisamrarn, Unnop Garland, Suzanne M. Salmeron, Jorge Apter, Dan Kitchener, Henry Teixeira, Julio C. Skinner, S. Rachel Limson, Genara Szarewski, Anne Romanowski, Barbara Aoki, Fred Y. Schwarz, Tino F. Poppe, Willy A. J. Xavier Bosch, F. de Carvalho, Newton S. Peters, Klaus Tjalma, Wiebren A. A. Safaeian, Mahboobeh Raillard, Alice Descamps, Dominique Struyf, Frank Dubin, Gary Rosillon, Dominique Baril, Laurence TI Risk of Newly Detected Infections and Cervical Abnormalities in Women Seropositive for Naturally Acquired Human Papillomavirus Type 16/18 Antibodies: Analysis of the Control Arm of PATRICIA SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HPV; naturally acquired antibodies; infection; cervical abnormality; risk reduction ID HPV-16/18 AS04-ADJUVANTED VACCINE; SUBSEQUENT HPV INFECTION; VIRUS-LIKE PARTICLES; OF-STUDY ANALYSIS; YOUNG-WOMEN; DOUBLE-BLIND; COSTA-RICA; INTRAEPITHELIAL NEOPLASIA; CONTROLLED-TRIAL; EFFICACY AB Background. We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681). Methods. Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15-25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]). Results. High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242-794), 204 (95% CI, 129-480), and 480 (95% CI, 250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively. Conclusions. Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type. C1 [Castellsague, Xavier; Xavier Bosch, F.] CIBER ESP, IDIBELL, Unit Infect & Canc, Inst Catala Oncol,Canc Epidemiol Res Program, Lhospitalet De Llobregat, Catalonia, Spain. [Naud, Paulo] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Dept Gynecol & Obstet, BR-90046900 Porto Alegre, RS, Brazil. [Chow, Song-Nan] Natl Taiwan Univ, Coll Med & Hosp, Dept Obstet & Gynecol, Taipei 10764, Taiwan. [Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Dept Obstet & Gynecol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Germar, Maria Julieta V.] Univ Philippines, Dept Obstet & Gynaecol, Coll Med, Philippine Gen Hosp, Manila, Philippines. [Lehtinen, Matti] Univ Tampere, Sch Publ Hlth, FIN-33101 Tampere, Finland. [Paavonen, Jorma] Univ Helsinki, Dept Obstet & Gynaecol, FIN-00014 Helsinki, Finland. [Jaisamrarn, Unnop] Chulalongkorn Univ, Fac Med, Dept Obstet & Gynaecol, Bangkok 10330, Thailand. [Garland, Suzanne M.] Univ Melbourne, Royal Womens Hosp, Dept Microbiol & Infect Dis, Parkville, Vic 3052, Australia. [Garland, Suzanne M.] Univ Melbourne, Dept Microbiol, Royal Childrens Hosp, Parkville Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Garland, Suzanne M.] Univ Melbourne, Dept Obstet & Gynaecol, Parkville, Vic 3052, Australia. [Salmeron, Jorge] Inst Mexicano Seguro Social, Unidad Invest Epidemiol & Serv Salud, Cuernavaca, Morelos, Mexico. [Apter, Dan] Family Federat Finland, Sexual Hlth Clin, Helsinki, Finland. [Kitchener, Henry] Cent Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Teixeira, Julio C.] Univ Estadual Campinas, Dept Tocoginecol, UNICAMP, Sao Paulo, Brazil. [Skinner, S. Rachel] Telethon Inst Child Hlth Res, Vaccines Trials Grp, Perth, WA, Australia. [Skinner, S. Rachel] Univ Sydney, Discipline Paediat & Child Hlth, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Limson, Genara] Univ Philippines, Coll Med, Philippine Gen Hosp, Makati Med Ctr, Makati, Philippines. [Szarewski, Anne] Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, London, England. [Romanowski, Barbara] Univ Alberta, Dept Med, Div Infect Dis, Fac Med & Dent, Edmonton, AB, Canada. [Aoki, Fred Y.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Schwarz, Tino F.] Univ Wurzburg, Cent Lab, Stiftung Juliusspital, Acad Teaching Hosp, Wurzburg, Germany. [Schwarz, Tino F.] Univ Wurzburg, Vaccinat Ctr, Stiftung Juliusspital, Acad Teaching Hosp, Wurzburg, Germany. [Poppe, Willy A. J.] KU Leuven Gasthuisberg, Univ Hosp, Dept Gynaecol, Leuven, Belgium. [Xavier Bosch, F.] RTICC, Network Cooperat Canc Res, Catalonia, Spain. [de Carvalho, Newton S.] Univ Fed Parana, Dept Gynecol & Obstet, Infect Dis Gynecol & Obstet Sect, BR-80060000 Curitiba, Parana, Brazil. [Peters, Klaus] Facharzt Frauenheilkunde & Geburtshilfe, Hamburg, Germany. [Tjalma, Wiebren A. A.] Univ Antwerp, Univ Antwerp Hosp, Multidisciplinary Breast Clin Gynecol Oncol, Antwerp, Belgium. [Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. [Raillard, Alice] 4Clinics, Paris, France. [Descamps, Dominique; Struyf, Frank; Rosillon, Dominique; Baril, Laurence] GlaxoSmithKline Vaccines, Wavre, Belgium. [Dubin, Gary] GlaxoSmithKline Vaccines, King Of Prussia, PA USA. RP Castellsague, X (reprint author), Inst Catala Oncol, Canc Epidemiol Res Program, Unit Infect & Canc, Avda Gran Via 199-203, Barcelona 08908, Spain. EM xcastellsague@iconcologia.net RI BOSCH JOSE, FRANCESC XAVIER/J-6339-2012; Castellsague Pique, Xavier/N-5795-2014; OI BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412; Castellsague Pique, Xavier/0000-0002-0802-3595; Baril, Laurence/0000-0003-2346-883X; Apter, Dan/0000-0002-5175-8845 FU GlaxoSmithKline Biologicals SA [NCT00122681] FX This work was supported by GlaxoSmithKline Biologicals SA (NCT00122681). Cervarix is a registered trademark of the GlaxoSmithKline group of companies. NR 35 TC 13 Z9 14 U1 1 U2 12 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 2014 VL 210 IS 4 BP 517 EP 534 DI 10.1093/infdis/jiu139 PG 18 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AN0AN UT WOS:000340243500004 PM 24610876 ER PT J AU Shive, CL Mudd, JC Funderburg, NT Sieg, SF Kyi, B Bazdar, DA Mangioni, D Gori, A Jacobson, JM Brooks, AD Hardacre, J Ammori, J Estes, JD Schacker, TW Rodriguez, B Lederman, MM AF Shive, Carey L. Mudd, Joseph C. Funderburg, Nicholas T. Sieg, Scott F. Kyi, Benjamin Bazdar, Doug A. Mangioni, Davide Gori, Andrea Jacobson, Jeffrey M. Brooks, Ari D. Hardacre, Jeffrey Ammori, John Estes, Jacob D. Schacker, Timothy W. Rodriguez, Benigno Lederman, Michael M. TI Inflammatory Cytokines Drive CD4(+) T-Cell Cycling and Impaired Responsiveness to Interleukin 7: Implications for Immune Failure in HIV Disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; interleukin 6; interleukin 7; interleukin 1 beta; immune failure; inflammation ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; RECEPTOR EXPRESSION; ACTIVATION; HOMEOSTASIS; LYMPHOCYTES; TURNOVER; IL-7; ANTIGEN; DEATH AB Background. Systemic inflammation has been linked to a failure to normalize CD4(+) T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure. Methods. We examined the in vitro effects of IL-6 and interleukin 1 beta (IL-1 beta) on peripheral blood T-cell cycling and CD127 surface expression. Results. The proinflammatory cytokine IL-1 beta induces cell cycling and turnover of memory CD4(+) T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1 beta and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor alpha chain (IL-7R alpha). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1 beta attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin alpha 4 beta 7. We found elevated expression of IL-1 beta in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy. Conclusions. Induction of CD4(+) T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1 beta and IL-6 exposure may contribute to the lack of CD4(+) T-cell reconstitution in treated HIV-infected subjects. C1 [Shive, Carey L.; Mudd, Joseph C.; Funderburg, Nicholas T.; Sieg, Scott F.; Kyi, Benjamin; Bazdar, Doug A.; Rodriguez, Benigno; Lederman, Michael M.] Case Western Reserve Univ, Ctr AIDS Res, Cleveland, OH 44106 USA. [Hardacre, Jeffrey; Ammori, John] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Funderburg, Nicholas T.] Ohio State Univ, Sch Hlth & Rehabil Sci, Columbus, OH 43210 USA. [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Brooks, Ari D.] Penn Hosp, Philadelphia, PA 19107 USA. [Estes, Jacob D.] SAIC Frederick, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Schacker, Timothy W.] Univ Minnesota, Minneapolis, MN USA. [Mangioni, Davide; Gori, Andrea] Univ Milano Bicocca, San Gerardo Hosp, Dept Internal Med, Div Infect Dis, Monza, Italy. RP Lederman, MM (reprint author), Case Western Reserve Univ, Ctr AIDS Res, 2061 Cornell Rd, Cleveland, OH 44106 USA. EM lederman.michael@clevelandactu.org RI Rodriguez, Benigno/C-3365-2009; Funderburg, Nicholas/L-8022-2013 OI Rodriguez, Benigno/0000-0001-9736-7957; FU National Institutes of Health [AI 076174, AI-68636]; CWRU Center for AIDS Research [AI 36219]; Fasenmyer Foundation FX This work was supported by the National Institutes of Health (grants AI 076174 and AI-68636), the CWRU Center for AIDS Research (grant AI 36219), and the Fasenmyer Foundation. NR 49 TC 20 Z9 20 U1 0 U2 6 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 2014 VL 210 IS 4 BP 619 EP 629 DI 10.1093/infdis/jiu125 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AN0AN UT WOS:000340243500016 PM 24585897 ER PT J AU Mabrouk, OS Dripps, IJ Ramani, S Chang, C Han, JL Rice, KC Jutkiewicz, EM AF Mabrouk, O. S. Dripps, I. J. Ramani, S. Chang, C. Han, J. L. Rice, K. C. Jutkiewicz, E. M. TI Automated touch screen device for recording complex rodent behaviors SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Behavior; Mouse; Light-dark box; Movement; Anxiety; Motor function; Technology; Open field ID RECEPTOR AGONIST SNC80; RATS; MOUSE; PARKINSONISM; STIMULATION; MODEL; MICE AB Background: Monitoring mouse behavior is a critical step in the development of modern pharmacotherapies. New method: Here we describe the application of a novel method that utilizes a touch display computer (tablet) and software to detect, record, and report fine motor behaviors. A consumer-grade tablet device is placed in the bottom of a specially made acrylic cage allowing the animal to walk on the device (MouseTrapp). We describe its application in open field (for general locomotor studies) which measures step lengths and velocity. The device can perform light-dark (anxiety) tests by illuminating half of the screen and keeping the other half darkened. A divider is built into the lid of the device allowing the animal free access to either side. Results: Treating mice with amphetamine and the delta opioid peptide receptor agonist SNC80 stimulated locomotor activity on the device. Amphetamine increased step velocity but not step length during its peak effect (40-70 min after treatment), thus indicating detection of subtle amphetamine-induced effects. Animals showed a preference (74% of time spent) for the darkened half compared to the illuminated side. Comparison with existing method: Animals were videotaped within the chamber to compare quadrant crosses to detect motion on the device. The slope, duration and magnitude of quadrant crosses tightly correlated with overall locomotor activity as detected by MouseTrapp. Conclusions: We suggest that modern touch display devices such as MouseTrapp will be an important step toward automation of behavioral analyses for characterizing phenotypes and drug effects. (C) 2014 Elsevier BM. All rights reserved. C1 [Mabrouk, O. S.] Neurolytical LLC, Ann Arbor, MI USA. [Mabrouk, O. S.; Dripps, I. J.; Ramani, S.; Chang, C.; Jutkiewicz, E. M.] Dept Pharmacol, Ann Arbor, MI USA. [Mabrouk, O. S.; Han, J. L.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Rice, K. C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, K. C.] NIAAA, Bethesda, MD USA. RP Jutkiewicz, EM (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM ejutkiew@umich.edu FU University of Michigan Medical School; National Institute on Drug Abuse National Institute on Alcohol Abuse and Alcoholism FX This work was supported by startup funds/discretionary provided to EMJ by the University of Michigan Medical School. A portion of this work was supported by the Intramural Research Program of the National Institute on Drug Abuse National Institute on Alcohol Abuse and Alcoholism. OSM has a personal financial interest related to the development of MouseTrapp. NR 15 TC 2 Z9 2 U1 0 U2 9 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 15 PY 2014 VL 233 BP 129 EP 136 DI 10.1016/j.jneumeth.2014.05.004 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AM9TT UT WOS:000340224600016 PM 24952323 ER PT J AU Fukushima, M Saunders, RC Mullarkey, M Doyle, AM Mishkin, M Fujii, N AF Fukushima, Makoto Saunders, Richard C. Mullarkey, Matthew Doyle, Alexandra M. Mishkin, Mortimer Fujii, Naotaka TI An electrocorticographic electrode array for simultaneous recording from medial, lateral, and intrasulcal surface of the cortex in macaque monkeys SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Electrocorticography; ECoG; Electrophysiology; Evoked potentials; Multielectrode; Monkey ID AUDITORY-CORTEX; AREAS V1; OSCILLATIONS; SYNCHRONIZATION; COHERENCE; SELECTION; CIRCUITS; DYNAMICS; NETWORK; SYSTEM AB Background: Electrocorticography (ECoG) permits recording electrical field potentials with high spatiotemporal resolution over a large part of the cerebral cortex. Application of chronically implanted ECoG arrays in animal models provides an opportunity to investigate global spatiotemporal neural patterns and functional connectivity systematically under various experimental conditions. Although ECoG is conventionally used to cover the gyral cortical surface, recent studies have shown the feasibility of intrasulcal ECoG recordings in macaque monkeys. New method: Here we developed a new ECoG array to record neural activity simultaneously from much of the medial and lateral cortical surface of a single hemisphere, together with the supratemporal plane (STP) of the lateral sulcus in macaque monkeys. The ECoG array consisted of 256 electrodes for bipolar recording at 128 sites. Results: We successfully implanted the ECoG array in the left hemisphere of three rhesus monkeys. The electrodes in the auditory and visual cortex detected robust event related potentials to auditory and visual stimuli, respectively. Bipolar recording from adjacent electrode pairs effectively eliminated chewing artifacts evident in monopolar recording, demonstrating the advantage of using the ECoG array under conditions that generate significant movement artifacts. Comparison with existing methods: Compared with bipolar ECoG arrays previously developed for macaque monkeys, this array significantly expands the number of cortical target areas in gyral and intralsulcal cortex. Conclusions: This new ECoG array provides an opportunity to investigate global network interactions among gyral and intrasulcal cortical areas. (C) 2014 Published by Elsevier B.V. C1 [Fukushima, Makoto; Saunders, Richard C.; Mullarkey, Matthew; Doyle, Alexandra M.; Mishkin, Mortimer] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Fujii, Naotaka] RIKEN, Lab Adapt Intelligence, Brain Sci Inst, Wako, Saitama 3510198, Japan. RP Fukushima, M (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM makoto_fukushima@me.com OI Fukushima, Makoto/0000-0002-8809-7892 FU National Institute of Mental Health (NIMH), NIH, DHHS [MH000478]; MEXT, Japan [23118003] FX We thank T. Shirayanagi for technical assistance in electrode design and schematics of the array, D. Johnson for assistance with CT scans, R. Reoli for assistance with MR scans, D. Glen for assistance in co-registration of the CT and MR scans with AFNI, and D. Rickrode for animal care. This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH), NIH, DHHS (MH000478), and by a Grant-in-Aid for Scientific Research on Innovative Areas (23118003; Adolescent Mind & Self-Regulation) and the Strategic Research Program for Brain Science by MEXT, Japan (23118003). NR 48 TC 13 Z9 13 U1 0 U2 10 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 15 PY 2014 VL 233 BP 155 EP 165 DI 10.1016/j.jneumeth.2014.06.022 PG 11 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AM9TT UT WOS:000340224600019 PM 24972186 ER PT J AU Hassan, SA AF Hassan, Sergio A. TI Implicit Treatment of Solvent Dispersion Forces in Protein Simulations SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE dispersion interactions; protein-protein association; implicit salvation; hydration; binding enthalpy ID MOLECULAR-DYNAMICS SIMULATIONS; SCREENED COULOMB POTENTIALS; LIQUID-STRUCTURE FORCES; DER-WAALS INTERACTIONS; SURFACE-AREA; SOLVATION MODELS; FREE-ENERGY; HYDRATION; WATER; HYDROPHOBICITY AB A model is proposed for the evaluation of dispersive forces in a continuum solvent representation for use in large-scale computer simulations. The model captures the short-and long-range effects of water-exclusion in conditions of partial and anisotropic hydration. The model introduces three parameters, one of which represents the degree of hydration (water occupancy) at any point in the system, which depends on the solute conformation, and two that represent the strength of water-water and water-solute dispersive interactions. The model is optimized for proteins, using hydration data of a sub-optimally hydrated binding site and results from dynamics simulations in explicit water. The model is applied to a series of aliphatic-alcohol/protein complexes and a set of binary and ternary complexes of various sizes. Implications for weak and ultra-weak protein-protein association and for simulation in crowded media are discussed. Published 2014. This article is a U.S. Government work and is in the public domain in the USA C1 NIH, Ctr Mol Modeling, DCB, CIT, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, DCB, CIT, Bethesda, MD 20892 USA. EM hassan@mail.nih.gov FU CIT (NIH Intramural Research Program) FX Contract grant sponsor: CIT (NIH Intramural Research Program) NR 55 TC 3 Z9 3 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD AUG 15 PY 2014 VL 35 IS 22 BP 1621 EP 1629 DI 10.1002/jcc.23655 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA AM6FH UT WOS:000339958300003 PM 24919463 ER PT J AU Wang, YJ Kathawala, RJ Zhang, YK Patel, A Kumar, P Shukla, S Fung, KL Ambudkar, SV Talele, TT Chen, ZS AF Wang, Yi-Jun Kathawala, Rishil J. Zhang, Yun-Kai Patel, Atish Kumar, Priyank Shukla, Suneet Fung, King Leung Ambudkar, Suresh V. Talele, Tanaji T. Chen, Zhe-Sheng TI Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1 SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Multidrug resistance; ABC transporters; ABCB1; Tyrosine kinase inhibitor; Motesanib ID TYROSINE KINASE INHIBITOR; CELL LUNG-CANCER; ENDOTHELIAL GROWTH-FACTOR; DRUG-RESISTANCE; P-GLYCOPROTEIN; KIT RECEPTORS; PACLITAXEL RESISTANCE; ANTITUMOR-ACTIVITY; ORAL INHIBITOR; THYROID-CANCER AB Cancer cells often become resistant to chemotherapy through a phenomenon known as multidrug resistance (MDR). Several factors are responsible for the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP binding cassette (ABC) transporters. Some small molecule tyrosine kinase inhibitors (TKIs) were recently reported to modulate the activity of ABC transporters. Therefore, the purpose of this study was to determine if motesanib, a multikinase inhibitor, could reverse ABCB1-mediated MDR. The results showed that motesanib significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Motesanib significantly increased the accumulation of [H-3]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant change in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 3 mu M motesanib for 72 h. Moreover, motesanib stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, the docking studies indicated favorable binding of motesanib within the transmembrane region of homology modeled human ABCB1. Here, we report for the first time, motesanib, at clinically achievable plasma concentrations, antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings may be useful for cancer combination therapy with TKIs in the clinic. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wang, Yi-Jun; Kathawala, Rishil J.; Zhang, Yun-Kai; Patel, Atish; Kumar, Priyank; Talele, Tanaji T.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. [Shukla, Suneet; Fung, King Leung; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, ZS (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. EM chenz@stjohns.edu RI Wang, Yi-Jun/K-3218-2016; Patel, Atish/J-4699-2014 OI Kumar, Priyank/0000-0002-4772-2073; Patel, Atish/0000-0002-5549-9166 FU NIH [1R15CA143701]; Ray Biotech Inc.; St. John's University Research Seed Grant [579-1110-7002]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by funds from NIH (No. 1R15CA143701), Ray Biotech Inc. and St. John's University Research Seed Grant (No. 579-1110-7002) to Z.S. Chen. Drs. SS, KLF and SVA were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 64 TC 15 Z9 17 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2014 VL 90 IS 4 BP 367 EP 378 DI 10.1016/j.bcp.2014.06.006 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL9KO UT WOS:000339460200005 PM 24937702 ER PT J AU Shi, Z Yang, WJ Goldstein, JA Zhang, SY AF Shi, Zhe Yang, Wenjun Goldstein, Joyce A. Zhang, Shu-Yun TI Med25 is required for estrogen receptor alpha (ER alpha)-mediated regulation of human CYP2C9 expression SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE CYP2C9; Med25; ER alpha; Transcription regulation ID CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE-X-RECEPTOR; TRANSCRIPTIONAL REGULATION; GLUCOCORTICOID-RECEPTOR; MEDIATOR COMPLEX; COACTIVATOR COMPLEX; ACTIVATION; GENE; SUBFAMILY; PROMOTER AB The CYP2C subfamily of cytochrome P450 enzymes is an important class of drug metabolizing enzymes in human liver. CYP2C9 is the most abundant member of the human CYP2C subfamily in liver and metabolizes similar to 15% of the therapeutic drugs as well as other xenobiotics and endogenous compounds. A number of nuclear receptors including xenobiotic-sensing receptors such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR) as well as liver enriched receptors hepatic nuclear factor 4 alpha (HNF4 alpha) and the estrogen receptor alpha (ER alpha) regulate CYP2C9 expression. Here, we show that Med25, a variable component of Mediator complex, enhanced ligand dependent ER alpha-mediated transcriptional activation of CYP2C9 promoter and interacts with activated ERa by 17 beta-estradiol through its C-terminal LXXLL motif. In conclusion, Med25 is identified as a new coactivator of ER alpha that is required for ERa-mediated regulation of CYP2C9 expression. (C) 2014 Elsevier Inc. All rights reserved. C1 [Shi, Zhe; Zhang, Shu-Yun] Wenzhou Med Univ, Sch Environm Sci & Publ Hlth, Dept Prevent Med, Wenzhou 325035, Zhejiang, Peoples R China. [Yang, Wenjun] Wenzhou Med Univ, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China. [Goldstein, Joyce A.] NIEHS, Human Metab Sect, Lab Toxicol & Pharmacol, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Zhang, SY (reprint author), Wenzhou Med Univ, Sch Environm Sci & Publ Hlth, Dept Prevent Med, Wenzhou 325035, Zhejiang, Peoples R China. EM shuyunzh@gmail.com FU Wenzhou Medical University (Wenzhou, China) [QTJ13011]; National Institute of Environmental Health Sciences [ES021024-32] FX We thank Dr. Negishi's lab, Dr. Surapureddi S, (NIEHS/NIH, Research Triangle Park, NC) for their kind help, Dr. Korach's lab for the ER alpha expression construct and Dr. McDonnell's lab for pACTER alpha construct. This work was supported by funds from Wenzhou Medical University (Wenzhou, China) (Project QTJ13011, to Zhang SY) and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (Project ES021024-32) (J.A.G). NR 30 TC 3 Z9 3 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2014 VL 90 IS 4 BP 425 EP 431 DI 10.1016/j.bcp.2014.06.016 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL9KO UT WOS:000339460200011 PM 24960263 ER PT J AU Ford, N Shubber, Z Jao, J Abrams, EJ Frigati, L Mofenson, L AF Ford, Nathan Shubber, Zara Jao, Jennifer Abrams, Elaine J. Frigati, Lisa Mofenson, Lynne TI Safety of Cotrimoxazole in Pregnancy: A Systematic Review and Meta-Analysis SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Review DE birth defects; congenital anomalies; cotrimoxazole; HIV/AIDS; pregnancy ID FOLIC-ACID ANTAGONISTS; NEURAL-TUBE DEFECTS; HIV-INFECTED WOMEN; ANTIRETROVIRAL THERAPY; TRIMETHOPRIM-SULFAMETHOXAZOLE; CONGENITAL-ABNORMALITIES; BIRTH-DEFECTS; RISK; EXPOSURE; PROPHYLAXIS AB Introduction: Cotrimoxazole is widely prescribed to treat a range of infections, and for HIV-infected individuals it is administered as prophylaxis to protect against opportunistic infections. Some reports suggest that fetuses exposed to cotrimoxazole during early pregnancy may have an increased risk of congenital anomalies. We carried out this systematic review to update the evidence of cotrimoxazole safety in pregnancy. Methods: Three databases and 1 conference abstract site were searched in duplicate up to October 31, 2013, for studies reporting adverse maternal and infant outcomes among women receiving cotrimoxazole during pregnancy. This search was updated in MEDLINE via PubMed to April 28, 2014. Studies were included irrespective of HIV infection status or the presence of other coinfections. Our primary outcome was birth defects of any kind. Secondary outcomes included spontaneous abortions, terminations of pregnancy, stillbirths, preterm deliveries, and drug-associated toxicity. Results: Twenty-four studies were included for review. There were 232 infants with congenital anomalies among 4196 women receiving cotrimoxazole during pregnancy, giving an overall pooled prevalence of 3.5% (95% confidence interval: 1.8% to 5.1%; tau(2) = 0.03). Three studies reported 31 infants with neural tube defects associated with first trimester exposure to cotrimoxazole, giving a crude prevalence of 0.7% (95% confidence interval: 0.5% to 1.0%) with most data (29 neural tube defects) coming from a single study. The majority of adverse drug reactions were mild. The quality of the evidence was very low. Conclusions: The findings of this review support continued recommendations for cotrimoxazole as a priority intervention for HIV-infected pregnant women. It is critical to improve data collection on maternal and infant outcomes. C1 [Ford, Nathan] WHO, Dept HIV AIDS, CH-1211 Geneva, Switzerland. [Shubber, Zara] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Infect Dis Epidemiol, London, England. [Jao, Jennifer] Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, New York, NY 10029 USA. [Jao, Jennifer] Icahn Sch Med Mt Sinai, Dept Med, Div Gen Internal Med, New York, NY 10029 USA. [Abrams, Elaine J.] Columbia Univ, Mailman Sch Publ Hlth, ICAP, New York, NY USA. [Abrams, Elaine J.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Frigati, Lisa] Univ Stellenbosch, Tygerberg Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa. [Mofenson, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Rockville, MD USA. RP Ford, N (reprint author), WHO, Dept HIV AIDS, Ave Appia 20, CH-1211 Geneva, Switzerland. EM fordn@who.int FU Bill and Melinda Gates Foundation; National Institute of Child Health and Human Development [K23HD070760] FX Partially funded by a grant from the Bill and Melinda Gates Foundation. J.J. received salary support from National Institute of Child Health and Human Development K23HD070760 during the preparation of the manuscript. NR 53 TC 6 Z9 6 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2014 VL 66 IS 5 BP 512 EP 521 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL3FT UT WOS:000339012600011 PM 24853309 ER PT J AU Liu, CL Liu, AY Hu, J Yuan, VVA Halabi, S AF Liu, Chunling Liu, Aiyi Hu, Jiang Yuan, Vivian Halabi, Susan TI Adjusting for misclassification in a stratified biomarker clinical trial SO STATISTICS IN MEDICINE LA English DT Article DE biomarkers; classification error; correction for error; personalized medicine; power and sample size; prevalence; randomized controlled clinical trials; sensitivity and specificity ID RENAL-CELL CARCINOMA; THERAPEUTIC RESPONSE; INTERFERON-ALPHA; CANCER; DESIGNS; CHALLENGES; EFFICIENCY; ERROR AB Clinical trials utilizing predictive biomarkers have become a research focus in personalized medicine. We investigate the effects of biomarker misclassification on the design and analysis of stratified biomarker clinical trials. For a variety of inference problems including marker-treatment interaction in particular, we show that marker misclassification may have profound adverse effects on the coverage of confidence intervals, power of the tests, and required sample sizes. For each inferential problem, we propose methods to adjust for the classification errors. Copyright (C) 2014 JohnWiley & Sons, Ltd. C1 [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Hu, Jiang] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Yuan, Vivian] US FDA, Ctr Drug Dev & Res, Silver Spring, MD 20993 USA. [Halabi, Susan] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27708 USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. EM liua@mail.nih.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; [R01-CA155296]; [U01-CA157703] FX Research of A. Liu was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Research of S. Halabi was supported by grants R01-CA155296 and U01-CA157703. NR 19 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2014 VL 33 IS 18 BP 3100 EP 3113 DI 10.1002/sim.6164 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AL4OX UT WOS:000339113400004 PM 24733510 ER PT J AU Cheon, K Thoma, ME Kong, XR Albert, PS AF Cheon, Kyeongmi Thoma, Marie E. Kong, Xiangrong Albert, Paul S. TI A mixture of transition models for heterogeneous longitudinal ordinal data: with applications to longitudinal bacterial vaginosis data SO STATISTICS IN MEDICINE LA English DT Article DE mixture model; mover stayer model; heterogeneity; longitudinal data; Markov model; bacterial vaginosis ID VAGINAL FLORA; MENSTRUAL-CYCLE; NATURAL-HISTORY; GRAM STAIN; RECURRENCE; REGRESSION; BIVARIATE; RATIO; WOMEN AB Markov models used to analyze transition patterns in discrete longitudinal data are based on the limiting assumption that individuals follow the common underlying transition process. However, when one is interested in diseases with different disease or severity subtypes, explicitly modeling subpopulation-specific transition patterns may be appropriate. We propose a model which captures heterogeneity in the transition process through a finite mixture model formulation and provides a framework for identifying subpopulations at different risks. We apply the procedure to longitudinal bacterial vaginosis study data and demonstrate that the model fits the data well. Further, we show that under the mixture model formulation, we can make the important distinction between how covariates affect transition patterns unique to each of the subpopulations and how they affect which subgroup a participant will belong to. Practically, covariate effects on subpopulation-specific transition behavior and those on subpopulation membership can be interpreted as effects on short-term and long-term transition behavior. We further investigate models with higher-order subpopulation-specific transition dependence. Copyright (C) 2014 JohnWiley & Sons, Ltd. C1 [Cheon, Kyeongmi] Merck Sharp & Dohme Ltd, Biometr Res, West Point, PA 19486 USA. [Thoma, Marie E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Kong, Xiangrong] Johns Hopkins Univ, Baltimore, MD 21205 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. RP Albert, PS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. EM albertp@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) [R01AI47608]; Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are grateful to the participants in the vaginal flora study and the RHSP directors (Drs. Maria Wawer, Ronald Gray, Nelson Sewankambo, David Serwadda, Noah Kiwanuka, Fred Nalugoda, and Godfrey Kigozi) and study team. The vaginal flora study was supported by a grant (R01AI47608) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). The work on this paper was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors thank the Center for Information Technology, NIH, for providing the high-performance computational facility of the Biowulf cluster. NR 29 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2014 VL 33 IS 18 BP 3204 EP 3213 DI 10.1002/sim.6151 PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AL4OX UT WOS:000339113400011 PM 24676689 ER PT J AU Long, Y Chen, WJ Lin, ZX Sun, HM Xia, MH Zheng, W Li, ZY AF Long, Yan Chen, Wanjuan Lin, Zuoxian Sun, Hongmao Xia, Menghang Zheng, Wei Li, Zhiyuan TI Inhibition of HERG potassium channels by domiphen bromide and didecyl dimethylammonium bromide SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Quaternary ammonium compounds; Patch clamp; HERG channel ID DELAYED K+ CURRENT; DEPENDENT BLOCK; DOFETILIDE; MYOCYTES; AXONS AB Domiphen bromide and didecyl dimethylammonium bromide were widely used environmental chemicals with potent activity on blockade of human ether-a-go-go related gene (HERG) channels. But the mechanism of their action is not clear. The kinetics of block of HERG channels by domiphen bromide and didecyl dimethylammonium bromide was studied in order to characterize the inhibition of HERG currents by these quaternary ammonium compounds (QACs). Domiphen bromide and didecyl climethylammonium bromide inhibited HERG channel currents in a dose-dependent manner with lCso values of 9 Oil and 5 nM, respectively. Block of HERG channel by clomiphen bromide and didecyl climethylammonium bromide was voltage-dependent and use-dependent. Domiphen bromide and didecyl dimethylammonium bromide caused substantial negative shift of the activation curves, accelerated activated process, but had no effects on the deactivation and reactivation processes. The clocking models implied that these two compounds bound to PAS domain of HERG channels and inhibited its function. Our data demonstrated that domiphen bromide and didecyl dimethylammonium bromide blocked the HERG channel with a preference for the activated channel state. (C) 2014 Elsevier B.V. All rights reserved C1 [Long, Yan; Lin, Zuoxian; Li, Zhiyuan] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China. [Chen, Wanjuan] Anhui Univ, Sch Life Sci, Hefei 230027, Peoples R China. [Sun, Hongmao; Xia, Menghang; Zheng, Wei] Natl Ctr Advancing Translat Sci, NIH, Bethesda, MD 20892 USA. RP Li, ZY (reprint author), Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Kaiyuan Rd 190,Guangzhou Sci Pk, Guangzhou 510530, Guangdong, Peoples R China. EM li_zhiyuan@gibh.ac.cn RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU National Natural Science Foundation of China [81171037]; 973 Programme [201203966404] FX This research was supported by Grants from the National Natural Science Foundation of China (81171037) and 973 Programme(201203966404). NR 16 TC 0 Z9 0 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 EI 1879-0712 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD AUG 15 PY 2014 VL 737 BP 202 EP 209 DI 10.1016/j.ejphar.2014.05.002 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AK8VH UT WOS:000338706200024 PM 24846011 ER PT J AU Park, SR Kinders, RJ Khin, S Hollingshead, M Antony, S Parchment, RE Tomaszewski, JE Kummar, S Doroshow, JH AF Park, Sook Ryun Kinders, Robert J. Khin, Sonny Hollingshead, Melinda Antony, Smitha Parchment, Ralph E. Tomaszewski, Joseph E. Kummar, Shivaani Doroshow, James H. TI Validation of a hypoxia-inducible factor-1 alpha specimen collection procedure and quantitative enzyme-linked immunosorbent assay in solid tumor tissues SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Hypoxia-inducible factor; HIF-1 alpha; Quantitative ELISA; Pharmacodynamics; Solid tumors ID FACTOR 1-ALPHA HIF-1-ALPHA; HUMAN PROSTATE-CANCER; TOPOISOMERASE-I; PHASE-0 TRIALS; OXYGEN; EXPRESSION; GROWTH; XENOGRAFTS; INHIBITOR; THERAPY AB Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is an important marker of hypoxia in human tumors and has been implicated in tumor progression. Drugs targeting HIF-1 alpha are being developed, but the ability to measure drug-induced changes in HIF-1 alpha is limited by the lability of the protein in normoxia. Our goal was to devise methods for specimen collection and processing that preserve HIF-1 alpha in solid tumor tissues and to develop and validate a two-site chemiluminescent quantitative enzyme-linked immunosorbent assay (ELISA) for HIF-1 alpha. We tested various strategies for HIF-1 alpha stabilization in solid tumors, including nitrogen gas-purged lysis buffer, the addition of proteasome inhibitors or the prolyl hydroxylase inhibitor 2-hydroxyglutarate, and bead homogenization. Degassing and the addition of 2-hydroxyglutarate to the collection buffer significantly increased HIF-1 alpha recovery, whereas bead homogenization in sealed tubes improved HIF-1 alpha recovery and reduced sample variability. Validation of the ELISA demonstrated intra- and inter-assay variability of less than 15% and accuracy of 99.8 +/- 8.3% as assessed by spike recovery. Inter-laboratory reproducibility was also demonstrated (R-2 = 0.999). Careful sample handling techniques allow us to quantitatively detect HIF-1 alpha a in samples as small as 2.5 mu g of total protein extract, and this method is currently being applied to analyze tumor biopsy specimens in early-phase clinical trials. (C) 2014 Elsevier Inc. All rights reserved. C1 [Park, Sook Ryun; Antony, Smitha; Tomaszewski, Joseph E.; Kummar, Shivaani; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kinders, Robert J.; Khin, Sonny; Parchment, Ralph E.] Frederick Natl Lab Canc Res, Lab Human Toxicol & Pharmacol, Appl Dev Res Directorate, Leidos Biomed Res, Frederick, MD 21702 USA. [Hollingshead, Melinda] Frederick Natl Lab Canc Res, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 20892 USA. [Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kinders, RJ (reprint author), Frederick Natl Lab Canc Res, Lab Human Toxicol & Pharmacol, Appl Dev Res Directorate, Leidos Biomed Res, Frederick, MD 21702 USA. EM kindersr@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program of the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX We thank Katherine V. Ferry-Galow (Leidos Biomedical Research, Frederick National Laboratory for Cancer Research [FNLCR]) for conducting the 2-HG enantiomer studies. We thank Yvonne A. Evrard (Leidos Biomedical Research, FNLCR) for medical writing support in the preparation of this manuscript. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported in part by the Developmental Therapeutics Program of the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 38 TC 4 Z9 4 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 15 PY 2014 VL 459 BP 1 EP 11 DI 10.1016/j.ab.2014.04.025 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AK4PL UT WOS:000338406500001 PM 24799347 ER PT J AU Farsaci, B Jochems, C Grenga, I Donahue, RN Tucker, JA Pinto, PA Merino, MJ Heery, CR Madan, RA Gulley, JL Schlom, J AF Farsaci, Benedetto Jochems, Caroline Grenga, Italia Donahue, Renee N. Tucker, Jo A. Pinto, Peter A. Merino, Maria J. Heery, Christopher R. Madan, Ravi A. Gulley, James L. Schlom, Jeffrey TI Identification by digital immunohistochemistry of intratumoral changes of immune infiltrates after vaccine in the absence of modifications of PBMC immune cell subsets SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer vaccine; tumor-infiltrating lymphocytes; intratumoral vaccine; PROSTVAC; digital immunohistochemistry ID PROGRESSIVE PROSTATE-CANCER; MULTISITE PERFORMANCE; COMPUTER MONITOR; IMAGE-ANALYSIS; IMMUNOTHERAPY; SLIDES AB Preclinical studies have demonstrated that the combination of systemic subcutaneous (s.c.) vaccination with intratumoral (i.t.) vaccination was superior in the induction of antitumor activity vs. vaccination with either route alone. A subsequent phase I study employing i.t.-s.c. vaccination was carried out in men with locally recurrent or progressive prostate cancer. rF-PSA-TRICOM (PROSTVAC) vaccine was administered intraprostatically and rV-PSA-TRICOM followed by rF-PSA-TRICOM vaccine was administered systemically. In that study no dose limiting toxicities were observed, 19/21 patients had stable or improved prostate-specific antigen (PSA) values and tumor-infiltrating lymphocytes (TILs) increased in post-vs. pre-treatment tumor biopsies, analyzed employing conventional immunohistochemistry (IHC). In the studies reported here, 31 phenotypes of peripheral blood mononuclear cells (PBMCs) were analyzed prevaccination and postvaccination as well as the functions of PBMC regulatory T cells (Tregs) and natural killer cells. A trend was observed in decreases in serum PSA with the reduction of circulating Tregs postvaccination. Digital IHC was employed prevaccination and postvaccination to measure CD4 and CD8 TILs, as well as Treg TILs by conventional IHC. Few correlations were observed with CD4, CD8 or Treg in TILs vs. PBMCs. However, patients with lower levels of CD4 TILs prevaccination showed the greatest increases in CD4 TILs postvaccine, while Treg TILs decreased postvaccine. There was also a strong correlation between decreases in serum PSA and increases in CD8 TILs postvaccine. These studies provide additional rationale for the use of i.t.-s.c. vaccinations and demonstrate a noncoordinate expression of specific immune subsets in PBMCs vs. tumor. C1 [Farsaci, Benedetto; Jochems, Caroline; Grenga, Italia; Donahue, Renee N.; Tucker, Jo A.; Heery, Christopher R.; Gulley, James L.; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.; Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Farsaci, Benedetto/L-9837-2014; Gulley, James/K-4139-2016 OI Farsaci, Benedetto/0000-0001-8275-2561; Gulley, James/0000-0002-6569-2912 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Grant sponsor: Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health NR 15 TC 3 Z9 3 U1 1 U2 5 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 AUG 15 PY 2014 VL 135 IS 4 BP 862 EP 870 DI 10.1002/ijc.28743 PG 9 WC Oncology SC Oncology GA AJ3ZL UT WOS:000337607600009 PM 24474335 ER PT J AU Zhang, B Jia, WH Matsuo, K Shin, A Xiang, YB Matsuda, K Jee, SH Kim, DH Cheah, PY Ren, ZF Cai, QY Long, JR Shi, JJ Wen, WQ Yang, G Ji, BT Pan, ZZ Matsuda, F Gao, YT Oh, JH Ahn, YO Kubo, M Thean, LF Park, EJ Li, HL Park, JW Jo, J Jeong, JY Hosono, S Nakamura, Y Shu, XO Zeng, YX Zheng, W AF Zhang, Ben Jia, Wei-Hua Matsuo, Keitaro Shin, Aesun Xiang, Yong-Bing Matsuda, Koichi Jee, Sun Ha Kim, Dong-Hyun Cheah, Peh Yean Ren, Zefang Cai, Qiuyin Long, Jirong Shi, Jiajun Wen, Wanqing Yang, Gong Ji, Bu-Tian Pan, Zhi-Zhong Matsuda, Fumihiko Gao, Yu-Tang Oh, Jae Hwan Ahn, Yoon-Ok Kubo, Michiaki Thean, Lai Fun Park, Eun Jung Li, Hong-Lan Park, Ji Won Jo, Jaeseong Jeong, Jin-Young Hosono, Satoyo Nakamura, Yusuke Shu, Xiao-Ou Zeng, Yi-Xin Zheng, Wei TI Genome-wide association study identifies a new SMAD7 risk variant associated with colorectal cancer risk in East Asians SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Genome-wide association study; GWAS; colorectal cancer; SMAD7; genetic susceptibility; single-nucleotide polymorphisms; epidemiology ID SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; METAANALYSIS; SCAN; BETA; VISUALIZATION; EXPRESSION; COMPONENTS; GENOTYPES; SURVIVAL AB Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been conducted primarily in European descendants. In a GWAS conducted in East Asians, we first analyzed approximately 1.7 million single-nucleotide polymorphisms (SNPs) in four studies with 1,773 CRC cases and 2,642 controls. We then selected 66 promising SNPs for replication and genotyped them in three independent studies with 3,612 cases and 3,523 controls. Five SNPs were further evaluated using data from four additional studies including up to 3,290 cases and 4,339 controls. SNP rs7229639 in the SMAD7 gene was found to be associated with CRC risk with an odds ratio (95% confidence interval) associated with the minor allele (A) of 1.22 (1.15-1.29) in the combined analysis of all 11 studies (p = 2.93 x 10(-11)). SNP rs7229639 is 2,487 bp upstream from rs4939827, a risk variant identified previously in a European-ancestry GWAS in relation to CRC risk. However, these two SNPs are not correlated in East Asians (r(2) = 0.008) nor in Europeans (r(2) = 0.146). The CRC association with rs7229639 remained statistically significant after adjusting for rs4939827 as well as three additional CRC risk variants (rs58920878, rs12953717 and rs4464148) C1 [Zhang, Ben; Cai, Qiuyin; Long, Jirong; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37203 USA. [Jia, Wei-Hua; Ren, Zefang; Pan, Zhi-Zhong; Zeng, Yi-Xin] Sun Yat Sen Univ, State Key Lab Oncol South China, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Matsuo, Keitaro; Hosono, Satoyo] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Shin, Aesun] Natl Canc Ctr, Mol Epidemiol Branch, Goyang Si, South Korea. [Xiang, Yong-Bing; Gao, Yu-Tang; Li, Hong-Lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Matsuda, Koichi; Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan. [Jee, Sun Ha; Park, Eun Jung; Jo, Jaeseong] Yonsei Univ, Inst Hlth Promot, Dept Epidemiol & Hlth Promot, Grad Sch Publ Hlth, Seoul 120749, South Korea. [Kim, Dong-Hyun; Jeong, Jin-Young] Hallym Univ, Coll Med, Dept Social & Prevent Med, Okcheon Dong, South Korea. [Cheah, Peh Yean; Thean, Lai Fun] Singapore Gen Hosp, Dept Colorectal Surg, Singapore, Singapore. [Cheah, Peh Yean] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Cheah, Peh Yean] Natl Univ Singapore, Duke NUS Grad Med Sch, Singapore 117548, Singapore. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan. [Oh, Jae Hwan; Park, Ji Won] Natl Canc Ctr, Ctr Colorectal Canc, Goyang Si, South Korea. [Ahn, Yoon-Ok] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Kubo, Michiaki] Inst Phys & Chem Res RIKEN, Ctr Genom Med, Yokohama, Kanagawa, Japan. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Shin, Aesun/E-9145-2014; Kubo, Michiaki/N-7947-2015; OI Shin, Aesun/0000-0002-6426-1969; Matsuda, Koichi/0000-0001-7292-2686; Matsuo, Keitaro/0000-0003-1761-6314 FU US National Institutes of Health [R37CA070867, R01CA082729, R01CA124558, R01CA148667, R01CA122364]; Vanderbilt University School of Medicine; Shanghai Women's Health Study [R37CA070867]; Shanghai Men's Health Study [R01CA082729]; Shanghai Breast and Endometrial Cancer Studies [R01CA064277, R01CA092585]; Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project) [2011ZX09307-001-04]; National Basic Research Program [2011CB504303]; Natural Science Foundation of China [81072383]; Aichi Colorectal Cancer Study; Grant for the Third Term Comprehensive Control Research for Cancer; Japanese Ministry of Education, Culture, Sports, Science and Technology [17015018, 221S0001]; Korea-NCC Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea) [2010-0010276]; Korea-NCC Colorectal Cancer Study (National Cancer Center Korea) [0910220]; Japan-BioBank Colorectal Cancer Study (Ministry of Education, Culture, Sports, Science and Technology of the Japanese government); KCPS-II colorectal cancer study (National R&D Program for cancer control) [0920330]; KCPS-II colorectal cancer study (Seoul RD Program) [10526]; Korea-Seoul Colorectal Cancer Study; Singapore Chinese Study [NMRC/1193/2008] FX The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The authors wish to thank the study participants and research staff for their contributions and commitment to this project, Regina Courtney for DNA preparation, Jing He for data processing and analyses, and Mary Jo Daly for clerical support in manuscript preparation. This research was supported in part by US National Institutes of Health grants R37CA070867, R01CA082729, R01CA124558, R01CA148667 and R01CA122364, as well as Ingram Professorship and Research Reward funds from the Vanderbilt University School of Medicine. Participating studies (grant support) in the consortium are as follows: Shanghai Women's Health Study (R37CA070867), Shanghai Men's Health Study (R01CA082729), Shanghai Breast and Endometrial Cancer Studies (R01CA064277 and R01CA092585, contributing only controls), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project-2011ZX09307-001-04; the National Basic Research Program-2011CB504303, contributing only controls; the Natural Science Foundation of China-81072383, contributing only controls), Aichi Colorectal Cancer Study (Grant-in-aid for Cancer Research, the Grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Nos. 17015018 and 221S0001), Korea-NCC Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276 and National Cancer Center Korea, 0910220), Japan-BioBank Colorectal Cancer Study (Grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), KCPS-II colorectal cancer study (National R&D Program for cancer control, 0920330; Seoul R&D Program, 10526), Korea-Seoul Colorectal Cancer Study (none reported) and Singapore Chinese Study (NMRC/1193/2008). NR 41 TC 20 Z9 21 U1 0 U2 8 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 AUG 15 PY 2014 VL 135 IS 4 BP 948 EP 955 DI 10.1002/ijc.28733 PG 8 WC Oncology SC Oncology GA AJ3ZL UT WOS:000337607600019 PM 24448986 ER PT J AU Zhu, JQ Chin, K Aerbajinai, W Kumkhaek, C Li, HZ Rodgers, GP AF Zhu, Jianqiong Chin, Kyung Aerbajinai, Wulin Kumkhaek, Chutima Li, Hongzhen Rodgers, Griffin P. TI Hydroxyurea-inducible SAR1 gene acts through the Gi alpha/JNK/Jun pathway to regulate gamma-globin expression SO BLOOD LA English DT Article ID SICKLE-CELL-DISEASE; NF-KAPPA-B; BETA-THALASSEMIA MAJOR; HUMAN ERYTHROID-CELLS; FETAL-HEMOGLOBIN; K562 CELLS; INDUCED DIFFERENTIATION; ERYTHROLEUKEMIA-CELLS; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION AB Hydroxyurea (HU) is effectively used in the management of beta-hemoglobinopathies by augmentingthe productionof fetal hemoglobin (HbF). However, themolecularmechanisms underlying HU-mediated HbF regulation remain unclear. We previously reported that overexpression of the HU-induced SAR1 gene closelymimics the known effects of HU on K562 and CD34(+) cells, including gamma-globin induction and cell-cycle regulation. Here, we show thatHUstimulated nuclear factor-kappa B interaction with its cognate-binding site on the SAR1 promoter to regulate transcriptional expression of SAR1 in K562 and CD34(+) cells. Silencing SAR1 expression not only significantly lowered both basal and HU-elicited HbF production in K562 and CD34(+) cells, but also significantly reduced HU-mediated S-phase cell-cycle arrest and apoptosis in K562 cells. Inhibition of c-Jun N-terminal kinase (JNK)/ Jun phosphorylation and silencing of Gi alpha expression in SAR1-transfected K562 and CD34(+) cells reduced both gamma-globin expression and HbF level, indicating that activation of Gi alpha/JNK/Jun proteins is required for SAR1-mediated HbF induction. Furthermore, reciprocal coimmunoprecipitation assays revealed an association between forcibly expressed SAR1 and Gi alpha 2 or Gi alpha 3 proteins in both K562 and nonerythroid cells. These results indicate that HU induces SAR1, which in turn activates gamma-globin expression, predominantly through the Gi alpha/JNK/Jun pathway. Our findings identify SAR1 as an alternative therapeutic target for beta-globin disorders. C1 [Zhu, Jianqiong; Chin, Kyung; Aerbajinai, Wulin; Kumkhaek, Chutima; Li, Hongzhen; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,10 Ctr Dr, Bethesda, MD 20892 USA. EM gr5n@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 49 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD AUG 14 PY 2014 VL 124 IS 7 BP 1146 EP 1156 DI 10.1182/blood-2013-10-534842 PG 11 WC Hematology SC Hematology GA AQ2MQ UT WOS:000342621100027 PM 24914133 ER PT J AU Purev, E Winkler, T Danner, RL Fahle, GA Cook, L Zerr, DM Jerome, KR Childs, RW AF Purev, Enkhtsetseg Winkler, Thomas Danner, Robert L. Fahle, Gary A. Cook, Linda Zerr, Danielle M. Jerome, Keith R. Childs, Richard W. TI Engraftment of donor cells with germ-line integration of HHV6 mimics HHV6 reactivation following cord blood/haplo transplantation SO BLOOD LA English DT Letter ID HUMAN-HERPESVIRUS 6; CHROMOSOMAL INTEGRATION; HUMAN-HERPESVIRUS-6 C1 [Purev, Enkhtsetseg; Winkler, Thomas; Childs, Richard W.] NHLBI, NIH, Bethesda, MD 20814 USA. [Danner, Robert L.] NIH, Funct Genom & Prote Facil, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Fahle, Gary A.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Cook, Linda; Jerome, Keith R.] Univ Washington, Dept Lab Med, Med Ctr, Seattle, WA 98195 USA. [Zerr, Danielle M.] Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Jerome, Keith R.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. RP Childs, RW (reprint author), NHLBI, NIH, 10 Ctr Dr,Rm 3E-5330, Bethesda, MD 20814 USA. EM childsr@nih.gov FU Intramural NIH HHS NR 8 TC 1 Z9 1 U1 1 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 14 PY 2014 VL 124 IS 7 BP 1198 EP 1199 DI 10.1182/blood-2014-06-577684 PG 2 WC Hematology SC Hematology GA AQ2MQ UT WOS:000342621100034 PM 25124787 ER PT J AU Mehta, NN Matthews, GJ Krishnamoorthy, P Shah, R McLaughlin, C Patel, P Budoff, M Chen, J Wolman, M Go, A He, J Kanetsky, PA Master, SR Rader, DJ Raj, D Gadegbeku, CA Shah, R Schreiber, M Fischer, MJ Townsend, RR Kusek, J Feldman, HI Foulkes, AS Reilly, MP AF Mehta, Nehal N. Matthews, Gregory J. Krishnamoorthy, Parasuram Shah, Rhia McLaughlin, Catherine Patel, Parth Budoff, Matthew Chen, Jing Wolman, Melanie Go, Alan He, Jiang Kanetsky, Peter A. Master, Stephen R. Rader, Daniel J. Raj, Dominic Gadegbeku, Crystal A. Shah, Rachana Schreiber, Marty Fischer, Michael J. Townsend, Raymond R. Kusek, John Feldman, Harold I. Foulkes, Andrea S. Reilly, Muredach P. CA Chronic Renal Insufficiency Cohort TI Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study SO EUROPEAN HEART JOURNAL LA English DT Article DE Atherosclerosis; Chemokines; Myocardial infarction; CXCL12 ID CORONARY-ARTERY-DISEASE; CELL-DERIVED FACTOR-1-ALPHA; BASE-LINE CHARACTERISTICS; ASSOCIATION ANALYSIS; PROGENITOR CELLS; ATHEROSCLEROSIS; CHEMOKINE; CXCR7; RISK; RECRUITMENT AB Aims Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown. Methods and results We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin: creatinine ratio. Conclusions In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials. C1 [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Matthews, Gregory J.; Foulkes, Andrea S.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Krishnamoorthy, Parasuram; Shah, Rhia; McLaughlin, Catherine; Patel, Parth; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Budoff, Matthew] Los Angeles Biomed Res Inst, Torrancem, CA USA. [Chen, Jing; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. [Wolman, Melanie; Kanetsky, Peter A.; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Go, Alan] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Master, Stephen R.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Raj, Dominic] George Washington Univ, Washington, DC USA. [Gadegbeku, Crystal A.] Temple Univ, Sch Med, Dept Med, Philadelphia, PA 19122 USA. [Shah, Rachana] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Schreiber, Marty] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Fischer, Michael J.] Jesse Brown VA Med Ctr, Dept Med, Chicago, IL USA. [Fischer, Michael J.] Univ Hosp & Hlth Sci Syst, Chicago, IL USA. [Fischer, Michael J.] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Townsend, Raymond R.; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Kusek, John] NIDDK, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov; muredach@mail.med.upenn.edu OI Krishnamoorthy, Parasuram/0000-0002-4560-7346; Shah, Rachana/0000-0001-7866-557X FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; University of Pennsylvania [CTRC CTSA UL1 RR-024134]; Johns Hopkins University [UL1 RR-025005]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1RR024986]; University of Illinois at Chicago [CTSA UL1RR029879]; Clinical and Translational Research, Education, and Commercialization Project (CTRECP); Kaiser NIH/NCRR [UCSF-CTSI UL1 RR-024131]; National Institutes of Health Intramural Award [HL-Z0000]; Department of Veterans Affairs Health Services Research and Development Service Award; [R01-DK071224]; [K24-DK002651]; [R01-HL107196]; [K24-HL107643]; [R01-DK090505]; [U01-HL108636]; [R01-HL113147] FX This work was supported under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). This work was supported in part by: the University of Pennsylvania (CTRC CTSA UL1 RR-024134), Johns Hopkins University (UL1 RR-025005), University of Maryland (GCRC M01 RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1TR000439) from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) (UL1RR024986), University of Illinois at Chicago (CTSA UL1RR029879), The Clinical and Translational Research, Education, and Commercialization Project (CTRECP), Kaiser NIH/NCRR (UCSF-CTSI UL1 RR-024131). This work was supported directly by R01-DK071224 (to M.P.R.). N.N.M. is supported by National Institutes of Health Intramural Award HL-Z0000. M.J.F. is supported by a Department of Veterans Affairs Health Services Research and Development Service Award. H.F. is supported by K24-DK002651. A.F. is supported by R01-HL107196. M.P.R. is also supported by K24-HL107643, R01-DK090505, U01-HL108636, and R01-HL113147. NR 30 TC 12 Z9 12 U1 5 U2 10 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 14 PY 2014 VL 35 IS 31 BP 2115 EP + DI 10.1093/eurheartj/eht481 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP7BM UT WOS:000342232600017 PM 24306482 ER PT J AU Borde, V Lichten, M AF Borde, Valerie Lichten, Michael TI A Timeless but Timely Connection between Replication and Recombination SO CELL LA English DT Editorial Material ID DOUBLE-STRAND BREAKS; DNA; MEIOSIS AB Initiation of meiotic recombination by DNA double-strand break formation is temporally coordinated with replication. Murakami and Keeney show that this coordination requires recruitment of the Dbf4-dependent kinase to the replication fork by the conserved TIM-TIPIN complex. The same mechanism may regulate other important replication-associated processes. C1 [Borde, Valerie] Inst Curie, CNRS, Ctr Rech, UMR3664, F-75248 Paris, France. [Lichten, Michael] NCI, Ctr Canc Res, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. RP Borde, V (reprint author), Inst Curie, CNRS, Ctr Rech, UMR3664, F-75248 Paris, France. EM valerie.borde@curie.fr; mlichten@helix.nih.gov RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 FU Intramural NIH HHS NR 9 TC 1 Z9 1 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 697 EP 698 DI 10.1016/j.cell.2014.07.029 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700002 PM 25126777 ER PT J AU Guo, M Ehrlicher, AJ Jensen, MH Renz, M Moore, JR Goldman, RD Lippincott-Schwartz, J Mackintosh, FC Weitz, DA AF Guo, Ming Ehrlicher, Allen J. Jensen, Mikkel H. Renz, Malte Moore, Jeffrey R. Goldman, Robert D. Lippincott-Schwartz, Jennifer Mackintosh, Frederick C. Weitz, David A. TI Probing the Stochastic, Motor-Driven Properties of the Cytoplasm Using Force Spectrum Microscopy SO CELL LA English DT Article ID BREAST-CANCER CELLS; LIVING CELLS; MOLECULAR MOTORS; CHROMOSOMAL LOCI; DIFFUSION; MECHANICS; DYNAMICS; MICRORHEOLOGY; SPECTROSCOPY; MIGRATION AB Molecular motors in cells typically produce highly directed motion; however, the aggregate, incoherent effect of all active processes also creates randomly fluctuating forces, which drive diffusive-like, non-thermal motion. Here, we introduce force-spectrum-microscopy (FSM) to directly quantify random forces within the cytoplasm of cells and thereby probe stochastic motor activity. This technique combines measurements of the random motion of probe particles with independent micromechanical measurements of the cytoplasm to quantify the spectrum of force fluctuations. Using FSM, we show that force fluctuations substantially enhance intracellular movement of small and large components. The fluctuations are three times larger in malignant cells than in their benign counterparts. We further demonstrate that vimentin acts globally to anchor organelles against randomly fluctuating forces in the cytoplasm, with no effect on their magnitude. Thus, FSM has broad applications for understanding the cytoplasm and its intracellular processes in relation to cell physiology in healthy and diseased states. C1 [Guo, Ming; Ehrlicher, Allen J.; Jensen, Mikkel H.; Weitz, David A.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Ehrlicher, Allen J.] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Jensen, Mikkel H.; Moore, Jeffrey R.] Boston Univ, Dept Phys & Biophys, Boston, MA 02118 USA. [Renz, Malte; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Goldman, Robert D.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Mackintosh, Frederick C.] Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands. [Weitz, David A.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. RP Weitz, DA (reprint author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM weitz@seas.harvard.edu RI guo, ming/D-4564-2015; MacKintosh, Fred/A-9450-2008 OI MacKintosh, Fred/0000-0002-2607-9541 FU NIH [PO1GM096971, DK083592, HL86655, HL077280]; Harvard Materials Research Science and Engineering Center [DMR-0820484]; NSF [DMR-1310266]; FOM/NWO; Hannah's Hope Fund FX We thank A. Rowat, S. Lindstrom, K. Kasza for helpful discussions; we thank F. Deng and A. Pegoraro for comments on the manuscript. This work was supported by the NIH (PO1GM096971), the Harvard Materials Research Science and Engineering Center (DMR-0820484), the NSF (DMR-1310266). A.J.E. was supported by NIH grant DK083592; M.H.J. and J.R.M. were supported by NIH grants HL86655 and HL077280; F.C.M. was supported in part by FOM/NWO. R.D.G. was supported by NIH PO1GM096971 and Hannah's Hope Fund. NR 55 TC 85 Z9 85 U1 17 U2 82 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 822 EP 832 DI 10.1016/j.cell.2014.06.051 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700013 PM 25126787 ER PT J AU Deng, WL Rupon, JW Krivega, I Breda, L Motta, I Jahn, KS Reik, A Gregory, PD Rivella, S Dean, A Blobel, GA AF Deng, Wulan Rupon, Jeremy W. Krivega, Ivan Breda, Laura Motta, Irene Jahn, Kristen S. Reik, Andreas Gregory, Philip D. Rivella, Stefano Dean, Ann Blobel, Gerd A. TI Reactivation of Developmentally Silenced Globin Genes by Forced Chromatin Looping SO CELL LA English DT Article ID SICKLE-CELL-DISEASE; LOCUS-CONTROL REGION; FETAL-HEMOGLOBIN EXPRESSION; TRANSCRIPTION FACTOR GATA-1; LONG-RANGE INTERACTIONS; ADULT ERYTHROID-CELLS; GAMMA-GLOBIN; TRANSGENIC MICE; RISK-FACTORS; BCL11A AB Distal enhancers commonly contact target promoters via chromatin looping. In erythroid cells, the locus control region (LCR) contacts beta-type globin genes in a developmental stage-specific manner to stimulate transcription. Previously, we induced LCR-promoter looping by tethering the self-association domain (SA) of Ldb1 to the beta-globin promoter via artificial zinc fingers. Here, we show that targeting the SA to a developmentally silenced embryonic globin gene in adult murine erythroblasts triggers its transcriptional reactivation. This activity depends on the LCR, consistent with an LCR-promoter looping mechanism. Strikingly, targeting the SA to the fetal gamma-globin promoter in primary adult human erythroblasts increases gamma-globin promoter-LCR contacts, stimulating transcription to approximately 85% of total beta-globin synthesis, with a reciprocal reduction in adult beta-globin expression. Our findings demonstrate that forced chromatin looping can override a stringent developmental gene expression program and suggest a novel approach to control the balance of globin gene transcription for therapeutic applications. C1 [Deng, Wulan; Rupon, Jeremy W.; Jahn, Kristen S.; Blobel, Gerd A.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Deng, Wulan] Howard Hughes Med Inst, Transcript Imaging Consortium, Ashburn, VA 20147 USA. [Krivega, Ivan; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Breda, Laura; Motta, Irene; Rivella, Stefano] Weill Cornell Med Coll, Dept Pediat, Div Hematol Oncol, New York, NY 10021 USA. [Reik, Andreas; Gregory, Philip D.] Sangamo BioSci, Richmond, CA 94804 USA. [Rivella, Stefano] Weill Cornell Med Coll, Dept Cell & Biol Dev, Div Hematol Oncol, New York, NY 10021 USA. [Blobel, Gerd A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Blobel, GA (reprint author), Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. EM blobel@email.chop.edu RI Krivega, Ivan/G-9247-2015 OI Krivega, Ivan/0000-0002-3473-4198 FU NIH [5R37DK058044, 1RO1HL119479, NHLBI-5R01HL102449, DK015508]; American Heart Association postdoctoral fellowship [13POST16950014]; NIDDK; Associazione Veneta per la Lotta alla Talassemia (AVLT, IT); European Community [FP7-HEALTH-2012-INNOVATION] FX We thank Andrew Wilber for the GG1 constructs. We are grateful to Hongxin Wang for technical assistance, Jongjoo Lee for help with mouse experiments, and members of the laboratory for valuable discussions. This work was supported by NIH grants (5R37DK058044 and 1RO1HL119479) (to G.A.B.). J.W.R. was supported by an American Heart Association postdoctoral fellowship (13POST16950014). A.D. and I.K. were supported by the intramural program of the NIDDK, NIH (DK015508). Additional support was provided by the Associazione Veneta per la Lotta alla Talassemia (AVLT, IT) (to L.B.), by an NIH grant (NHLBI-5R01HL102449) (to S.R.), and by a European Community grant (FP7-HEALTH-2012-INNOVATION) (to L.B. and S.R.). A.R. and P.D.G. are employees of Sangamo Biosciences Inc. NR 47 TC 75 Z9 76 U1 5 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 849 EP 860 DI 10.1016/j.cell.2014.05.050 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700015 PM 25126789 ER PT J AU Lisewski, AM Quiros, JP Ng, CL Adikesavan, AK Miura, K Putluri, N Eastman, RT Scanfeld, D Regenbogen, SJ Altenhofen, L Llinas, M Sreekumar, A Long, C Fidock, DA Lichtarge, O AF Lisewski, Andreas Martin Quiros, Joel P. Ng, Caroline L. Adikesavan, Anbu Karani Miura, Kazutoyo Putluri, Nagireddy Eastman, Richard T. Scanfeld, Daniel Regenbogen, Sam J. Altenhofen, Lindsey Llinas, Manuel Sreekumar, Arun Long, Carole Fidock, David A. Lichtarge, Olivier TI Supergenomic Network Compression and the Discovery of EXP1 as a Glutathione Transferase Inhibited by Artesunate SO CELL LA English DT Article ID PARASITE PLASMODIUM-FALCIPARUM; PROTEIN FUNCTION PREDICTION; HUMAN MALARIA PARASITE; OXIDATIVE STRESS; BLOOD STAGES; IN-VITRO; ARTEMISININ; MECHANISM; SEQUENCE; METABOLISM AB A central problem in biology is to identify gene function. One approach is to infer function in large supergenomic networks of interactions and ancestral relationships among genes; however, their analysis can be computationally prohibitive. We show here that these biological networks are compressible. They can be shrunk dramatically by eliminating redundant evolutionary relationships, and this process is efficient because in these networks the number of compressible elements rises linearly rather than exponentially as in other complex networks. Compression enables global network analysis to computationally harness hundreds of interconnected genomes and to produce functional predictions. As a demonstration, we show that the essential, but functionally uncharacterized Plasmodium falciparum antigen EXP1 is a membrane glutathione S-transferase. EXP1 efficiently degrades cytotoxic hematin, is potently inhibited by artesunate, and is associated with artesunate metabolism and susceptibility in drug-pressured malaria parasites. These data implicate EXP1 in the mode of action of a frontline antimalarial drug. C1 [Lisewski, Andreas Martin; Adikesavan, Anbu Karani; Lichtarge, Olivier] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Lisewski, Andreas Martin; Lichtarge, Olivier] Baylor Coll Med, Computat & Integrat Biomed Res Ctr, Houston, TX 77030 USA. [Quiros, Joel P.] Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA. [Adikesavan, Anbu Karani; Putluri, Nagireddy; Sreekumar, Arun] Baylor Coll Med, Dept Cell & Mol Biol, Houston, TX 77030 USA. [Putluri, Nagireddy; Sreekumar, Arun; Lichtarge, Olivier] Baylor Coll Med, Verna & Marrs McLean Dept Biochem, Houston, TX 77030 USA. [Putluri, Nagireddy; Sreekumar, Arun; Lichtarge, Olivier] Baylor Coll Med, Alkek Ctr Mol Discovery, Houston, TX 77030 USA. [Sreekumar, Arun] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Regenbogen, Sam J.; Lichtarge, Olivier] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Ng, Caroline L.; Eastman, Richard T.; Scanfeld, Daniel; Fidock, David A.] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Fidock, David A.] Columbia Univ, Med Ctr, Dept Med, Div Infect Dis, New York, NY 10032 USA. [Miura, Kazutoyo; Eastman, Richard T.; Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Altenhofen, Lindsey; Llinas, Manuel] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Altenhofen, Lindsey; Llinas, Manuel] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Altenhofen, Lindsey; Llinas, Manuel] Penn State Univ, Dept Biochem & Mol Biol, State Coll, PA 16802 USA. [Altenhofen, Lindsey; Llinas, Manuel] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA 16802 USA. RP Lisewski, AM (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM lisewski@bcm.edu; lichtarge@bcm.edu FU NIH [GM066099, GM079656, AI50234, AI109023]; NSF [CCF-0905536, DBI-1062455]; Alkek CMD Grants; Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Burroughs Wellcome Fund Investigators in Pathogenesis of Infectious Disease Grant; NIH Director's New Innovators award [1DP2OD001315-01]; Centre for Quantitative Biology [P50 GM071508] FX Financial support came from NIH GM066099 and GM079656 and NSF CCF-0905536, DBI-1062455 (to O.L.) and from NIH AI50234 and AI109023 (to D. A. F.). N.P. and A.S. were supported by Alkek CMD Grants. K.M., R.E., and C.L. were supported by the Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. M.L. is funded through a Burroughs Wellcome Fund Investigators in Pathogenesis of Infectious Disease Grant and an NIH Director's New Innovators award (1DP2OD001315-01) with generous support from the Centre for Quantitative Biology (P50 GM071508). The authors gratefully acknowledge comments and help from Dr. Theodore Wensel, Dr. Christophe Herman, Dr. Timothy Palzkill, Dr. Santha Kumar, and Dr. David Marciano. NR 55 TC 18 Z9 19 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 916 EP 928 DI 10.1016/j.cell.2014.07.011 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700020 PM 25126794 ER PT J AU Hoadley, KA Yau, C Wolf, DM Cherniack, AD Tamborero, D Ng, S Leiserson, MDM Niu, BF McLellan, MD Uzunangelov, V Zhang, JS Kandoth, C Akbani, R Shen, H Omberg, L Chu, A Margolin, AA van't Veer, LJ Lopez-Bigas, N Laird, PW Raphael, BJ Ding, L Robertson, AG Byers, LA Mills, GB Weinstein, JN Van Waes, C Chen, Z Collisson, EA Benz, CC Perou, CM Stuart, JM Abbott, R Abbott, S Aksoy, BA Aldape, K Ally, A Amin, S Anastassiou, D Auman, JT Baggerly, KA Balasundaram, M Balu, S Baylin, SB Benz, SC Berman, BP Bernard, B Bhatt, AS Birol, I Black, AD Bodenheimer, T Bootwalla, MS Bowen, J Bressler, R Bristow, CA Brooks, AN Broom, B Buda, E Burton, R Butterfield, YSN Carlin, D Carter, SL Casasent, TD Chang, K Chanock, S Chin, L Cho, DY Cho, J Chuah, E Chun, HJE Cibulskis, K Ciriello, G Cleland, J Cline, M Craft, B Creighton, CJ Danilova, L Davidsen, T Davis, C Dees, ND Delehaunty, K Demchok, JA Dhalla, N DiCara, D Dinh, H Dobson, JR Dodda, D Doddapaneni, H Donehower, L Dooling, DJ Dresdner, G Drummond, J Eakin, A Edgerton, M Eldred, JM Eley, G Ellrott, K Fan, C Fei, S Felau, I Frazer, S Freeman, SS Frick, J Fronick, CC Fulton, LL Fulton, R Gabriel, SB Gao, JJ Gastier-Foster, JM Gehlenborg, N George, M Getz, G Gibbs, R Goldman, M Gonzalez-Perez, A Gross, B Guin, R Gunaratne, P Hadjipanayis, A Hamilton, MP Hamilton, SR Han, L Han, Y Harper, HA Haseley, P Haussler, D Hayes, DN Heiman, DI Helman, E Helsel, C Herbrich, SM Herman, JG Hinoue, T Hirst, C Hirst, M Holt, RA Hoyle, AP Iype, L Jacobsen, A Jeffreys, SR Jensen, MA Jones, CD Jones, SJM Ju, ZL Jung, J Kahles, A Kahn, A Kalicki-Veizer, J Kalra, D Kanchi, KL Kane, DW Kim, H Kim, J Knijnenburg, T Koboldt, DC Kovar, C Kramer, R Kreisberg, R Kucherlapati, R Ladanyi, M Lander, ES Larson, DE Lawrence, MS Lee, D Lee, E Lee, S Lee, W Lehmann, KV Leinonen, K Leraas, KM Lerner, S Levine, DA Lewis, L Ley, TJ Li, HI Li, J Li, W Liang, H Lichtenberg, TM Lin, J Lin, L Lin, P Liu, WB Liu, YC Liu, YX Lorenzi, PL Lu, C Lu, YL Luquette, LJ Ma, S Magrini, VJ Mahadeshwar, HS Mardis, ER Margolin, A Marra, MA Mayo, M McAllister, C McGuire, SE McMichael, JF Melott, J Meng, SW Meyerson, M Mieczkowski, PA Miller, CA Miller, ML Miller, M Moore, RA Morgan, M Morton, D Mose, LE Mungall, AJ Muzny, D Nguyen, L Noble, MS Noushmehr, H O'Laughlin, M Ojesina, AI Yang, TO Ozenberger, B Pantazi, A Parfenov, M Park, PJ Parker, JS Paull, E Pedamallu, CS Pihl, T Pohl, C Pot, D Protopopov, A Przytycka, T Radenbaugh, A Ramirez, NC Ramirez, R Ratsch, G Reid, J Ren, XJ Reva, B Reynolds, SM Rhie, SK Roach, J Rovira, H Ryan, M Saksena, G Salama, S Sander, C Santoso, N Schein, JE Schmidt, H Schultz, N Schumacher, SE Seidman, J Senbabaoglu, Y Seth, S Sharpe, S Shen, RL Sheth, M Shi, Y Shmulevich, I Silva, GO Simons, JV Sinha, R Sipahimalani, P Smith, SM Sofia, HJ Sokolov, A Soloway, MG Song, XZ Sougnez, C Spellman, P Staudt, L Stewart, C Stojanov, P Su, XP Sumer, SO Sun, YC Swatloski, T Tabak, B Tam, A Tan, DH Tang, JB Tarnuzzer, R Taylor, BS Thiessen, N Thorsson, V Triche, T Van Den Berg, DJ Vandin, F Varhol, RJ Vaske, CJ Veluvolu, U Verhaak, R Voet, D Walker, J Wallis, JW Waltman, P Wan, YH Wang, M Wang, WY Wang, ZN Waring, S Weinhold, N Weisenberger, DJ Wendl, MC Wheeler, D Wilkerson, MD Wilson, RK Wise, L Wong, A Wu, CJ Wu, CC Wu, HT Wu, JY Wylie, T Xi, L Xi, RB Xia, Z Xu, AW Yang, D Yang, LM Yang, LX Yang, Y Yao, J Yao, R Ye, K Yoshihara, K Yuan, Y Yung, AK Zack, T Zeng, D Zenklusen, JC Zhang, HL Zhang, JH Zhang, NX Zhang, QY Zhang, W Zhao, W Zheng, SY Zhu, J Zmuda, E Zou, LH AF Hoadley, Katherine A. Yau, Christina Wolf, Denise M. Cherniack, Andrew D. Tamborero, David Ng, Sam Leiserson, Max D. M. Niu, Beifang McLellan, Michael D. Uzunangelov, Vladislav Zhang, Jiashan Kandoth, Cyriac Akbani, Rehan Shen, Hui Omberg, Larsson Chu, Andy Margolin, Adam A. van't Veer, Laura J. Lopez-Bigas, Nuria Laird, Peter W. Raphael, Benjamin J. Ding, Li Robertson, A. Gordon Byers, Lauren A. Mills, Gordon B. Weinstein, John N. Van Waes, Carter Chen, Zhong Collisson, Eric A. Benz, Christopher C. Perou, Charles M. Stuart, Joshua M. Abbott, Rachel Abbott, Scott Aksoy, B. Arman Aldape, Kenneth Ally, Adrian Amin, Samirkumar Anastassiou, Dimitris Auman, J. Todd Baggerly, Keith A. Balasundaram, Miruna Balu, Saianand Baylin, Stephen B. Benz, Stephen C. Berman, Benjamin P. Bernard, Brady Bhatt, Ami S. Birol, Inanc Black, Aaron D. Bodenheimer, Tom Bootwalla, Moiz S. Bowen, Jay Bressler, Ryan Bristow, Christopher A. Brooks, Angela N. Broom, Bradley Buda, Elizabeth Burton, Robert Butterfield, Yaron S. N. Carlin, Daniel Carter, Scott L. Casasent, Tod D. Chang, Kyle Chanock, Stephen Chin, Lynda Cho, Dong-Yeon Cho, Juok Chuah, Eric Chun, Hye-Jung E. Cibulskis, Kristian Ciriello, Giovanni Cleland, James Cline, Melisssa Craft, Brian Creighton, Chad J. Danilova, Ludmila Davidsen, Tanja Davis, Caleb Dees, Nathan D. Delehaunty, Kim Demchok, John A. Dhalla, Noreen DiCara, Daniel Dinh, Huyen Dobson, Jason R. Dodda, Deepti Doddapaneni, HarshaVardhan Donehower, Lawrence Dooling, David J. Dresdner, Gideon Drummond, Jennifer Eakin, Andrea Edgerton, Mary Eldred, Jim M. Eley, Greg Ellrott, Kyle Fan, Cheng Fei, Suzanne Felau, Ina Frazer, Scott Freeman, Samuel S. Frick, Jessica Fronick, Catrina C. Fulton, Lucinda L. Fulton, Robert Gabriel, Stacey B. Gao, Jianjiong Gastier-Foster, Julie M. Gehlenborg, Nils George, Myra Getz, Gad Gibbs, Richard Goldman, Mary Gonzalez-Perez, Abel Gross, Benjamin Guin, Ranabir Gunaratne, Preethi Hadjipanayis, Angela Hamilton, Mark P. Hamilton, Stanley R. Han, Leng Han, Yi Harper, Hollie A. Haseley, Psalm Haussler, David Hayes, D. Neil Heiman, David I. Helman, Elena Helsel, Carmen Herbrich, Shelley M. Herman, James G. Hinoue, Toshinori Hirst, Carrie Hirst, Martin Holt, Robert A. Hoyle, Alan P. Iype, Lisa Jacobsen, Anders Jeffreys, Stuart R. Jensen, Mark A. Jones, Corbin D. Jones, Steven J. M. Ju, Zhenlin Jung, Joonil Kahles, Andre Kahn, Ari Kalicki-Veizer, Joelle Kalra, Divya Kanchi, Krishna-Latha Kane, David W. Kim, Hoon Kim, Jaegil Knijnenburg, Theo Koboldt, Daniel C. Kovar, Christie Kramer, Roger Kreisberg, Richard Kucherlapati, Raju Ladanyi, Marc Lander, Eric S. Larson, David E. Lawrence, Michael S. Lee, Darlene Lee, Eunjung Lee, Semin Lee, William Lehmann, Kjong-Van Leinonen, Kalle Leraas, Kristen M. Lerner, Seth Levine, Douglas A. Lewis, Lora Ley, Timothy J. Li, Haiyan I. Li, Jun Li, Wei Liang, Han Lichtenberg, Tara M. Lin, Jake Lin, Ling Lin, Pei Liu, Wenbin Liu, Yingchun Liu, Yuexin Lorenzi, Philip L. Lu, Charles Lu, Yiling Luquette, Lovelace J. Ma, Singer Magrini, Vincent J. Mahadeshwar, Harshad S. Mardis, Elaine R. Margolin, Adam Marra, Marco A. Mayo, Michael McAllister, Cynthia McGuire, Sean E. McMichael, Joshua F. Melott, James Meng, Shaowu Meyerson, Matthew Mieczkowski, Piotr A. Miller, Christopher A. Miller, Martin L. Miller, Michael Moore, Richard A. Morgan, Margaret Morton, Donna Mose, Lisle E. Mungall, Andrew J. Muzny, Donna Nguyen, Lam Noble, Michael S. Noushmehr, Houtan O'Laughlin, Michelle Ojesina, Akinyemi I. Yang, TaiHsien Ou Ozenberger, Brad Pantazi, Angeliki Parfenov, Michael Park, Peter J. Parker, Joel S. Paull, Evan Pedamallu, Chandra Sekhar Pihl, Todd Pohl, Craig Pot, David Protopopov, Alexei Przytycka, Teresa Radenbaugh, Amie Ramirez, Nilsa C. Ramirez, Ricardo Ratsch, Gunnar Reid, Jeffrey Ren, Xiaojia Reva, Boris Reynolds, Sheila M. Rhie, Suhn K. Roach, Jeffrey Rovira, Hector Ryan, Michael Saksena, Gordon Salama, Sofie Sander, Chris Santoso, Netty Schein, Jacqueline E. Schmidt, Heather Schultz, Nikolaus Schumacher, Steven E. Seidman, Jonathan Senbabaoglu, Yasin Seth, Sahil Sharpe, Samantha Shen, Ronglai Sheth, Margi Shi, Yan Shmulevich, Ilya Silva, Grace O. Simons, Janae V. Sinha, Rileen Sipahimalani, Payal Smith, Scott M. Sofia, Heidi J. Sokolov, Artem Soloway, Mathew G. Song, Xingzhi Sougnez, Carrie Spellman, Paul Staudt, Louis Stewart, Chip Stojanov, Petar Su, Xiaoping Sumer, S. Onur Sun, Yichao Swatloski, Teresa Tabak, Barbara Tam, Angela Tan, Donghui Tang, Jiabin Tarnuzzer, Roy Taylor, Barry S. Thiessen, Nina Thorsson, Vesteinn Triche, Timothy, Jr. Van Den Berg, David J. Vandin, Fabio Varhol, Richard J. Vaske, Charles J. Veluvolu, Umadevi Verhaak, Roeland Voet, Doug Walker, Jason Wallis, John W. Waltman, Peter Wan, Yunhu Wang, Min Wang, Wenyi Wang, Zhining Waring, Scot Weinhold, Nils Weisenberger, Daniel J. Wendl, Michael C. Wheeler, David Wilkerson, Matthew D. Wilson, Richard K. Wise, Lisa Wong, Andrew Wu, Chang-Jiun Wu, Chia-Chin Wu, Hsin-Ta Wu, Junyuan Wylie, Todd Xi, Liu Xi, Ruibin Xia, Zheng Xu, Andrew W. Yang, Da Yang, Liming Yang, Lixing Yang, Yang Yao, Jun Yao, Rong Ye, Kai Yoshihara, Kosuke Yuan, Yuan Yung, Alfred K. Zack, Travis Zeng, Dong Zenklusen, Jean Claude Zhang, Hailei Zhang, Jianhua Zhang, Nianxiang Zhang, Qunyuan Zhang, Wei Zhao, Wei Zheng, Siyuan Zhu, Jing Zmuda, Erik Zou, Lihua CA Canc Genome Atlas Res Network TI Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin SO CELL LA English DT Article ID CELL LUNG-CANCER; COMPREHENSIVE GENOMIC CHARACTERIZATION; BREAST-CANCER; NECK-CANCER; MUTATIONS; CARCINOMA; GENES; PORTRAITS; CISPLATIN; MIGRATION AB Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue'' disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-oforigin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pancancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies. C1 [Hoadley, Katherine A.; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Yau, Christina; Benz, Christopher C.] Buck Inst Res Aging, Novato, CA 94945 USA. [Wolf, Denise M.; van't Veer, Laura J.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94115 USA. [Cherniack, Andrew D.] Harvard & MIT, Eli & Edythe Broad Inst, Cambridge, MA 02142 USA. [Tamborero, David; Lopez-Bigas, Nuria] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Res Unit Biomed Informat, Barcelona 08003, Spain. [Ng, Sam; Uzunangelov, Vladislav; Stuart, Joshua M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Leiserson, Max D. M.; Raphael, Benjamin J.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Leiserson, Max D. M.; Raphael, Benjamin J.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA. [Niu, Beifang; McLellan, Michael D.; Kandoth, Cyriac; Ding, Li] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Zhang, Jiashan] NCI, NIH, Bethesda, MD 20892 USA. [Akbani, Rehan; Byers, Lauren A.; Mills, Gordon B.; Weinstein, John N.] UT MD Anderson Canc Ctr, Houston, TX 77030 USA. [Shen, Hui; Laird, Peter W.] Univ So Calif, Keck Sch Med, Epigenome Ctr, Los Angeles, CA 90033 USA. [Omberg, Larsson; Margolin, Adam A.] Sage Bionetworks, Seattle, WA 98109 USA. [Chu, Andy; Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Lopez-Bigas, Nuria] Catalan Inst Res & Adv Studies ICREA, Barcelona 08010, Spain. [Collisson, Eric A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94148 USA. [Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Perou, Charles M.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Van Waes, Carter] NIDCD, NIH, Bethesda, MD 20892 USA. [Chen, Zhong] NIDCD, NIH, Head & Neck Surg Branch, Bethesda, MD 20892 USA. RP Benz, CC (reprint author), Buck Inst Res Aging, Novato, CA 94945 USA. EM cbenz@buckinstitute.org; cperou@med.unc.edu; jstuart@ucsc.edu RI Vaske, Charles/D-6018-2013; Li, Jun/O-9911-2014; Yuan, Yuan/H-4007-2013; Laird, Peter/G-8683-2012; Jacobsen, Anders/K-1081-2013; Lopez-Bigas, Nuria/F-6193-2011; Holt, Robert/C-3303-2009; tamborero, david/M-5283-2015; Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Gasull, Martina/A-6630-2013; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011 OI Benz, Stephen/0000-0002-4067-0602; Vaske, Charles/0000-0001-8151-6612; Kandoth, Cyriac/0000-0002-1345-3573; Pot, David/0000-0002-1480-9826; Gonzalez-Perez, Abel/0000-0002-8582-4660; Sinha, Rileen/0000-0001-5497-5055; Perou, Charles/0000-0001-9827-2247; Li, Jun/0000-0002-1171-7141; Yuan, Yuan/0000-0003-4706-7897; Jacobsen, Anders/0000-0001-6847-4980; Lopez-Bigas, Nuria/0000-0003-4925-8988; tamborero, david/0000-0002-7218-2806; Birol, Inanc/0000-0003-0950-7839 FU Chapman Foundation; Dell Foundation; MD Anderson Physician Scientist Award; Burroughs Welcome Career Award at the Scientific Interface; United States National Institutes of Health [K08 CA137153, K08 CA176561, P50 CA083639, R01 CA071468, R01 HG005690, R01 HG007069, R01CA180006, R21 CA155679, U01 CA168394, U24 CA143867-05, U24 CA143883, U24 CA143848, U24 CA143858]; [U54 CA112970]; [U24 CA143799]; [U24 CA143835]; [U24 CA143840]; [U24 CA143843]; [U24 CA143845]; [U24 CA143866]; [U24 CA143867]; [U24 CA143882]; [U24 CA144025]; [U54 HG003273]; [U54 HG003067]; [U54 HG003079]; [ZIA-DC-000073]; [ZIA-DC-000074]; [P30 CA016672] FX We thank the thousands of patients and their loved ones who contributed materially, emotionally, and intellectually to this study. We thank D. A. Wheeler and M. L. Meyerson for scientific review of the work and M. P. Schroeder for help setting up Gitools. We thank K. R. Shaw, B. A. Ozenberger, H.J. Sofia, C. M. Hutter, and J.C. Zenklusen for administrative support. This work was supported by grants from the Chapman Foundation and Dell Foundation to J.N.W., a MD Anderson Physician Scientist Award to L. A. B., a Burroughs Welcome Career Award at the Scientific Interface to B. J. R., and support from the following grants from the United States National Institutes of Health: K08 CA137153, K08 CA176561, P50 CA083639, R01 CA071468, R01 HG005690, R01 HG007069, R01CA180006, R21 CA155679, U01 CA168394, U24 CA143858, U24 CA143867-05, U24 CA143883, U24 CA143848, U24 CA143858, U24 CA143866, U54 CA112970, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, U54 HG003273, U54 HG003067, U54 HG003079, ZIA-DC-000073, ZIA-DC-000074, and P30 CA016672 for the MD Anderson CCSG Functional Proteomics Core. NR 39 TC 237 Z9 243 U1 20 U2 78 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 929 EP 944 DI 10.1016/j.cell.2014.06.049 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700021 PM 25109877 ER PT J AU Le Naour, M Lunzer, MM Powers, MD Kalyuzhny, AE Benneyworth, MA Thomas, MJ Portoghese, PS AF Le Naour, Morgan Lunzer, Mary M. Powers, Michael D. Kalyuzhny, Alexander E. Benneyworth, Michael A. Thomas, Mark J. Portoghese, Philip S. TI Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CONDITIONED PLACE PREFERENCE; NAPHTHOYL-BETA-NALTREXAMINE; MORPHINE-TOLERANCE; SALVINORIN-A; 6'-GUANIDINONALTRINDOLE 6'-GNTI; ANTINOCICEPTIVE TOLERANCE; FUNCTIONAL SELECTIVITY; NARCOTIC ANTAGONISTS; NOR-BINALTORPHIMINE AB It is now generally recognized that upon activation by an agonist, beta-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with K opioid agonists, a series of beta-naltrexamides 3-10 was synthesized in an effort to selectively target putative kappa opioid heteromers without recruiting beta-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of beta-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects. C1 [Le Naour, Morgan; Lunzer, Mary M.; Powers, Michael D.; Portoghese, Philip S.] Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55455 USA. [Kalyuzhny, Alexander E.; Benneyworth, Michael A.; Thomas, Mark J.] Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. [Benneyworth, Michael A.; Thomas, Mark J.] Univ Minnesota, NINDS Mouse Behav Phenotyping Core, Minneapolis, MN 55455 USA. RP Portoghese, PS (reprint author), Univ Minnesota, Coll Pharm, Dept Med Chem, WDH 8-114,308 Harvard St SE, Minneapolis, MN 55455 USA. EM porto001@umn.edu FU National Institutes of Health [DA030316, NS062158] FX This research was supported by National Institutes of Health research grants DA030316 (P. P.) and NS062158 (M. J. T.). We also thank Bryan Roth from the NIMH Psychoactive Drug Screening Program (PDSP) University of North Carolina, Chapel Hill, for the competition binding data. NR 95 TC 8 Z9 8 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD AUG 14 PY 2014 VL 57 IS 15 BP 6383 EP 6392 DI 10.1021/jm500159d PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AN2WE UT WOS:000340445900009 PM 24978316 ER PT J AU La Regina, G Bai, RL Coluccia, A Famiglini, V Pelliccia, S Passacantilli, S Mazzoccoli, C Ruggieri, V Sisinni, L Bolognesi, A Rensen, WM Miele, A Nalli, M Alfonsi, R Di Marcotullio, L Gulino, A Brancale, A Novellino, E Dondio, G Vultaggio, S Varasi, M Mercurio, C Hamel, E Lavia, P Silvestri, R AF La Regina, Giuseppe Bai, Ruoli Coluccia, Antonio Famiglini, Valeria Pelliccia, Sveva Passacantilli, Sara Mazzoccoli, Carmela Ruggieri, Vitalba Sisinni, Lorenza Bolognesi, Alessio Rensen, Whilelmina Maria Miele, Andrea Nalli, Marianna Alfonsi, Romina Di Marcotullio, Lucia Gulino, Alberto Brancale, Andrea Novellino, Ettore Dondio, Giulio Vultaggio, Stefania Varasi, Mario Mercurio, Ciro Hamel, Ernest Lavia, Patrizia Silvestri, Romano TI New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MICROTUBULE INHIBITORS; COLCHICINE; BINDING; CELLS; DOMAIN; DRUGS; ACYLTHIOUREA; DISCOVERY; APOPTOSIS; STATHMIN AB We synthesized 3-aroy1-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 343,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light 11 cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. C1 [La Regina, Giuseppe; Coluccia, Antonio; Famiglini, Valeria; Passacantilli, Sara; Nalli, Marianna; Silvestri, Romano] Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Pelliccia, Sveva; Novellino, Ettore] Univ Naples Federico II, Dipartimento Farm, I-80131 Naples, Italy. [Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza] IRCCS, Ctr Riferimento Oncol Basilicata, Lab Ric Preclin & Traslaz, I-85028 Rionero In Vulture, Italy. [Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Lavia, Patrizia] Sapienza Univ Roma, CNR Natl Res Council Italy, Inst Mol Biol & Pathol IBPM, I-00185 Rome, Italy. [Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto] Sapienza Univ Roma, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. [Brancale, Andrea] Cardiff Univ, Cardiff Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales. [Dondio, Giulio] NiKem Res Srl, I-20021 Milan, Italy. [Vultaggio, Stefania; Varasi, Mario] European Inst Oncol, I-20139 Milan, Italy. [Mercurio, Ciro] DAC SRL, Genextra Grp, I-20139 Milan, Italy. RP Silvestri, R (reprint author), Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Piazza Aldo Moro 5, I-00185 Rome, Italy. EM romano.silvestri@uniroma1.it RI La Regina, Giuseppe/I-2161-2012; Brancale, Andrea/N-9445-2014; Sisinni, Lorenza/K-7543-2016; Alfonsi, Romina/C-2641-2017; OI Alfonsi, Romina/0000-0001-5100-5491; /0000-0002-7940-8206; Lavia, Patrizia/0000-0003-3310-6701; La Regina, Giuseppe/0000-0003-3252-1161; Brancale, Andrea/0000-0002-9728-3419; Sisinni, Lorenza/0000-0002-8159-8109; Silvestri, Romano/0000-0003-2489-0178; Passacantilli, Sara/0000-0001-9781-0621; Nalli, Marianna/0000-0003-2774-6868 FU PRIN [2010W7YRLZ_001, 2010W7YRLZ_001006, 2012CSYJSK002]; AIRC [IG 14535, IG14723]; Bando Futuro in Ricerca [RBFR10ZJQT]; Progetti di Ricerca di Universita, Sapienza Universita di Roma [C26H135FL5] FX This research was supported by grants PRIN 2010-2011 (2010W7YRLZ_001 and 2010W7YRLZ_001006), PRIN 2012-2013 (2012CSYJSK002), AIRC IG 14535, AIRC IG14723, Bando Futuro in Ricerca 2010 (grant no. RBFR10ZJQT), and Progetti di Ricerca di Universita, Sapienza Universita di Roma (grant no. C26H135FL5). We are grateful to Giulia Guarguaglini and Italia Anna Asteriti for microscopy analysis. We also thank Professor Claudia Piccoli and to Dr. Matteo Landriscina, University of Foggia, Italy, for providing cell lines. NR 40 TC 13 Z9 13 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD AUG 14 PY 2014 VL 57 IS 15 BP 6531 EP 6552 DI 10.1021/jm500561a PG 22 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AN2WE UT WOS:000340445900020 PM 25025991 ER PT J AU Romagnoli, R Baraldi, PG Salvador, MK Prencipe, F Bertolasi, V Cancellieri, M Brancale, A Hamel, E Castagliuolo, I Consolaro, F Porcu, E Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Salvador, Maria Kimatrai Prencipe, Filippo Bertolasi, Valerio Cancellieri, Michela Brancale, Andrea Hamel, Ernest Castagliuolo, Ignazio Consolaro, Francesca Porcu, Elena Basso, Giuseppe Viola, Giampietro TI Synthesis, Antimitotic and Antivascular Activity of 1-(3 ',4 ',5 '-Trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TUBULIN POLYMERIZATION INHIBITORS; COMBRETASTATIN A-4; BIOLOGICAL EVALUATION; MICROTUBULE STRUCTURE; ANTITUMOR-ACTIVITY; ANTICANCER AGENTS; ENDOTHELIAL-CELLS; IN-VITRO; CANCER; POTENT AB A new class of compounds that incorporated the structural motif of the 1-(3',4',5'-trimethoxtbenzoyl)-3-arylamino-5-amino-1,2,4-triazole molecular skeleton was synthesized and evaluated for their antiproliferative activity in vitro, interactions with tubufin, and cell cycle effects. The most active agent, 3c, was evaluated for antitumor activity in vivo. Structure-activity relationships were elucidated with various substituents on the phenyl ring of the anilino moiety at the C-3 position of the 1,2,4-triazole ring. The best results for inhibition of cancer cell growth were obtained with the p-Me, m,p-diMe, and p-Et phenyl derivatives 3c, 3e, and 3f, respectively, and overall, these compounds were more or less as active as CA-4. Their vascular disrupting activity was evaluated in HUVEC cells, with compound 3c showing activity comparable with that of CA-4. Compound 3c almost eliminated the growth of syngeneic hepatocellular carcinoma in Balb/c mice, suggesting that 3c could be a new antimitotic agent with clinical potential. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Prencipe, Filippo; Bertolasi, Valerio] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44100 Ferrara, Italy. [Consolaro, Francesca; Porcu, Elena; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Lab Oncoematol, Dipartimento Salute Donna & Bambino, Padua, Italy. [Cancellieri, Michela; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm & Pharmaceut Sci, Cardiff CF10 3AX, S Glam, Wales. [Castagliuolo, Ignazio] Univ Padua, Dipartimento Med Mol, Padua, Italy. [Hamel, Ernest] NIH, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Lab Canc Res, Frederick, MD USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.viola1@unipd.it RI Brancale, Andrea/N-9445-2014; Viola, Giampietro/I-4095-2012; Bertolasi, Valerio/F-7490-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; CASTAGLIUOLO, IGNAZIO/K-9963-2016; OI Brancale, Andrea/0000-0002-9728-3419; Viola, Giampietro/0000-0001-9329-165X; Bertolasi, Valerio/0000-0002-7572-3532; CASTAGLIUOLO, IGNAZIO/0000-0001-9888-7030; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Intramural NIH HHS [Z99 CA999999] NR 52 TC 11 Z9 11 U1 1 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD AUG 14 PY 2014 VL 57 IS 15 BP 6795 EP 6808 DI 10.1021/jm5008193 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AN2WE UT WOS:000340445900040 PM 25025853 ER PT J AU Chow, HHS Garland, LL Heckman-Stoddard, BM Hsu, CH Butler, VD Cordova, CA Chew, WM Cornelison, TL AF Chow, H-H Sherry Garland, Linda L. Heckman-Stoddard, Brandy M. Hsu, Chiu-Hsieh Butler, Valerie D. Cordova, Catherine A. Chew, Wade M. Cornelison, Terri L. TI A pilot clinical study of resveratrol in postmenopausal women with high body mass index: effects on systemic sex steroid hormones SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Resveratrol; Sex steroid hormones; High adiposity; Post-menopausal women ID BREAST-CANCER CELLS; ARYL-HYDROCARBON RECEPTOR; RED WINE; FAT DISTRIBUTION; INHIBITION; RISK; METABOLITES; INDOLE-3-CARBINOL; TESTOSTERONE; SPECTROMETRY AB Background: Breast cancer risk is partially determined by several hormone-related factors. Preclinical and clinical studies suggested that resveratrol may modulate these hormonal factors. Methods: We conducted a pilot study in postmenopausal women with high body mass index (BMI >= 25 kg/m(2)) to determine the clinical effect of resveratrol on systemic sex steroid hormones. Forty subjects initiated the resveratrol intervention (1 gm daily for 12 weeks) with six withdrawn early due to adverse events (AEs). Thirty-four subjects completed the intervention. Results: Resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone but led to an average of 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG). Resveratrol intervention resulted in an average of 73% increase in urinary 2-hydroxyestrone (2-OHE1) levels leading to a favorable change in urinary 2-OHE1/16 alpha-OHE1 ratio. One participant had asymptomatic Grade 4 elevation of liver enzymes at the end of study intervention. Two subjects had Grade 3 skin rashes. The remaining adverse events were Grade 1 or 2 events. The most common adverse events were diarrhea and increased total cholesterol, reported in 30% and 27.5% of the subjects, respectively. Conclusion: We conclude that among overweight and obese postmenopausal women, daily 1 gm dose of resveratrol has favorable effects on estrogen metabolism and SHBG. Further placebo-controlled studies are needed to confirm our findings on these hormone-related breast cancer risk factors and the attribution of the adverse effects observed in the study population. C1 [Chow, H-H Sherry; Garland, Linda L.; Hsu, Chiu-Hsieh; Butler, Valerie D.; Cordova, Catherine A.; Chew, Wade M.] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Heckman-Stoddard, Brandy M.; Cornelison, Terri L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Chow, HHS (reprint author), Univ Arizona, Ctr Canc, 1515 N Campbell Ave, Tucson, AZ 85724 USA. EM schow@azcc.arizona.edu FU National Cancer Institute, Division of Cancer Prevention [N01CN35158]; University of Arizona Cancer Center Support Grant from the National Cancer Institute [CA023074] FX This work was supported by a contract (N01CN35158) from the National Cancer Institute, Division of Cancer Prevention and the University of Arizona Cancer Center Support Grant (CA023074) from the National Cancer Institute. NR 35 TC 12 Z9 12 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 14 PY 2014 VL 12 AR 223 DI 10.1186/s12967-014-0223-0 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AO3EM UT WOS:000341211600001 PM 25115686 ER PT J AU Goswami, SC Thierry-Mieg, D Thierry-Mieg, J Mishra, S Hoon, MA Mannes, AJ Iadarola, MJ AF Goswami, Samridhi C. Thierry-Mieg, Danielle Thierry-Mieg, Jean Mishra, Santosh Hoon, Mark A. Mannes, Andrew J. Iadarola, Michael J. TI Itch-associated peptides: RNA-Seq and bioinformatic analysis of natriuretic precursor peptide B and gastrin releasing peptide in dorsal root and trigeminal ganglia, and the spinal cord SO MOLECULAR PAIN LA English DT Article DE Pruritis; Bombesin; Ranatensin; GRP; GRPR; NMB; NMBR; Tac1; Nppa; Nppb; Nppc; Npr1; Npr2; Npr3; RNA-Seq; PolyA(+) mRNA; RNA-Seq unified mapper; Peptidylglycine alpha-amidating monooxygenase; Immunocytochemistry; Cross-reaction ID NEUROMEDIN-B; NERVOUS-SYSTEM; RECEPTORS; BOMBESIN; MODULATION; NEURONS; RAT; EXPRESSION; MECHANISM; SENSATION AB Background: Three neuropeptides, gastrin releasing peptide (GRP), natriuritic precursor peptide B (NPPB), and neuromedin B (NMB) have been proposed to play roles in itch sensation. However, the tissues in which these peptides are expressed and their positions in the itch circuit has recently become the subject of debate. Here we used next-gen RNA-Seq to examine the expression of transcripts coding for GRP, NPPB, NMB, and other peptides in DRG, trigeminal ganglion, and the spinal cord as well as expression levels for their cognate receptors in these tissues. Results: RNA-Seq demonstrates that GRP is not transcribed in mouse, rat, or human sensory ganglia. NPPB, which activates natriuretic peptide receptor 1 (NPR1), is well expressed in mouse DRG and less so in rat and human, whereas NPPA, which also acts on the NPR1 receptor, is expressed in all three species. Analysis of transcripts expressed in the spinal cord of mouse, rat, and human reveals no expression of Nppb, but unambiguously detects expression of Grp and the GRP-receptor (Grpr). The transcripts coding for NMB and tachykinin peptides are among the most highly expressed in DRG. Bioinformatics comparisons using the sequence of the peptides used to produce GRP-antibodies with proteome databases revealed that the C-terminal primary sequence of NMB and Substance P can potentially account for results from previous studies which showed GRP-immunostaining in the DRG. Conclusions: RNA-Seq corroborates a primary itch afferent role for NPPB in mouse and potentially NPPB and NPPA in rats and humans, but does not support GRP as a primary itch neurotransmitter in mouse, rat, or humans. As such, our results are at odds with the initial proposal of Sun and Chen (2007) that GRP is expressed in DRG. By contrast, our data strongly support an itch pathway where the itch-inducing actions of GRP are exerted through its release from spinal cord neurons. C1 [Goswami, Samridhi C.; Mannes, Andrew J.; Iadarola, Michael J.] NIH, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. [Thierry-Mieg, Danielle; Thierry-Mieg, Jean] NIH, Natl Ctr Biomed Informat, Bethesda, MD 20892 USA. [Mishra, Santosh; Hoon, Mark A.] Natl Inst Dent & Craniofacial Res, Mol Genet Unit, Lab Sensory Biol, NIH, Bethesda, MD USA. RP Iadarola, MJ (reprint author), NIH, Dept Perioperat Med, Ctr Clin, Bldg 10,Room 2C401,MSC 1510,10 Ctr Dr, Bethesda, MD 20892 USA. EM michael.iadarola@nih.gov RI THIERRY-MIEG, Jean/F-1975-2017 OI THIERRY-MIEG, Jean/0000-0002-0396-6789 FU Intramural Research Programs of the National Center for Complementary and Alternative Medicine; National Institute of Dental and Craniofacial Research, National Library of Medicine; Department of Perioperative Medicine, Clinical Center of the National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Center for Complementary and Alternative Medicine, the National Institute of Dental and Craniofacial Research, National Library of Medicine, and the Department of Perioperative Medicine, Clinical Center of the National Institutes of Health. Next-Gen Sequencing was done at the NIH Intramural Sequencing Center (NISC), Rockville, MD. NR 30 TC 16 Z9 16 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD AUG 14 PY 2014 VL 10 AR 44 DI 10.1186/1744-8069-10-44 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AO0US UT WOS:000341028500001 PM 25123163 ER PT J AU Engi, SA Cruz, FC Leao, RM Spolidorio, LC Planeta, CS Crestani, CC AF Engi, Sheila A. Cruz, Fabio C. Leao, Rodrigo M. Spolidorio, Luis C. Planeta, Cleopatra S. Crestani, Carlos C. TI Cardiovascular Complications following Chronic Treatment with Cocaine and Testosterone in Adolescent Rats SO PLOS ONE LA English DT Article ID CONDITIONED PLACE PREFERENCE; ANABOLIC-ANDROGENIC STEROIDS; CORONARY-HEART-DISEASE; DRUG-USE; UNANESTHETIZED RATS; BAROREFLEX FUNCTION; BLOOD-PRESSURE; UNITED-STATES; ADULT RATS; BRAIN AB Concomitant use of anabolic androgenic steroids and cocaine has increased in the last years. However, the effects of chronic exposure to these substances during adolescence on cardiovascular function are unknown. Here, we investigated the effects of treatment for 10 consecutive days with testosterone and cocaine alone or in combination on basal cardiovascular parameters, baroreflex activity, hemodynamic responses to vasoactive agents, and cardiac morphology in adolescent rats. Administration of testosterone alone increased arterial pressure, reduced heart rate (HR), and exacerbated the tachycardiac baroreflex response. Cocaine-treated animals showed resting bradycardia without changes in arterial pressure and baroreflex activity. Combined treatment with testosterone and cocaine did not affect baseline arterial pressure and HR, but reduced baroreflex-mediated tachycardia. None of the treatments affected arterial pressure response to either vasoconstrictor or vasodilator agents. Also, heart to body ratio and left and right ventricular wall thickness were not modified by drug treatments. However, histological analysis of left ventricular sections of animals subjected to treatment with testosterone and cocaine alone and combined showed a greater spacing between cardiac muscle fibers, dilated blood vessels, and fibrosis. These data show important cardiovascular changes following treatment with testosterone in adolescent rats. However, the results suggest that exposure to cocaine alone or combined with testosterone during adolescence minimally affect cardiovascular function. C1 [Engi, Sheila A.; Planeta, Cleopatra S.; Crestani, Carlos C.] UNESP, Sch Pharmaceut Sci, Dept Nat Act Principles & Toxicol, Pharmacol Lab, Araraquara, SP, Brazil. [Engi, Sheila A.; Planeta, Cleopatra S.; Crestani, Carlos C.] UNESP, Grad Program Physiol Sci, Joint UFSCar, Sao Carlos, SP, Brazil. [Cruz, Fabio C.; Leao, Rodrigo M.] NIDA, Behav Neurosci Branch, Intramural Res Program, US NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Spolidorio, Luis C.] UNESP, Sch Dent Araraquara, Dept Physiol & Pathol, Araraquara, SP, Brazil. RP Crestani, CC (reprint author), UNESP, Sch Pharmaceut Sci, Dept Nat Act Principles & Toxicol, Pharmacol Lab, Araraquara, SP, Brazil. EM cccrestani@yahoo.com.br RI Crestani, Carlos/E-4161-2012; Spolidorio, Luis Carlos/G-1857-2012; ENGI, SHIELA/O-2141-2013 FU Sao Paulo Research Foundation (FAPESP) [2010/16192-8, 2012/14376-0, 2012/50549-6]; PADC-School of Pharmaceutical Sciences-Sao Paulo State University FX This work was supported by Sao Paulo Research Foundation (FAPESP) grant#2010/16192-8, 2012/14376-0 and 2012/50549-6; and PADC-School of Pharmaceutical Sciences-Sao Paulo State University. CSP is a CNPq research fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 2 Z9 2 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2014 VL 9 IS 8 AR e105172 DI 10.1371/journal.pone.0105172 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO0QT UT WOS:000341017000102 PM 25121974 ER PT J AU Knodler, LA Crowley, SM Sham, HP Yang, HJ Wrande, M Ma, CX Ernst, RK Steele-Mortimer, O Celli, J Vallance, BA AF Knodler, Leigh A. Crowley, Shauna M. Sham, Ho Pan Yang, Hyungjun Wrande, Marie Ma, Caixia Ernst, Robert K. Steele-Mortimer, Olivia Celli, Jean Vallance, Bruce A. TI Noncanonical Inflammasome Activation of Caspase-4/Caspase-11 Mediates Epithelial Defenses against Enteric Bacterial Pathogens SO CELL HOST & MICROBE LA English DT Article ID SALMONELLA-TYPHIMURIUM; INTERFERON-GAMMA; CASPASE-11; INFECTION; PROMOTES; EXTRUSION; ENZYME; CELLS AB Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11-deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human ortholog of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium-infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore, an epithelial cell-intrinsic noncanonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface. C1 [Knodler, Leigh A.; Wrande, Marie; Celli, Jean] Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. [Knodler, Leigh A.; Steele-Mortimer, Olivia; Celli, Jean] NIAID, Lab Intracellular Parasites, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Crowley, Shauna M.; Sham, Ho Pan; Yang, Hyungjun; Ma, Caixia; Vallance, Bruce A.] Univ British Columbia, Child & Family Res Inst, Div Gastroenterol, Dept Pediat, Vancouver, BC V6H 3V4, Canada. [Ernst, Robert K.] Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA. RP Knodler, LA (reprint author), Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. EM lknodler@vetmed.wsu.edu; bvallance@cw.bc.ca RI Ernst, Richard/I-1870-2016 FU Paul G. Allen School of Global Animal Health; Washington State University New Faculty Seed Grant Program; University of Maryland, Baltimore; Wenner-Gren Foundations; Swedish Research Council Formas; Intramural Research Program/DIR/NIAID/NIH; Crohn's and Colitis Canada; Canadian Institutes of Health Research FX The authors thank Daniel Muruve and Vishva Dixit for providing mice; Guy Palmer, Mike Konkel, Santanu Bose, and Paul Beck for critically reading this manuscript; and Tina Huang, Tregei Starr, and Andrew Galbraith for technical assistance. B.A.V. is the Canada Research Chair (tier 2) in Pediatric Gastroenterology and the C.H.I.L.D. Foundation Chair in Pediatric Gastroenterology. This work was supported by startup funds from the Paul G. Allen School of Global Animal Health (to L.A.K. and J.C.), by the Washington State University New Faculty Seed Grant Program (to L.A.K.), by startup funds from the University of Maryland, Baltimore (to R.K.E.), by the Wenner-Gren Foundations and the Swedish Research Council Formas (to M.W.), by the Intramural Research Program/DIR/NIAID/NIH (to O.S.-M. and J.C.), and by grants from Crohn's and Colitis Canada and the Canadian Institutes of Health Research (to B.A.V.). NR 42 TC 59 Z9 62 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 13 PY 2014 VL 16 IS 2 BP 249 EP 256 DI 10.1016/j.chom.2014.07.002 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO2IQ UT WOS:000341144100014 PM 25121752 ER PT J AU Sherman, SL Curnow, EC Easley, CA Jin, P Hukema, RK Tejada, MI Willemsen, R Usdin, K AF Sherman, Stephanie L. Curnow, Eliza C. Easley, Charles A. Jin, Peng Hukema, Renate K. Isabel Tejada, Maria Willemsen, Rob Usdin, Karen TI Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Review DE Primary ovarian insufficiency; Premature ovarian failure; Fragile X syndrome; Fertility; Repeat expansion disorder; CGG repeat ID FEMALE PREMUTATION CARRIERS; PLURIPOTENT STEM-CELLS; CEREBELLAR-TREMOR/ATAXIA-SYNDROME; MENTAL-RETARDATION PROTEIN; ANTI-MULLERIAN HORMONE; FMR1 MESSENGER-RNA; CGG REPEAT NUMBER; CHROMOSOME INACTIVATION; MOUSE MODEL; HOMOLOGOUS RECOMBINATION AB Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. C1 [Sherman, Stephanie L.; Jin, Peng] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Curnow, Eliza C.] Univ Washington, Washington Natl Primate Ctr, Seattle, WA 98195 USA. [Easley, Charles A.] Emory Univ, Lab Translat Cell Biol, Dept Cell Biol, Atlanta, GA 30322 USA. [Hukema, Renate K.; Willemsen, Rob] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Isabel Tejada, Maria] Hosp Univ Cruces, Mol Genet Lab, Genet Serv, BioCruces Hlth Res Inst, Baracaldo, Biscay, Spain. [Usdin, Karen] NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD USA. RP Sherman, SL (reprint author), Emory Univ, Dept Human Genet, 615 Michael St, Atlanta, GA 30322 USA. EM ssherma@emory.edu RI Hukema, Renate/E-1422-2013 OI Hukema, Renate/0000-0002-1580-4154 FU Emory's Genetics Discovery Fund; National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health; National Institute of Child Health and Development; National Institute of Mental Health at the National Institutes of Health [R21HD071876]; National Fragile X Foundation FX The authors would like to thank the following funding sources: Emory's Genetics Discovery Fund (SLS); the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (KU); National Institute of Child Health and Development and National Institute of Mental Health at the National Institutes of Health R21HD071876 for support of NHP studies (ECC) and the National Fragile X Foundation (RKH, RW). NR 83 TC 13 Z9 13 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1866-1947 EI 1866-1955 J9 J NEURODEV DISORD JI J. Neurodev. Disord. PD AUG 13 PY 2014 VL 6 AR 26 DI 10.1186/1866-1955-6-26 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AO2PE UT WOS:000341166400001 PM 25147583 ER PT J AU Boyack, KW Chen, MC Chacko, G AF Boyack, Kevin W. Chen, Mei-Ching Chacko, George TI Characterization of the Peer Review Network at the Center for Scientific Review, National Institutes of Health SO PLOS ONE LA English DT Review ID COCITATION ANALYSIS; SCIENCE; MAPS; FIELDS AB The National Institutes of Health (NIH) is the largest source of funding for biomedical research in the world. This funding is largely effected through a competitive grants process. Each year the Center for Scientific Review (CSR) at NIH manages the evaluation, by peer review, of more than 55,000 grant applications. A relevant management question is how this scientific evaluation system, supported by finite resources, could be continuously evaluated and improved for maximal benefit to the scientific community and the taxpaying public. Towards this purpose, we have created the first system-level description of peer review at CSR by applying text analysis, bibliometric, and graph visualization techniques to administrative records. We identify otherwise latent relationships across scientific clusters, which in turn suggest opportunities for structural reorganization of the system based on expert evaluation. Such studies support the creation of monitoring tools and provide transparency and knowledge to stakeholders. C1 [Boyack, Kevin W.] SciTech Strategies Inc, Albuquerque, NM USA. [Chen, Mei-Ching; Chacko, George] NIH, Off Planning Anal & Evaluat, Ctr Sci Review, Bethesda, MD 20892 USA. [Chacko, George] Univ Illinois, Off Vice Chancellor Res, Champaign, IL USA. [Chacko, George] Univ Illinois, Grad Sch Lib & Informat Sci, Champaign, IL USA. RP Chacko, G (reprint author), NIH, Off Planning Anal & Evaluat, Ctr Sci Review, Bldg 10, Bethesda, MD 20892 USA. EM george.chacko@nih.gov RI Chacko, George/I-4945-2014; OI Chacko, George/0000-0002-2127-1892; Boyack, Kevin/0000-0001-7814-8951 FU US government [HHSN268201200369P, HHSN268200800281U]; Office of Planning, Analysis, and Evaluation, Center for Scientific Review, National Institutes of Health, United States Department of Health and Human Services FX The effort contributed by SciTech Strategies was partially supported by US government contracts HHSN268201200369P and HHSN268200800281U. The Office of Planning, Analysis, and Evaluation, Center for Scientific Review, National Institutes of Health, United States Department of Health and Human Services, provided all other support for this study. NR 26 TC 1 Z9 1 U1 3 U2 33 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 13 PY 2014 VL 9 IS 8 AR e104244 DI 10.1371/journal.pone.0104244 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9BM UT WOS:000340900600043 PM 25119140 ER PT J AU Li, M Jurado, KA Lin, SQ Engelman, A Craigie, R AF Li, Min Jurado, Kellie A. Lin, Shiqiang Engelman, Alan Craigie, Robert TI Engineered Hyperactive Integrase for Concerted HIV-1 DNA Integration SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTOTYPE FOAMY VIRUS; VIRAL-DNA; IN-VITRO; STRAND TRANSFER; SYNAPTIC COMPLEX; STABLE COMPLEX; PROTEIN; INHIBITION; ENDS AB The DNA cutting and joining reactions of HIV-1 integration are catalyzed by integrase (IN), a viral protein that functions as a tetramer bridging the two viral DNA ends (intasome). Two major obstacles for biochemical and structural studies of HIV-1 intasomes are 1) the low efficiency of assembly with oligonucleotide DNA substrates, and 2) the non-specific aggregation of both intasomes and free IN in the reaction mixture. By fusing IN with a small non-specific DNA binding protein, Sulfolobus solfataricus chromosomal protein Sso7d (PDB: 1BNZ), we have engineered a highly soluble and hyperactive IN. Unlike wildtype IN, it efficiently catalyzes intasome assembly and concerted integration with oligonucleotide DNA substrates. The fusion IN protein also functions to integrate viral reverse transcripts during HIV-infection. The hyperactive HIV-1 IN may assist in facilitating future biochemical and structural studies of HIV-1 intasomes. Understanding the mechanistic basis of the Sso7d-IN fusion protein could provide insight into the factors that have hindered biophysical studies of wild-type HIV-1 IN and intasomes. C1 [Li, Min; Lin, Shiqiang; Craigie, Robert] Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, Bethesda, MD 20892 USA. [Jurado, Kellie A.; Engelman, Alan] Harvard Med Sch, Dana Farber Canc Inst & Dept Med, Dept Canc Immunol & AIDS, Boston, MA USA. RP Craigie, R (reprint author), Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov FU Intramural Program of NIDDK, NIH; AIDS Targeted Antiviral Program of the Office of the Director of the NIH; NIH [AI070042] FX Intramural Program of NIDDK, NIH, by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to R. C.), and by NIH grant AI070042 (to A.E.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 6 Z9 6 U1 1 U2 11 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 13 PY 2014 VL 9 IS 8 AR e105078 DI 10.1371/journal.pone.0105078 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9BM UT WOS:000340900600121 PM 25119883 ER PT J AU Monjazeb, AM Tietze, JK Grossenbacher, SK Hsiao, HH Zamora, AE Mirsoian, A Koehn, B Blazar, BR Weiss, JM Wiltrout, RH Sckisel, GD Murphy, WJ AF Monjazeb, Arta M. Tietze, Julia K. Grossenbacher, Steven K. Hsiao, Hui-Hua Zamora, Anthony E. Mirsoian, Annie Koehn, Brent Blazar, Bruce R. Weiss, Jonathan M. Wiltrout, Robert H. Sckisel, Gail D. Murphy, William J. TI Bystander Activation and Anti-Tumor Effects of CD8+T Cells Following Interleukin-2 Based Immunotherapy Is Independent of CD4+T Cell Help SO PLOS ONE LA English DT Article ID CD4(+) T-CELLS; IN-VIVO; PROGRAMMED DEATH-1; CD8-T-CELL MEMORY; VIRAL-INFECTION; PD-1 EXPRESSION; CD4-T-CELL HELP; KILLER-CELL; RESPONSES; LYMPHOCYTES AB We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander-activated'' (CD8(+)CD44(high)) T cells displaying a CD25(-) NKG2D(+) phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion. C1 [Monjazeb, Arta M.] Univ Calif Davis, Sch Med, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Tietze, Julia K.; Grossenbacher, Steven K.; Hsiao, Hui-Hua; Zamora, Anthony E.; Mirsoian, Annie; Sckisel, Gail D.; Murphy, William J.] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Koehn, Brent; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MA USA. [Koehn, Brent; Blazar, Bruce R.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MA USA. [Weiss, Jonathan M.; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Murphy, William J.] Univ Calif Davis, Sch Med, Dept Internal Med, Sacramento, CA 95817 USA. RP Murphy, WJ (reprint author), Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. EM wmjmurphy@ucdavis.edu FU NIH [R01 CA095572] FX This work was supported by a grant from the NIH R01 CA095572. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 5 Z9 5 U1 0 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 13 PY 2014 VL 9 IS 8 AR e102709 DI 10.1371/journal.pone.0102709 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9BM UT WOS:000340900600009 PM 25119341 ER PT J AU Zhang, JL Bera, TK Liu, WH Du, X Alewine, C Hassan, R Pastan, I AF Zhang, Jingli Bera, Tapan K. Liu, Wenhai Du, Xing Alewine, Christine Hassan, Raffit Pastan, Ira TI Megakaryocytic Potentiating Factor and Mature Mesothelin Stimulate the Growth of a Lung Cancer Cell Line in the Peritoneal Cavity of Mice SO PLOS ONE LA English DT Article ID MOLECULAR-CLONING; BREAST-CANCER; EXPRESSION; ADENOCARCINOMAS; IMMUNOTHERAPY; PANCREAS; BINDING; MARKER; TARGET; CDNA AB The mesothelin (MSLN) gene encodes a 71 kilodalton (kDa) precursor protein that is processed into megakaryocytic potentiating factor (MPF), a 31 kDa protein that is secreted from the cell, and mature mesothelin (mMSLN), a 40 kDa cell surface protein. The mMSLN binds to CA125, an interaction that has been implicated in the intra-cavitary spread of mesothelioma and ovarian cancer. To better define the role of MPF and mMSLN, growth of the lung cancer cell line A549 was evaluated in immuno-deficient mice with inactivation of the Msln gene. We observed that Msln-/- mice xenografted with intraperitoneal A549 tumors survive significantly long than tumor-bearing Msln+/+ mice. When tumor-bearing Msln-/- mice are supplemented with recombinant MPF (and to a lesser extent mMSLN), most of this survival advantage is lost. These studies demonstrate that MPF and mMSLN have an important role in the growth of lung cancer cells in vivo and raise the possibility that inactivation of MPF may be a useful treatment for lung and other MSLN expressing cancers. C1 [Zhang, Jingli; Bera, Tapan K.; Liu, Wenhai; Du, Xing; Alewine, Christine; Hassan, Raffit; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov; pastani@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 2 Z9 3 U1 0 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 13 PY 2014 VL 9 IS 8 AR e104388 DI 10.1371/journal.pone.0104388 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN9BM UT WOS:000340900600054 PM 25118887 ER PT J AU Soetkamp, D Nguyen, TT Menazza, S Hirschhauser, C Hendgen-Cotta, UB Rassaf, T Schluter, KD Boengler, K Murphy, E Schulz, R AF Soetkamp, Daniel Nguyen, Tiffany T. Menazza, Sara Hirschhaeuser, Christine Hendgen-Cotta, Ulrike B. Rassaf, Tienush Schlueter, Klaus D. Boengler, Kerstin Murphy, Elizabeth Schulz, Rainer TI S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function SO BASIC RESEARCH IN CARDIOLOGY LA English DT Article DE Cardioprotection; Connexin hemichannel; Ischemic preconditioning (IPC); S-nitrosation (SNO); Nitric oxide (NO) ID GENERATES NITRIC-OXIDE; HEART-MITOCHONDRIA; INTERCELLULAR COMMUNICATION; CARDIOMYOCYTE MITOCHONDRIA; GLYCYRRHETINIC ACID; ENDOTHELIAL-CELLS; XENOPUS-OOCYTES; COMPLEX I; NITROSYLATION; CARDIOPROTECTION AB S-nitrosation (SNO) of connexin 43 (Cx43)-formed channels modifies dye uptake in astrocytes and gap junctional communication in endothelial cells. Apart from forming channels at the plasma membrane of several cell types, Cx43 is also located at the inner membrane of myocardial subsarcolemmal mitochondria (SSM), but not in interfibrillar mitochondria (IFM). The absence or pharmacological blockade of mitochondrial Cx43 (mtCx43) reduces dye and potassium uptake. Lack of mtCx43 is associated with loss of endogenous cardioprotection by ischemic preconditioning (IPC), which is mediated by formation of reactive oxygen species (ROS). Whether or not mitochondrial Lucifer Yellow (LY), ion uptake, or ROS generation are affected by SNO of mtCx43 and whether or not cardioprotective interventions affect SNO of mtCx43 remains unknown. In SSM from rat hearts, application of NO donors (48 nmol to 1 mmol) increased LY uptake (0.5 mmol SNAP 38.4 +/- A 7.1 %, p < 0.05; 1 mmol GSNO 28.1 +/- A 7.4 %, p < 0.05) and the refilling rate of potassium (SNAP 227.9 +/- A 30.1 %, p < 0.05; GSNO 122.6 +/- A 28.1 %, p < 0.05). These effects were absent following blockade of Cx43 hemichannels by carbenoxolone as well as in IFM lacking Cx43. Unlike potassium, the sodium permeability was not affected by application of NO. Furthermore, mitochondrial ROS formation was increased following NO application compared to control SSM (0.5 mmol SNAP 22.9 +/- A 1.8 %, p < 0.05; 1 mmol GSNO 40.6 +/- A 7.1 %, p < 0.05), but decreased in NO treated IFM compared to control (0.5 mmol SNAP 14.4 +/- A 4 %, p < 0.05; 1 mmol GSNO 13.8 +/- A 4 %, p < 0.05). NO donor administration to isolated SSM increased SNO of mtCx43 by 109.2 +/- A 15.8 %. Nitrite application (48 nmol) to mice was also associated with elevated SNO of mtCx43 by 59.3 +/- A 18.2 % (p < 0.05). IPC by four cycles of 5 min of ischemia and 5 min of reperfusion increased SNO of mtCx43 by 41.6 +/- A 1.7 % (p < 0.05) when compared to control perfused rat hearts. These data suggest that SNO of mtCx43 increases mitochondrial permeability, especially for potassium and leads to increased ROS formation. The increased amount of SNO mtCx43 by IPC or nitrite administration may link NO and Cx43 in the signal transduction cascade of cardioprotective interventions. C1 [Soetkamp, Daniel; Nguyen, Tiffany T.; Menazza, Sara; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Soetkamp, Daniel; Hirschhaeuser, Christine; Schlueter, Klaus D.; Boengler, Kerstin; Schulz, Rainer] Univ Giessen, Physiol Inst, Fachbereich Med, D-35392 Giessen, Germany. [Hendgen-Cotta, Ulrike B.; Rassaf, Tienush] Univ Dusseldorf, Dept Med, Div Cardiol Pulmonol & Vasc Med, D-40225 Dusseldorf, Germany. RP Schulz, R (reprint author), Univ Giessen, Physiol Inst, Fachbereich Med, Aulweg 129, D-35392 Giessen, Germany. EM Rainer.Schulz@physiologie.med.uni-giessen.de FU German research foundation [DFG Schu 843/7-2]; international research training group 1566 Giessen, Bad Nauheim, Barcelona "Protecting the Heart from Ischemia'' (PROMISE); international Giessen graduate center for the life sciences (GGL) FX The technical support by E. Ungefug, P. Volk, Sabrina Bohme, Dominik Semmler and Anna Reis is gratefully acknowledged. This work was supported by the German research foundation (DFG Schu 843/7-2), the international research training group 1566 Giessen, Bad Nauheim, Barcelona "Protecting the Heart from Ischemia'' (PROMISE), and the international Giessen graduate center for the life sciences (GGL). NR 81 TC 14 Z9 16 U1 4 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8428 EI 1435-1803 J9 BASIC RES CARDIOL JI Basic Res. Cardiol. PD AUG 13 PY 2014 VL 109 IS 5 AR 433 DI 10.1007/s00395-014-0433-x PG 19 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN4QN UT WOS:000340572800001 PM 25115184 ER PT J AU Shriner, D Tekola-Ayele, F Adeyemo, A Rotimi, CN AF Shriner, Daniel Tekola-Ayele, Fasil Adeyemo, Adebowale Rotimi, Charles N. TI Genome-wide genotype and sequence-based reconstruction of the 140,000 year history of modern human ancestry SO SCIENTIFIC REPORTS LA English DT Article ID AFRICAN-AMERICANS; GENETIC DIVERSITY; HUMAN-POPULATIONS; NORTH-AFRICA; ADMIXTURE; STRATIFICATION; INFERENCE; PATTERNS; MAXIMUM; PEOPLE AB We investigated ancestry of 3,528 modern humans from 163 samples. We identified 19 ancestral components, with 94.4% of individuals showing mixed ancestry. After using whole genome sequences to correct for ascertainment biases in genome-wide genotype data, we dated the oldest divergence event to 140,000 years ago. We detected an Out-of-Africa migration 100,000-87,000 years ago, leading to peoples of the Americas, east and north Asia, and Oceania, followed by another migration 61,000-44,000 years ago, leading to peoples of the Caucasus, Europe, the Middle East, and south Asia. We dated eight divergence events to 33,000-20,000 years ago, coincident with the Last Glacial Maximum. We refined understanding of the ancestry of several ethno-linguistic groups, including African Americans, Ethiopians, the Kalash, Latin Americans, Mozabites, Pygmies, and Uygurs, as well as the CEU sample. Ubiquity of mixed ancestry emphasizes the importance of accounting for ancestry in history, forensics, and health. C1 [Shriner, Daniel; Tekola-Ayele, Fasil; Adeyemo, Adebowale; Rotimi, Charles N.] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047,12 South Dr, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; National Institutes of Health [Z01HG200362] FX The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). NR 40 TC 11 Z9 12 U1 0 U2 43 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 13 PY 2014 VL 4 AR 6055 DI 10.1038/srep06055 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6AC UT WOS:000340674400015 PM 25116736 ER PT J AU Kohli, A Shaffer, A Sherman, A Kottilil, S AF Kohli, Anita Shaffer, Ashton Sherman, Amy Kottilil, Shyam TI Treatment of Hepatitis C A Systematic Review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID GENOTYPE 1 INFECTION; TREATMENT-NAIVE PATIENTS; SUSTAINED VIROLOGICAL RESPONSE; DRUG-DRUG INTERACTIONS; CHRONIC HCV INFECTION; VIRUS-INFECTION; PEGINTERFERON ALPHA-2A; PEGYLATED INTERFERON; PLUS RIBAVIRIN; PHASE-2 TRIAL AB IMPORTANCE Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon. OBJECTIVES To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration-approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence. EVIDENCE REVIEW A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19 063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine. FINDINGS Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks' duration: 82%-93%; SVR for genotype 3, 24 weeks' duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients. CONCLUSIONS AND RELEVANCE New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapiesmay lead to the treatment of many more people with chronic HCV infection. C1 [Kohli, Anita] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Kohli, Anita] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Shaffer, Ashton; Sherman, Amy; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, 10 Ctr Dr,Bldg 10,Room 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases and the Clinical Research Center); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases and the Clinical Research Center). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 58 TC 136 Z9 138 U1 10 U2 59 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 13 PY 2014 VL 312 IS 6 BP 631 EP 640 DI 10.1001/jama.2014.7085 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AM8OU UT WOS:000340136400022 PM 25117132 ER PT J AU Ismail, TF Hsu, LY Greve, AM Goncalves, C Jabbour, A Gulati, A Hewins, B Mistry, N Wage, R Roughton, M Ferreira, PF Gatehouse, P Firmin, D O'Hanlon, R Pennell, DJ Prasad, SK Arai, AE AF Ismail, Tevfik F. Hsu, Li-Yueh Greve, Anders M. Goncalves, Carla Jabbour, Andrew Gulati, Ankur Hewins, Benjamin Mistry, Niraj Wage, Ricardo Roughton, Michael Ferreira, Pedro F. Gatehouse, Peter Firmin, David O'Hanlon, Rory Pennell, Dudley J. Prasad, Sanjay K. Arai, Andrew E. TI Coronary microvascular ischemia in hypertrophic cardiomyopathy - a pixel-wise quantitative cardiovascular magnetic resonance perfusion study SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Hypertrophic cardiomyopathy; Perfusion; Cardiovascular magnetic resonance; Microvascular dysfunction; Sudden cardiac death ID LATE GADOLINIUM ENHANCEMENT; POSITRON-EMISSION-TOMOGRAPHY; DELAYED CONTRAST ENHANCEMENT; LEFT-VENTRICULAR HYPERTROPHY; REGIONAL OXYGEN-CONSUMPTION; MYOCARDIAL BLOOD-FLOW; VASODILATOR RESERVE; HEART-ASSOCIATION; TASK-FORCE; DYSFUNCTION AB Background: Microvascular dysfunction in HCM has been associated with adverse clinical outcomes. Advances in quantitative cardiovascular magnetic resonance (CMR) perfusion imaging now allow myocardial blood flow to be quantified at the pixel level. We applied these techniques to investigate the spectrum of microvascular dysfunction in hypertrophic cardiomyopathy (HCM) and to explore its relationship with fibrosis and wall thickness. Methods: CMR perfusion imaging was undertaken during adenosine-induced hyperemia and again at rest in 35 patients together with late gadolinium enhancement (LGE) imaging. Myocardial blood flow (MBF) was quantified on a pixel-by-pixel basis from CMR perfusion images using a Fermi-constrained deconvolution algorithm. Regions-of-interest (ROI) in hypoperfused and hyperemic myocardium were identified from the MBF pixel maps. The myocardium was also divided into 16 AHA segments. Results: Resting MBF was significantly higher in the endocardium than in the epicardium (mean +/- SD: 1.25 +/- 0.35 ml/g/min versus 1.20 +/- 0.35 ml/g/min, P < 0.001), a pattern that reversed with stress (2.00 +/- 0.76 ml/g/min versus 2.36 +/- 0.83 ml/g/min, P < 0.001). ROI analysis revealed 11 (31%) patients with stress MBF lower than resting values (1.05 +/- 0.39 ml/g/min versus 1.22 +/- 0.36 ml/g/min, P = 0.021). There was a significant negative association between hyperemic MBF and wall thickness (beta = -0.047 ml/g/min per mm, 95% CI: -0.057 to -0.038, P < 0.001) and a significantly lower probability of fibrosis in a segment with increasing hyperemic MBF (odds ratio per ml/g/min: 0.086, 95% CI: 0.078 to 0.095, P = 0.003). Conclusions: Pixel-wise quantitative CMR perfusion imaging identifies a subgroup of patients with HCM that have localised severe microvascular dysfunction which may give rise to myocardial ischemia. C1 [Ismail, Tevfik F.; Goncalves, Carla; Jabbour, Andrew; Gulati, Ankur; Hewins, Benjamin; Mistry, Niraj; Wage, Ricardo; Ferreira, Pedro F.; Gatehouse, Peter; Firmin, David; O'Hanlon, Rory; Pennell, Dudley J.; Prasad, Sanjay K.] Royal Brompton Hosp, Cardiovasc Magnet Resonance Unit, London SW3 6LY, England. [Ismail, Tevfik F.; Goncalves, Carla; Jabbour, Andrew; Gulati, Ankur; Hewins, Benjamin; Mistry, Niraj; Wage, Ricardo; Ferreira, Pedro F.; Gatehouse, Peter; Firmin, David; O'Hanlon, Rory; Pennell, Dudley J.; Prasad, Sanjay K.] Royal Brompton Hosp, Cardiovasc Biomed Res Units, London SW3 6LY, England. [Ismail, Tevfik F.; Mistry, Niraj; Ferreira, Pedro F.; Gatehouse, Peter; Firmin, David; Pennell, Dudley J.; Prasad, Sanjay K.] Univ London Imperial Coll Sci Technol & Med, London, England. [Hsu, Li-Yueh; Greve, Anders M.] NHLBI, Adv Cardiovasc Imaging Lab, NIH, Bethesda, MD 20892 USA. [Roughton, Michael] R Squared Stat, London, England. RP Arai, AE (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM araia@nih.gov OI Gatehouse, Peter/0000-0002-0260-4719; Ferreira, Pedro/0000-0002-0436-3496 FU National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London; British Heart Foundation; CORDA; research charity; Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health [HL 006137-04]; Rosetrees Trust FX The authors are grateful to the staff of the CMR Unit and the Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK and the National Institutes of Health, Bethesda, Maryland, USA, for their support with this work. This work was supported by the National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London. Dr Ismail and Dr Prasad are funded by the British Heart Foundation. Dr Prasad has also received funding from CORDA, a research charity, and the Rosetrees Trust. Dr Arai and Dr Hsu are funded by the Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health (Grant #HL 006137-04). NR 45 TC 11 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD AUG 12 PY 2014 VL 16 AR 49 DI 10.1186/s12968-014-0049-1 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AP1QM UT WOS:000341846000001 PM 25160568 ER PT J AU Sagher, E Hernandez, L Heywood, C Pauly, GT Young, MR Schneider, J Colburn, NH Annunziata, CM AF Sagher, Ethan Hernandez, Lidia Heywood, Callee Pauly, Gary T. Young, Matthew R. Schneider, Joel Colburn, Nancy H. Annunziata, Christina M. TI The small molecule NSC676914A is cytotoxic and differentially affects NF kappa B signaling in ovarian cancer cells and HEK293 cells SO CANCER CELL INTERNATIONAL LA English DT Article DE Ovarian cancer; NF-kappa B; IKK beta; NSC676914; Chemotherapy ID INHIBITOR; SCREEN; KINASE; ASSAY AB Background: The small molecule NSC676914A was previously identified as an NF-kappa B inhibitor in TPA-stimulated HEK293 cells (Mol Can Ther 8: 571-581, 2009). We hypothesized that this effect would also be seen in ovarian cancer cells, and serve as its mechanism of cytotoxicity. OVCAR3 and HEK293 cell lines stably containing a NF-kappa B luciferase reporter gene were generated. Methods: Levels of NF-kappa B activity were assessed by luciferase reporter assays, after stimulation with LPA, LPS, TPA, and TNFa, in the presence or absence of a known NF-kappa B inhibitor or NSC676914A, and cytotoxicity was measured. Results: NSC676914A was toxic to both OVCAR3 and HEK293 cells. We also investigated the cytotoxicity of NSC676914A on a panel of lymphoma cell lines with well characterized mutations previously shown to determine sensitivity or resistance to NF-kappa B inhibition. The compound did not show predicted patterns of effects on NF-kappa B activity in either lymphoma, ovarian or HEK293 cell lines. In HEK293 cells, the small molecule inhibited NF-kappa B when cells were stimulated, while in OVCAR3 cells it only partially inhibited NF-kappa B. Interestingly, we observed rescue of cell death with ROS inhibition. Conclusions: The current study suggests that the effect of NSC676914A on NF-kappa B depends on cell type and the manner in which the pathway is stimulated. Furthermore, as it is similarly toxic to lymphoma, OVCAR3 and HEK293 cells, NSC676914A shows promising NF-kappa B-independent anti-cancer activity in ovarian tumor cells. C1 [Sagher, Ethan; Hernandez, Lidia; Heywood, Callee; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pauly, Gary T.; Schneider, Joel] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. RP Annunziata, CM (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Schneider, Joel/N-2610-2014; Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU National Cancer Institute, Intramural Research Program (CMA) FX Funding was provided by the National Cancer Institute, Intramural Research Program (CMA). NR 11 TC 1 Z9 1 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2867 J9 CANCER CELL INT JI Cancer Cell Int. PD AUG 12 PY 2014 VL 14 AR 75 DI 10.1186/s12935-014-0075-y PG 8 WC Oncology SC Oncology GA AO5PH UT WOS:000341396700001 PM 25324692 ER PT J AU Irvin, MR Zhi, DG Joehanes, R Mendelson, M Aslibekyan, S Claas, SA Thibeault, KS Patel, N Day, K Jones, LW Liang, LM Chen, BH Yao, C Tiwari, HK Ordovas, JM Levy, D Absher, D Arnett, DK AF Irvin, Marguerite R. Zhi, Degui Joehanes, Roby Mendelson, Michael Aslibekyan, Stella Claas, Steven A. Thibeault, Krista S. Patel, Nikita Day, Kenneth Jones, Lindsay Waite Liang, Liming Chen, Brian H. Yao, Chen Tiwari, Hemant K. Ordovas, Jose M. Levy, Daniel Absher, Devin Arnett, Donna K. TI Epigenome-Wide Association Study of Fasting Blood Lipids in the Genetics of Lipid-Lowering Drugs and Diet Network Study SO CIRCULATION LA English DT Article DE cholesterol; fatty acids; genetics, medical; lipids; lipoproteins ID ACTIVATED RECEPTOR-ALPHA; CORONARY-HEART-DISEASE; FENOFIBRATE TREATMENT; INSULIN-RESISTANCE; MONONUCLEAR-CELLS; CPG SITES; GENOME; POLYMORPHISMS; PATTERNS; IDENTIFICATION AB Background-Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism. Methods and Results-To identify whether differential methylation of cytosine-(phosphate)-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T cells and quantified the proportion of sample methylation at >450 000 CpGs by using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled the percentage of methylation at individual CpGs as a function of fasting very-low-density lipoprotein cholesterol and triglycerides (TGs) by using mixed linear regression adjusted for age, sex, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, and cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly associated with very-low low-density lipoprotein cholesterol (P=1.8x10(-21) to 1.6x10(-8)) and TG (P=1.6x10(-26) to 1.5x10(-9)). Array findings were validated by bisulfite sequencing. We performed quantitative polymerase chain reaction experiments demonstrating that methylation of the top CpG (cg00574958) was correlated with CPT1A expression. The association of cg00574958 with TG and CPT1A expression were replicated in the Framingham Heart Study (P=4.1x10(-14) and 3.1x10(-13), respectively). DNA methylation at CPT1A cg00574958 explained 11.6% and 5.5% of the variation in TG in the discovery and replication cohorts, respectively. Conclusions-This genome-wide epigenomic study identified CPT1A methylation as strongly and robustly associated with fasting very-low low-density lipoprotein cholesterol and TG. Identifying novel epigenetic contributions to lipid traits may inform future efforts to identify new treatment targets and biomarkers of disease risk. C1 [Irvin, Marguerite R.; Aslibekyan, Stella; Claas, Steven A.; Arnett, Donna K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Zhi, Degui; Tiwari, Hemant K.] Univ Alabama Birmingham, Sect Stat Genet, Dept Biostat, Birmingham, AL 35294 USA. [Joehanes, Roby; Mendelson, Michael; Liang, Liming; Chen, Brian H.; Yao, Chen; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Joehanes, Roby; Mendelson, Michael; Liang, Liming; Chen, Brian H.; Yao, Chen; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Mendelson, Michael] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Thibeault, Krista S.; Patel, Nikita; Day, Kenneth; Jones, Lindsay Waite; Absher, Devin] Hudson Alpha Inst Biotechnol, Huntsville, AL USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Irvin, MR (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, 1665 Univ Blvd,RPHB Room 220F, Birmingham, AL 35294 USA. EM irvinr@uab.edu RI Mendelson, Michael/I-2874-2014; OI Mendelson, Michael/0000-0001-7590-3958; Claas, Steven/0000-0001-9789-8395 FU National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) [R01 HL104135-01]; NIH/NHLBI [N01-HC-25195] FX The GOLDN epigenetics study is funded by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL104135-01. The Framingham Heart Study is supported by NIH/NHLBI contract N01-HC-25195. NR 50 TC 33 Z9 33 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG 12 PY 2014 VL 130 IS 7 BP 565 EP + DI 10.1161/CIRCULATIONAHA.114.009158 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AN6CJ UT WOS:000340681000013 PM 24920721 ER PT J AU Floeter, MK Katipally, R Kim, MP Schanz, O Stephen, M Danielian, L Wu, TX Huey, ED Meoded, A AF Floeter, Mary Kay Katipally, Rohan Kim, Meredith P. Schanz, Olivia Stephen, Matthew Danielian, Laura Wu, Tianxia Huey, Edward D. Meoded, Avner TI Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL DEMENTIA; DIAGNOSTIC-CRITERIA; ALS; CEREBELLUM; LAUGHTER; SYSTEM; SCALE AB Objective: The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA. Methods: Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Forty-seven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA. Results: Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle. Conclusions: PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a "dysmetria" of emotional expression resulting from cerebellar dysmodulation. C1 [Floeter, Mary Kay; Katipally, Rohan; Kim, Meredith P.; Schanz, Olivia; Stephen, Matthew; Danielian, Laura; Wu, Tianxia; Meoded, Avner] NINDS, NIH, Bethesda, MD 20892 USA. [Huey, Edward D.] Columbia Univ, Dept Psychiat, New York, NY USA. [Huey, Edward D.] Columbia Univ, Dept Neurol, New York, NY USA. RP Floeter, MK (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM floeterm@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), NIH [Z01 NS002976]; NIH/NINDS [R00NS060766, R01NS076837]; Columbia University's CTSA grant from NCATS-NCRR/NIH [UL1RR024156] FX Supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), NIH (Z01 NS002976). E. D. Huey was funded by NIH/NINDS grants R00NS060766 and R01NS076837 and Columbia University's CTSA grant UL1RR024156 from NCATS-NCRR/NIH. NR 40 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 12 PY 2014 VL 83 IS 7 BP 620 EP 627 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AN6RB UT WOS:000340722700009 PM 25008395 ER PT J AU Wang, H Romano, G Frustaci, ME Bohidar, N Ma, HZ Sanga, P Ness, S Russell, LJ Fedgchin, M Kelly, KM Thipphawong, J AF Wang, Hao Romano, Gary Frustaci, Mary Ellen Bohidar, Norm Ma, Huizhong Sanga, Panna Ness, Seth Russell, Lucille J. Fedgchin, Margaret Kelly, Kathleen M. Thipphawong, John TI Fulranumab for treatment of diabetic peripheral neuropathic pain SO NEUROLOGY LA English DT Article ID NERVE GROWTH-FACTOR; LOW-BACK-PAIN; OSTEOARTHRITIS; TANEZUMAB; EFFICACY; SAFETY; NGF; QUESTIONNAIRE; THERAPY; KNEE AB Objective: To assess efficacy and safety of fulranumab, a fully human monoclonal antibody against nerve growth factor, in patients with diabetic peripheral neuropathic pain (DPNP). Methods: In this phase II, double-blind, placebo-controlled trial, patients with moderate to severe DPNP were randomized to treatments with fulranumab (1, 3, or 10 mg) or placebo administered subcutaneously every 4 weeks. Results: Because of early study termination (clinical hold) by the US Food and Drug Administration, 77 (intent-to-treat) of the planned 200 patients were enrolled. The primary endpoint, the mean reduction of average daily pain at week 12 compared with baseline, showed a positive dose-response relationship (p = 0.014, 1-sided); the pair-wise comparison between the 10-mg group and placebo was significant (unadjusted p = 0.040, 2-sided). An exploratory responder analysis revealed that a greater proportion of patients in the 10-mg group reported $ 30% reduction in the average DPNP intensity compared with placebo at week 12 (p = 0.006). Although not statistically significant, several secondary endpoints showed directionally similar results to the primary efficacy dose-response relationship. During the combined efficacy and safety extension phases, the top 3 treatment-emergent adverse events in the combined fulranumab group were arthralgia (11%), edema peripheral (11%), and diarrhea (9%). No cases of joint replacement or death were reported. Conclusion: Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated. Classification of evidence: This study provides Class I evidence that in patients with DPNP, fulranumab 10 mg reduces pain by 1.2 points on an 11-point scale compared with placebo. C1 [Wang, Hao] NINDS, Bethesda, MD 20892 USA. [Romano, Gary; Frustaci, Mary Ellen; Bohidar, Norm; Ma, Huizhong; Sanga, Panna; Ness, Seth; Russell, Lucille J.; Fedgchin, Margaret; Kelly, Kathleen M.; Thipphawong, John] Janssen Res & Dev LLC, Titusville, NJ USA. RP Wang, H (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM wangh16@ninds.nih.gov FU Janssen Research & Development, LLC. FX Supported by Janssen Research & Development, LLC. NR 33 TC 14 Z9 16 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 12 PY 2014 VL 83 IS 7 BP 628 EP 637 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AN6RB UT WOS:000340722700010 PM 25008392 ER PT J AU Jang, HY Burbelo, PD Chae, YS Kim, T Cho, Y Park, HT AF Jang, Hang-Yong Burbelo, Peter D. Chae, Yang-Seok Kim, Tak Cho, Yunjung Park, Hyun-Tae TI Nontuberculous mycobacterial infection in a clinical presentation of Fitz-Hugh-Curtis syndrome: a case report with multigene diagnostic approach SO BMC WOMENS HEALTH LA English DT Article DE Nontuberculous mycobacteria; Fitz-Hugh-Curtis syndrome; Laparoscopy ID DISEASE; SUSCEPTIBILITY; THAILAND; TAIWAN; HIV AB Background: Fitz-Hugh-Curtis syndrome (FHCS) is caused by inflammation of perihepatic capsules associated with pelvic inflammatory disease. In recent years, infections with nontuberculous mycobacteria (NTM) have been increasingly occurring in immunocompromised and immunocompetent patients. However, NTM has never been reported in patients with FHCS. We present the first case of a patient with extrapulmonary NTM infection in a clinical presentation of FHCS. Case presentation: A 26-year-old Korean woman presented with right upper quadrant and suprapubic pain. She was initially suspected to have FHCS. However, she was refractory to conventional antibiotic therapy. Laparoscopy revealed multiple violin-string adhesions of the parietal peritoneum to the liver and miliary-like nodules on the peritoneal surfaces. Diagnosis of NTM was confirmed by the polymerase chain reaction analysis results of biopsy specimens that showed caseating granulomas with positive acid-fast bacilli. Treatment with anti-NTM medications was initiated, and the patient's symptoms were considerably ameliorated. Conclusions: An awareness of NTM as potential pathogens, even in previously healthy adults, and efforts to exclude other confounding diseases are important to establish the diagnosis of NTM disease. NTM infection can cause various clinical manifestations, which in the present case, overlapped with the symptoms of perihepatic inflammation seen in FHCS. C1 [Jang, Hang-Yong; Kim, Tak; Park, Hyun-Tae] Korea Univ, Coll Med, Dept Obstet & Gynecol, Seoul 136705, South Korea. [Burbelo, Peter D.] NIH, Natl Inst Dent & Craniofacial Res, Dent Clin Res Core, Bethesda, MD 20892 USA. [Chae, Yang-Seok] Korea Univ, Coll Med, Dept Pathol, Seoul 136705, South Korea. [Cho, Yunjung] Korea Univ, Coll Med, Dept Lab Med, Seoul 136705, South Korea. RP Park, HT (reprint author), Korea Univ, Coll Med, Dept Obstet & Gynecol, 126-1 5 Ga Anam Dong, Seoul 136705, South Korea. EM cyberpelvis@gmail.com FU Korea University [KI300071, K1421581]; NIDCR; National Institutes of Health FX Sincere gratitude to Se-Yeon Hong and Ju-Hyun Kim for identifying nontuberculous mycobacteria species by 16S rRNA and ITS region analysis. This work was supported by grants from Korea University (KI300071 & K1421581) and in part by the intramural research program NIDCR, National Institutes of Health. NR 17 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6874 J9 BMC WOMENS HEALTH JI BMC Womens Health PD AUG 12 PY 2014 VL 14 AR 95 DI 10.1186/1472-6874-14-95 PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology SC Public, Environmental & Occupational Health; Obstetrics & Gynecology GA AN5SL UT WOS:000340651500001 PM 25115526 ER PT J AU Panza, JA Velazquez, EJ She, LL Smith, PK Nicolau, JC Favaloro, RR Gradinac, S Chrzanowski, L Prabhakaran, D Howlett, JG Jasinski, M Hill, JA Szwed, H Larbalestier, R Desvigne-Nickens, P Jones, RH Lee, KL Rouleau, JL AF Panza, Julio A. Velazquez, Eric J. She, Lilin Smith, Peter K. Nicolau, Jose C. Favaloro, Roberto R. Gradinac, Sinisa Chrzanowski, Lukasz Prabhakaran, Dorairaj Howlett, Jonathan G. Jasinski, Marek Hill, James A. Szwed, Hanna Larbalestier, Robert Desvigne-Nickens, Patrice Jones, Robert H. Lee, Kerry L. Rouleau, Jean L. TI Extent of Coronary and Myocardial Disease and Benefit From Surgical Revascularization in LV Dysfunction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary artery disease; heart failure; left ventricular dysfunction; myocardial ischemia; outcomes ID LEFT-VENTRICULAR DYSFUNCTION; ARTERY-BYPASS-SURGERY; LOW EJECTION FRACTION; HEART-FAILURE; ISCHEMIC CARDIOMYOPATHY; MEDICAL THERAPY; SURVIVAL; TRIAL; OUTCOMES; RECONSTRUCTION AB BACKGROUND Patients with ischemic left ventricular dysfunction have higher operative risk with coronary artery bypass graft surgery (CABG). However, those whose early risk is surpassed by subsequent survival benefit have not been identified. OBJECTIVES This study sought to examine the impact of anatomic variables associated with poor prognosis on the effect of CABG in ischemic cardiomyopathy. METHODS All 1,212 patients in the STICH (Surgical Treatment of IsChemic Heart failure) surgical revascularization trial were included. Patients had coronary artery disease (CAD) and ejection fraction (EF) of <= 35% and were randomized to receive CABG plus medical therapy or optimal medical therapy (OMT) alone. This study focused on 3 prognostic factors: presence of 3-vessel CAD, EF below the median (27%), and end-systolic volume index (ESVI) above the median (79 ml/m(2)). Patients were categorized as having 0 to 1 or 2 to 3 of these factors. RESULTS Patients with 2 to 3 prognostic factors (n = 636) had reduced mortality with CABG compared with those who received OMT (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56 to 0.89; p = 0.004); CABG had no such effect in patients with 0 to 1 factor (HR: 1.08; 95% CI: 0.81 to 1.44; p = 0.591). There was a significant interaction between the number of factors and the effect of CABG on mortality (p = 0.022). Although 30-day risk with CABG was higher, a net beneficial effect of CABG relative to OMT was observed at > 2 years in patients with 2 to 3 factors (HR: 0.53; 95% CI: 0.37 to 0.75; p< 0.001) but not in those with 0 to 1 factor (HR: 0.88; 95% CI: 0.59 to 1.31; p =0.535). CONCLUSIONS Patients with more advanced ischemic cardiomyopathy receive greater benefit from CABG. This supports the indication for surgical revascularization in patients with more extensive CAD and worse myocardial dysfunction and remodeling. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595) (C) 2014 by the American College of Cardiology Foundation. C1 [Panza, Julio A.] Westchester Cty Med Ctr, Valhalla, NY 10595 USA. [Panza, Julio A.] New York Med Coll, Valhalla, NY 10595 USA. [Velazquez, Eric J.] Duke Univ, Sch Med, Duke Clin Res Inst, Dept Med Cardiol, Durham, NC USA. [She, Lilin; Lee, Kerry L.] Duke Univ, Sch Med, Duke Clin Res Inst, Dept Biostat & Bioinformat, Durham, NC USA. [Smith, Peter K.; Jones, Robert H.] Duke Univ, Sch Med, Duke Clin Res Inst, Dept Cardiothorac Surg, Durham, NC USA. [Nicolau, Jose C.] Univ Sao Paulo, Sch Med, Sao Paulo, Brazil. [Favaloro, Roberto R.] Univ Hosp Favaloro Fdn, Buenos Aires, DF, Argentina. [Gradinac, Sinisa] Univ Belgrade, Sch Med, Belgrade, Serbia. [Chrzanowski, Lukasz] Med Univ Lodz, Dept Cardiol, Lodz, Poland. [Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Howlett, Jonathan G.] Foothills Med Ctr, Calgary, AB, Canada. [Jasinski, Marek] Med Univ Silesia, Katowice, Poland. [Hill, James A.] Univ Florida, Shands Hosp, Gainesville, FL USA. [Szwed, Hanna] Inst Cardiol, Warsaw, Poland. [Larbalestier, Robert] Royal Perth Hosp, Perth, WA 6001, Australia. [Desvigne-Nickens, Patrice] NHLBI, Bethesda, MD 20892 USA. [Rouleau, Jean L.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. RP Panza, JA (reprint author), Westchester Cty Med Ctr, Div Cardiol, 100 Woods Rd,Macy Pavil,Room 102, Valhalla, NY 10595 USA. EM PanzaJ@wcmc.com RI Nicolau, Jose/E-1487-2012 FU National Institutes of Health [U01HL69015, U01HL69013] FX This work was supported by the National Institutes of Health (grants: U01HL69015 and U01HL69013). Dr. Prabhakaran has received honoraria from Torrent Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 26 TC 22 Z9 25 U1 1 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 AUG 12 PY 2014 VL 64 IS 6 BP 553 EP 561 DI 10.1016/j.jacc.2014.04.064 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN0AB UT WOS:000340242100005 PM 25104523 ER PT J AU Bartesaghi, A Matthies, D Banerjee, S Merk, A Subramaniam, S AF Bartesaghi, Alberto Matthies, Doreen Banerjee, Soojay Merk, Alan Subramaniam, Sriram TI Structure of beta-galactosidase at 3.2-angstrom resolution obtained by cryo-electron microscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE single-particle EM; frame alignment; CTF determination; 3D reconstruction; structure refinement ID BEAM-INDUCED MOTION; ELECTRON-MICROSCOPY; CRYO-EM; RADIATION-DAMAGE; ESCHERICHIA-COLI; 3-DIMENSIONAL STRUCTURE; CRYOMICROSCOPY; BACTERIORHODOPSIN; CRYSTALLOGRAPHY; MACROMOLECULES AB We report the solution structure of Escherichia coli beta-galactosidase (similar to 465 kDa), solved at similar to 3.2-angstrom resolution by using single-particle cryo-electron microscopy (cryo-EM). Densities for most side chains, including those of residues in the active site, and a catalytic Mg2+ ion can be discerned in the map obtained by cryo-EM. The atomic model derived from our cryo-EM analysis closely matches the 1.7-angstrom crystal structure with a global rmsd of similar to 0.66 angstrom. There are significant local differences throughout the protein, with clear evidence for conformational changes resulting from contact zones in the crystal lattice. Inspection of the map reveals that although densities for residues with positively charged and neutral side chains are well resolved, systematically weaker densities are observed for residues with negatively charged side chains. We show that the weaker densities for negatively charged residues arise from their greater sensitivity to radiation damage from electron irradiation as determined by comparison of density maps obtained by using electron doses ranging from 10 to 30 e(-)/angstrom(2). In summary, we establish that it is feasible to use cryo-EM to determine near-atomic resolution structures of protein complexes (<500 kDa) with low symmetry, and that the residue-specific radiation damage that occurs with increasing electron dose can be monitored by using dose fractionation tools available with direct electron detector technology. C1 [Bartesaghi, Alberto; Matthies, Doreen; Banerjee, Soojay; Merk, Alan; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX We thank Drs. Lesley A. Earl and Mario J. Borgnia for helpful comments on the manuscript, Dr. Erin Tran for assistance with specimen preparation, and Robert Mueller for technical assistance with electron microscopy. The complete set of electron micrographs used to obtain the density map presented here is available through the Electron Microscopy Pilot Image ARchive (EMPIAR). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (NIH). This research was supported by funds from the Center for Cancer Research, National Cancer Institute, NIH. NR 48 TC 50 Z9 51 U1 5 U2 35 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 12 PY 2014 VL 111 IS 32 BP 11709 EP 11714 DI 10.1073/pnas.1402809111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM8CQ UT WOS:000340097900040 PM 25071206 ER PT J AU Kim, JD Toda, C D'Agostino, G Zeiss, CJ DiLeone, RJ Elsworth, JD Kibbey, RG Chan, O Harvey, BK Richie, CT Savolainen, M Myohanen, T Jeong, JK Diano, S AF Kim, Jung Dae Toda, Chitoku D'Agostino, Giuseppe Zeiss, Caroline J. DiLeone, Ralph J. Elsworth, John D. Kibbey, Richard G. Chan, Owen Harvey, Brandon K. Richie, Christopher T. Savolainen, Mari Myohanen, Timo Jeong, Jin Kwon Diano, Sabrina TI Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE central glucose sensing; sympathetic nervous system; peripheral hormonal regulation ID DIET-INDUCED OBESITY; DOPAMINE NEURONS; NERVOUS-SYSTEM; DEFICIENT MICE; MESSENGER-RNA; RAT-BRAIN; OLIGOPEPTIDASE; PITUITARY; PROTEIN; LOCALIZATION AB Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prep(gt/gt)) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/gt) mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus-PREP reversed the glucose-intolerant phenotype of the Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function. C1 [Kim, Jung Dae; Toda, Chitoku; D'Agostino, Giuseppe; Jeong, Jin Kwon; Diano, Sabrina] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA. [DiLeone, Ralph J.; Elsworth, John D.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Kibbey, Richard G.; Chan, Owen] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Kibbey, Richard G.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Diano, Sabrina] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA. [Kim, Jung Dae; Toda, Chitoku; D'Agostino, Giuseppe; Jeong, Jin Kwon; Diano, Sabrina] Yale Univ, Sch Med, Program Integrat Cell Signaling & Neurobiol Metab, New Haven, CT 06520 USA. [Zeiss, Caroline J.; Diano, Sabrina] Yale Univ, Sch Med, Sect Comparat Med, New Haven, CT 06520 USA. [Harvey, Brandon K.; Richie, Christopher T.; Savolainen, Mari] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Savolainen, Mari; Myohanen, Timo] Univ Helsinki, Fac Pharm, FIN-00014 Helsinki, Finland. RP Diano, S (reprint author), Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA. EM sabrina.diano@yale.edu RI Myohanen, Timo/N-8438-2014; D'Agostino, Giuseppe/F-3399-2012; OI D'Agostino, Giuseppe/0000-0002-3502-4251; DiLeone, Ralph/0000-0002-4770-2590; Myohanen, Timo/0000-0002-9277-6687 FU Yale Diabetes Research Center [P30 DK-45735]; National Institutes of Health [DK084065, DK097566]; American Diabetes Association Research Award [7-11-BS-33] FX We thank the Yale Diabetes Research Center for partially supporting the clamp studies (Grant P30 DK-45735). This work was supported by National Institutes of Health Grants DK084065 and DK097566 (to S. D.) and by American Diabetes Association Research Award 7-11-BS-33 (to S.D.). NR 34 TC 9 Z9 9 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 12 PY 2014 VL 111 IS 32 BP 11876 EP 11881 DI 10.1073/pnas.1406000111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM8CQ UT WOS:000340097900068 PM 25071172 ER PT J AU Wu, QZ Prager, KC Goldstein, T Alt, DP Galloway, RL Zuerner, RL Lloyd-Smith, JO Schwacke, L AF Wu, Qingzhong Prager, Katherine C. Goldstein, Tracey Alt, David P. Galloway, Renee L. Zuerner, Richard L. Lloyd-Smith, James O. Schwacke, Lori TI Development of a real-time PCR for the detection of pathogenic Leptospira spp. in California sea lions SO DISEASES OF AQUATIC ORGANISMS LA English DT Article DE Sea lions; Pathogenic Leptospira spp.; lipL32 gene; Real-time PCR; Urine; Kidney ID QUANTITATIVE PCR; IDENTIFICATION; GROWTH; POMONA AB Several real-time PCR assays are currently used for detection of pathogenic Leptospira spp.; however, few methods have been described for the successful evaluation of clinical urine samples. This study reports a rapid assay for the detection of pathogenic Leptospira spp. in California sea lions Zalophus californianus using real-time PCR with primers and a probe targeting the lipL32 gene. The PCR assay had high analytic sensitivity-the limit of detection was 3 genome copies per PCR volume using L. interrogans serovar Pomona DNA and 100% analytic specificity; it detected all pathogenic leptospiral serovars tested and none of the non-pathogenic Leptospira species (L. biflexa and L. meyeri serovar Semaranga), the intermediate species L. inadai, or the non-Leptospira pathogens tested. Our assay had an amplification efficiency of 1.00. Comparisons between the real-time PCR assay and culture isolation for detection of pathogenic Leptospira spp. in urine and kidney tissue samples from California sea lions showed that samples were more often positive by real-time PCR than by culture methods. Inclusion of an internal amplification control in the real-time PCR assay showed no inhibitory effects in PCR negative samples. These studies indicated that our real-time PCR assay has high analytic sensitivity and specificity for the rapid detection of pathogenic Leptospira species in urine and kidney tissue samples. C1 [Wu, Qingzhong; Schwacke, Lori] Natl Ocean Serv, Hollings Marine Lab, Natl Ctr Coastal Ocean Sci, NOAA, Charleston, SC 29412 USA. [Prager, Katherine C.; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Prager, Katherine C.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Prager, Katherine C.] Marine Mammal Ctr, Sausalito, CA 94965 USA. [Goldstein, Tracey] Univ Calif Davis, Sch Vet Med, Hlth Inst 1, Davis, CA 95616 USA. [Alt, David P.; Zuerner, Richard L.] Natl Anim Dis Ctr, Infect Bacterial Dis Res Unit, Ames, IA 50010 USA. [Galloway, Renee L.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Zuerner, Richard L.] USDA ARS, Washington, DC 20250 USA. RP Wu, QZ (reprint author), Natl Ocean Serv, Hollings Marine Lab, Natl Ctr Coastal Ocean Sci, NOAA, Charleston, SC 29412 USA. EM qingzhongwu@yahoo.com RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU NOAA's Oceans and Human Health Initiative; John H. Prescott Marine Mammal Rescue Assistance Grant Program; National Science Foundation [OCE-1335657]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank Brian Thompson, for providing non-Leptospira bacteria. We also thank the staff of The Marine Mammal Center in Sausalito, California for providing the samples from the stranded sea lions; Dr. Robert DeLong and his group at the National Marine Mammal Laboratory for their collaboration and assistance in collecting samples from wild-caught, free-ranging sea lions. This work was performed in part at the University of California Natural Reserve System Ano Nuevo Island Reserve. We thank Ano Nuevo State Park rangers for their logistical support and Rick Hornsby at the National Animal Disease Center for his excellent technical support. Funding for this research was provided by NOAA's Oceans and Human Health Initiative, the John H. Prescott Marine Mammal Rescue Assistance Grant Program, and the National Science Foundation (OCE-1335657). K.C.P. and J.L.S. acknowledge financial support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. This publication does not constitute an endorsement of any commercial product or intend to be an opinion beyond scientific or other results obtained by the NOAA or the ARS. NR 21 TC 1 Z9 1 U1 0 U2 8 PU INTER-RESEARCH PI OLDENDORF LUHE PA NORDBUNTE 23, D-21385 OLDENDORF LUHE, GERMANY SN 0177-5103 EI 1616-1580 J9 DIS AQUAT ORGAN JI Dis. Aquat. Org. PD AUG 11 PY 2014 VL 110 IS 3 BP 165 EP 172 DI 10.3354/dao02752 PG 8 WC Fisheries; Veterinary Sciences SC Fisheries; Veterinary Sciences GA AQ6LI UT WOS:000342923400001 PM 25114040 ER PT J AU Gonzalez-Freire, M de Cabo, R Studenski, SA Ferrucci, L AF Gonzalez-Freire, Marta de Cabo, Rafael Studenski, Stephanie A. Ferrucci, Luigi TI The neuromuscular junction: aging at the crossroad between nerves and muscle SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Review DE aging; denervation; motor unit; neuromuscular junction; sarcopenia ID RAT SKELETAL-MUSCLE; AMYOTROPHIC-LATERAL-SCLEROSIS; PERIPHERAL NERVOUS-SYSTEM; TERMINAL AGRIN FRAGMENT; AGE-RELATED-CHANGES; CALORIC RESTRICTION; NEUROTROPHIC FACTOR; SCHWANN-CELLS; MOTOR-NEURONS; OLDER-ADULTS AB Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many factors such as mitochondrial dysfunction, oxidative stress, inflammation, changes in the innervation of muscle fibers, and mechanical properties of the motor units probably perform an important role in NMJ degeneration and muscle mass and strength decline in late life. This review addresses the primary events that might lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. Interventions such as caloric restriction and exercise may positively affect the NMJ through this mechanism and attenuate the age-related progressive impairment in motor function. C1 [Gonzalez-Freire, Marta; de Cabo, Rafael; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gonzalez-Freire, Marta; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore Longitudinal Study Aging, NIH, Baltimore, MD 21224 USA. RP Gonzalez-Freire, M (reprint author), NIA, Translat Gerontol Branch, BRC Room 09C506,251 Bayview Blvd, Baltimore, MD 21224 USA. EM marta.gonzalezfreire@nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the NIH, National Institute on Aging FX This review was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 146 TC 37 Z9 38 U1 5 U2 37 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD AUG 11 PY 2014 VL 6 AR 208 DI 10.3389/fnagi.2014.00208 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AN9MT UT WOS:000340931700001 PM 25157231 ER PT J AU Jamain, S Cichon, S Etain, B Muhleisen, TW Georgi, A Zidane, N Chevallier, L Deshommes, J Nicolas, A Henrion, A Degenhardt, F Mattheisen, M Priebe, L Mathieu, F Kahn, JP Henry, C Boland, A Zelenika, D Gut, I Heath, S Lathrop, M Maier, W Albus, M Rietschel, M Schulze, TG McMahon, FJ Kelsoe, JR Hamshere, M Craddock, N Nothen, MM Bellivier, F Leboyer, M AF Jamain, Stephane Cichon, Sven Etain, Bruno Muehleisen, Thomas W. Georgi, Alexander Zidane, Nora Chevallier, Lucie Deshommes, Jasmine Nicolas, Aude Henrion, Annabelle Degenhardt, Franziska Mattheisen, Manuel Priebe, Lutz Mathieu, Flavie Kahn, Jean-Pierre Henry, Chantal Boland, Anne Zelenika, Diana Gut, Ivo Heath, Simon Lathrop, Mark Maier, Wolfgang Albus, Margot Rietschel, Marcella Schulze, Thomas G. McMahon, Francis J. Kelsoe, John R. Hamshere, Marian Craddock, Nicholas Noethen, Markus M. Bellivier, Frank Leboyer, Marion TI Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; I AFFECTIVE-DISORDER; COA TRANSFERASE SCOT; SUSCEPTIBILITY LOCI; LINKAGE SCAN; 3 SUBGROUPS; AGE; RISK; SCHIZOPHRENIA; FAMILIES AB Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder. C1 [Jamain, Stephane; Etain, Bruno; Zidane, Nora; Chevallier, Lucie; Deshommes, Jasmine; Nicolas, Aude; Henrion, Annabelle; Mathieu, Flavie; Henry, Chantal; Bellivier, Frank; Leboyer, Marion] Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France. [Jamain, Stephane; Etain, Bruno; Zidane, Nora; Chevallier, Lucie; Deshommes, Jasmine; Nicolas, Aude; Henrion, Annabelle; Mathieu, Flavie; Henry, Chantal; Leboyer, Marion] Univ Paris Est, Fac Med, Creteil, France. [Jamain, Stephane; Etain, Bruno; Zidane, Nora; Chevallier, Lucie; Deshommes, Jasmine; Nicolas, Aude; Henrion, Annabelle; Mathieu, Flavie; Kahn, Jean-Pierre; Henry, Chantal; Bellivier, Frank; Leboyer, Marion] Fdn FondaMental, Creteil, France. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM1, Julich, Germany. [Cichon, Sven; Muehleisen, Thomas W.; Degenhardt, Franziska; Mattheisen, Manuel; Priebe, Lutz; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cichon, Sven; Muehleisen, Thomas W.; Degenhardt, Franziska; Mattheisen, Manuel; Priebe, Lutz; Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Cichon, Sven] Univ Basel, Div Med Genet, Univ Hosp, Basel, Switzerland. [Cichon, Sven] Univ Basel, Dept Biomed, Basel, Switzerland. [Etain, Bruno; Deshommes, Jasmine; Henry, Chantal; Leboyer, Marion] Hop Henri Mondor Albert Chenevier, AP HP, Creteil, France. [Georgi, Alexander; Albus, Margot; Rietschel, Marcella; Schulze, Thomas G.] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Georgi, Alexander; Maier, Wolfgang; Rietschel, Marcella] Univ Bonn, Dept Psychiat, Bonn, Germany. [Deshommes, Jasmine] Hop Henri Mondor Albert Chenevier, INSERM, Pole Rech Clin Sante Publ, Ctr Invest Clin 006, Creteil, France. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] Aarhus Univ, Ctr Integrat Sequencing, Aarhus, Denmark. [Kahn, Jean-Pierre] Hop Jeanne dArc, Ctr Hosp Univ Nancy, Dept Psychiat, Toul, France. [Kahn, Jean-Pierre] Hop Jeanne dArc, Ctr Hosp Univ Nancy, Psychol Clin, Toul, France. [Boland, Anne; Zelenika, Diana; Gut, Ivo; Heath, Simon; Lathrop, Mark] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, Univ Med Ctr, D-37073 Gottingen, Germany. [McMahon, Francis J.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Hamshere, Marian; Craddock, Nicholas] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Bellivier, Frank] Grp Hosp Lariboisiere F Widal, AP HP, Pole Psychiat, Paris, France. [Bellivier, Frank] Univ Paris Diderot, Paris, France. RP Jamain, S (reprint author), Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France. EM stephane.jamain@inserm.fr RI Mattheisen, Manuel/B-4949-2012; BELLIVIER, FRANK/H-5197-2012; OI Mattheisen, Manuel/0000-0002-8442-493X; Georgi, Alexander/0000-0002-1499-8524; Jamain, Stephane/0000-0002-4321-4100; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464; Etain, Bruno/0000-0002-5377-1488 FU INSERM (Poste d'Accueil INSERM); Assistance Publique des Hopitaux de Paris; Agence Nationale pour la Recherche (ANR NEURO - Project MANAGE_BPAD); Centre National de Genotypage (Centre d'Energie Atomique, Evry, France); Reseau Thematique de Recherche et de Soins en Sante Mentale (Fondation FondaMental) FX This work was supported by INSERM (Poste d'Accueil INSERM to B. E.), Assistance Publique des Hopitaux de Paris, the Agence Nationale pour la Recherche (ANR NEURO2006 - Project MANAGE_BPAD), the Centre National de Genotypage (Centre d'Energie Atomique, Evry, France) and the Reseau Thematique de Recherche et de Soins en Sante Mentale (Fondation FondaMental). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 6 Z9 7 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 11 PY 2014 VL 9 IS 8 AR e104326 DI 10.1371/journal.pone.0104326 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1WB UT WOS:000341105100048 PM 25111785 ER PT J AU Jameson, JB Kantz, A Schultz, L Kalyanaraman, C Jacobson, MP Maloney, DJ Jadhav, A Simeonov, A Holman, TR AF Jameson, J. Brian, II Kantz, Auric Schultz, Lena Kalyanaraman, Chakrapani Jacobson, Matthew P. Maloney, David J. Jadhav, Ajit Simeonov, Anton Holman, Theodore R. TI A High Throughput Screen Identifies Potent and Selective Inhibitors to Human Epithelial 15-Lipoxygenase-2 SO PLOS ONE LA English DT Article ID HUMAN RETICULOCYTE; 12-HUMAN LIPOXYGENASE; SUBSTRATE-SPECIFICITY; DISCOVERY; 12-LIPOXYGENASE; EXPRESSION; 15-HUMAN; PURIFICATION; LIBRARIES; 15-LOX2 AB Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic acids with varying positional specificity to yield important biological signaling molecules. Human epithelial 15-lipoxygenase-2 (15-LOX-2) is a highly specific LOX isozyme that is expressed in epithelial tissue and whose activity has been correlated with suppression of tumor growth in prostate and other epithelial derived cancers. Despite the potential utility of an inhibitor to probe the specific role of 15-LOX-2 in tumor progression, no such potent/specific 15-LOX-2 inhibitors have been reported to date. This study employs high throughput screening to identify two novel, specific 15-LOX-2 inhibitors. MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a K-i of 0.9+/-20.4 mu M and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2. MLS000536924 is a competitive inhibitor with a K-i of 2.5+/-20.5 mu M and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above. Finally, neither compound possesses reductive activity towards the active-site ferrous ion. C1 [Jameson, J. Brian, II; Kantz, Auric; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Schultz, Lena; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Kalyanaraman, Chakrapani; Jacobson, Matthew P.] Univ Calif San Francisco, Sch Pharm, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. RP Simeonov, A (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov; tholman@chemistry.ucsc.edu FU National Institutes of Health [GM56062, S10-RR20939] FX This work was supported by the National Institutes of Health (GM56062 (TRH) and S10-RR20939 (University of California Santa Cruz)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 3 Z9 3 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 11 PY 2014 VL 9 IS 8 AR e104094 DI 10.1371/journal.pone.0104094 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1WB UT WOS:000341105100030 PM 25111178 ER PT J AU Sayers, KT Brooks, AD Sayers, TJ Chertov, O AF Sayers, Kevin T. Brooks, Alan D. Sayers, Thomas J. Chertov, Oleg TI Increased Secretory Leukocyte Protease Inhibitor (SLPI) Production by Highly Metastatic Mouse Breast Cancer Cells SO PLOS ONE LA English DT Article ID STIMULATES MIGRATION; EXTRACELLULAR-MATRIX; GROWTH-FACTOR; IN-VITRO; IDENTIFICATION; PROTEOMICS; CARCINOMA; PROMOTES; LINES AB The precise molecular mechanisms enabling cancer cells to metastasize from the primary tumor to different tissue locations are still largely unknown. Secretion of some proteins by metastatic cells could facilitate metastasis formation. The comparison of secreted proteins from cancer cells with different metastatic capabilities in vivo might provide insight into proteins involved in the metastatic process. Comparison of the secreted proteins from the mouse breast cancer cell line 4T1 and its highly metastatic 4T1.2 clone revealed a prominent differentially secreted protein which was identified as SLPI (secretory leukocyte protease inhibitor). Western blotting indicated higher levels of the protein in both conditioned media and whole cell lysates of 4T1.2 cells. Additionally higher levels of SLPI were also observed in 4T1.2 breast tumors in vivo following immunohistochemical staining. A comparison of SLPI mRNA levels by gene profiling using microarrays and RTPCR did not detect major differences in SLPI gene expression between the 4T1 and 4T1.2 cells indicating that SLPI secretion is regulated at the protein level. Our results demonstrate that secretion of SLPI is drastically increased in highly metastatic cells, suggesting a possible role for SLPI in enhancing the metastatic behavior of breast cancer cell line 4T1. C1 [Sayers, Kevin T.; Chertov, Oleg] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Brooks, Alan D.; Sayers, Thomas J.] Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Sayers, TJ (reprint author), Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM sayerst@mail.nih.gov RI Sayers, Thomas/G-4859-2015 FU Frederick National Laboratory for Cancer Research; National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. All funding for this research was funded under contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 2 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 11 PY 2014 VL 9 IS 8 AR e104223 DI 10.1371/journal.pone.0104223 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1WB UT WOS:000341105100038 PM 25110884 ER PT J AU Bhandari, N Rongsen-Chandola, T Bavdekar, A John, J Antony, K Taneja, S Goyal, N Kawade, A Kang, G Rathore, SS Juvekar, S Muliyil, J Arya, A Shaikh, H Abraham, V Vrati, S Proschan, M Kohberger, R Thiry, G Glass, R Greenberg, HB Curlin, G Mohan, K Harshavardhan, GVJA Prasad, S Rao, TS Boslego, J Bhan, MK AF Bhandari, Nita Rongsen-Chandola, Temsunaro Bavdekar, Ashish John, Jacob Antony, Kalpana Taneja, Sunita Goyal, Nidhi Kawade, Anand Kang, Gagandeep Rathore, Sudeep Singh Juvekar, Sanjay Muliyil, Jayaprakash Arya, Alok Shaikh, Hanif Abraham, Vinod Vrati, Sudhanshu Proschan, Michael Kohberger, Robert Thiry, Georges Glass, Roger Greenberg, Harry B. Curlin, George Mohan, Krishna Harshavardhan, G. V. J. A. Prasad, Sai Rao, T. S. Boslego, John Bhan, Maharaj Kishan CA India Rotavirus Vaccine Grp TI Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life SO VACCINE LA English DT Article DE Rotavirus; Gastroenteritis; Vaccine efficacy ID PLACEBO-CONTROLLED TRIAL; 1ST 2 YEARS; DOUBLE-BLIND; INFANTS; GASTROENTERITIS; SAFETY; POPULATION; DISEASE; PCR AB Rotavirus gastroenteritis is one of the leading causes of diarrhea in Indian children less than 2 years of age. The 116E rotavirus strain was developed as part of the Indo-US Vaccine Action Program and has undergone efficacy trials. This paper reports the efficacy and additional safety data in children up to 2 years of age. In a double-blind placebo controlled multicenter trial, 6799 infants aged 6-7 weeks were randomized to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. The primary outcome was severe (>= 11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. We randomly assigned 4532 and 2267 subjects to receive vaccine and placebo, respectively, with over 96% subjects receiving all three doses of the vaccine or placebo. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. The overall incidence of severe RVGE per 100 person years was 1.3 in the vaccine group and 2.9 in the placebo recipients. Vaccine efficacy against severe rotavirus gastroenteritis in children up to 2 years of age was 55.1% (95% CI 39.9 to 66.4; p<0.0001); vaccine efficacy in the second year of life of 48.9% (95% CI 17.4 to 68.4; p = 0.0056) was only marginally less than in the first year of life [56.3% (95% CI 36.7 to 69.9; p < 0.0001)]. The number of infants needed to be immunized to prevent one episode of severe RVGE in the first 2 years of life was 40(95% CI 28.0 to 63.0) and for RVGE of any severity, it was 21(95% CI 16.0 to 32.0). Serious adverse events were observed at the same rates in the two groups. None of the eight intussusception events occurred within 30 days of a vaccine dose and all were reported only after the third dose. The sustained efficacy of the 116E in the second year of life is reassuring. (C) 2014 Published by Elsevier Ltd. C1 [Bhandari, Nita; Rongsen-Chandola, Temsunaro; Taneja, Sunita; Goyal, Nidhi; Rathore, Sudeep Singh; Arya, Alok] Soc Appl Studies, Ctr Hlth Res & Dev, New Delhi, India. [Bavdekar, Ashish; Kawade, Anand; Juvekar, Sanjay; Shaikh, Hanif] KEM Hosp Res Ctr, Pune, Maharashtra, India. [John, Jacob; Kang, Gagandeep; Muliyil, Jayaprakash; Abraham, Vinod] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Antony, Kalpana] PATH India, New Delhi, India. [Vrati, Sudhanshu] Translat Hlth Sci & Technol Inst, Gurgaon, Haryana, India. [Vrati, Sudhanshu] Natl Inst Immunol, New Delhi 110067, India. [Proschan, Michael; Glass, Roger; Curlin, George] NIH, Bethesda, MD 20892 USA. [Kohberger, Robert] Blair & Co, Greenwich, CT USA. [Thiry, Georges] PATH, Adv Rotavirus Vaccines Dev Project, Paris, France. [Greenberg, Harry B.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Mohan, Krishna; Harshavardhan, G. V. J. A.; Prasad, Sai] Bharat Biotech Int Ltd, Genome Valley, Andhra Pradesh, India. [Rao, T. S.] Govt India, Minist Sci & Technol, Dept Biotechnol, New Delhi, India. [Boslego, John] PATH, Vaccine Dev Global Program, Miami, FL USA. [Bhan, Maharaj Kishan] Govt India, Minist Sci & Technol, New Delhi, India. RP Bhan, MK (reprint author), Govt India, Minist Sci & Technol, B-10, New Delhi 110017, India. EM rajkbhan@gmail.com OI John, Jacob/0000-0003-3654-5099; Strand, Tor/0000-0002-4038-151X FU Department of Biotechnology, and Biotechnology Industry Research Assistance Council, Government of India, New Delhi, India; Bill & Melinda Gates Foundation, USA [52714]; Research Council of Norway, UK Department for International Development; National Institutes of Health, Bethesda, USA; Bharat Biotech International, Hyderabad, India FX This trial was funded by the Department of Biotechnology, and Biotechnology Industry Research Assistance Council, Government of India, New Delhi, India; by a grant from the Bill & Melinda Gates Foundation (number 52714) to PATH, USA; by the Research Council of Norway, UK Department for International Development; by National Institutes of Health, Bethesda, USA; and by Bharat Biotech International, Hyderabad, India. We thank infants and families who willingly participated in the trial; local governments for the support extended to the study team; pediatricians in referral hospitals who provided care to enrolled infants; data management, project management, medical monitoring, and pharmaco-vigilance teams at Quintiles (India); the clinical data operations and biostatistics team at Quintiles (South Africa and UK); Jean-Michel Andrieux (ANTHA Clinical Quality Consulting, France) for quality assurance audits at the three sites and the central investigation laboratory, and Monica McNeal (Cincinnati Children's Hospital Medical Centre, USA) for the laboratory audits; VK Paul and the neonatal unit at All India Institute of Medical Sciences (New Delhi, India); V M Katoch (Indian Council of Medical Research, India); K Vijay Raghavan (Department of Biotechnology, Government of India); N K Ganguly (Indian Council of Medical Research, India); Krishna Ella (Bharat Biotech International, Hyderabad, India) for sustained mentoring and support to this innovation; the National Institute of Allergy and Infectious Diseases (NIAID) at National Institutes of Health (NIH), USA, and Centers for Diseases Control, USA; Stanford University, USA; and Centre for International Health, University of Bergen, Norway; and committees and departments of the Government of India's Ministry of Health and Family Welfare and Ministry of Science and Technology for their guidance and encouragement. NR 24 TC 15 Z9 15 U1 2 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD AUG 11 PY 2014 VL 32 SU 1 BP A110 EP A116 DI 10.1016/j.vaccine.2014.04.079 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AO0CU UT WOS:000340977500022 PM 25091663 ER PT J AU Appella, DH AF Appella, Daniel H. TI Targeting HIV nucleocapsid protein via a small molecule platform and related preclinical development SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 889-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403452 ER PT J AU Barchi, JJ Biswas, S Brinas, RP Rittenhouse-Olson, K Sahoo, P AF Barchi, Joseph J. Biswas, Souvik Brinas, Raymond P. Rittenhouse-Olson, Kate Sahoo, Padmini TI Glycopeptide conjugates of tumor-associated carbohydrate antigens as anticancer agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Barchi, Joseph J.; Biswas, Souvik; Brinas, Raymond P.] NCI, Frederick, MD 21702 USA. [Rittenhouse-Olson, Kate; Sahoo, Padmini] SUNY Buffalo, Buffalo, NY 14214 USA. EM barchij@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 102-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165102257 ER PT J AU Bolton, E AF Bolton, Evan TI PubChem: Celebrating ten years online SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 139-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103420 ER PT J AU Bolton, E AF Bolton, Evan TI Mining PubChem data: Interfaces, approaches, and best practices SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 143-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103423 ER PT J AU Bolton, E AF Bolton, Evan TI Data linking in PubChem using InChI SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 33-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103319 ER PT J AU Brothers, RC Shear, B Haymond, A Johnny, C Couch, RD Boshoff, HI Dowd, CS AF Brothers, Robert C. Shear, Brian Haymond, Amanda Johnny, Chinchu Couch, Robin D. Boshoff, Helena I. Dowd, Cynthia S. TI Synthesis of natural product FR33289 and analogs targeting inhibition of Mtb Dxr SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Brothers, Robert C.; Shear, Brian; Dowd, Cynthia S.] George Washington Univ, Washington, DC USA. [Haymond, Amanda; Johnny, Chinchu; Couch, Robin D.] George Mason Univ, Manassas, VA 20110 USA. [Boshoff, Helena I.] NIH, Bethesda, MD 20814 USA. EM Carl_b@gwmail.gwu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 534-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402324 ER PT J AU Chavan, TS Jang, H Khavrutskii, L Freed, BC Tarasov, SG Gaponenko, V Tarasova, NI Nussinov, R AF Chavan, Tanmay S. Jang, Hyunbum Khavrutskii, Lyuba Freed, Benjamin C. Tarasov, Sergey G. Gaponenko, Vadim Tarasova, Nadya I. Nussinov, Ruth TI High affinity interaction of K-Ras4B hypervariable region with Ras active site SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jang, Hyunbum; Khavrutskii, Lyuba; Freed, Benjamin C.; Tarasov, Sergey G.; Tarasova, Nadya I.; Nussinov, Ruth] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Jang, Hyunbum; Khavrutskii, Lyuba; Freed, Benjamin C.; Tarasov, Sergey G.; Tarasova, Nadya I.; Nussinov, Ruth] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. [Chavan, Tanmay S.; Gaponenko, Vadim] Univ Illinois, Dept Med Chem, Chicago, IL 60607 USA. [Chavan, Tanmay S.; Gaponenko, Vadim] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. EM nussinor@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 109-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104349 ER PT J AU Das, D Maeda, K Hayashi, Y Gavande, N Desai, DV Chang, SB Ghosh, AK Mitsuya, H AF Das, Debananda Maeda, Kenji Hayashi, Yasuhiro Gavande, Navnath Desai, Darshan V. Chang, Simon B. Ghosh, Arun K. Mitsuya, Hiroaki TI Identification of novel small molecule CXCR4 inhibitors as anti-HIV agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Das, Debananda; Maeda, Kenji; Hayashi, Yasuhiro; Desai, Darshan V.; Chang, Simon B.; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol, Grad Sch Med & Pharmaceut Sci, Kumamoto, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Infect Dis, Grad Sch Med & Pharmaceut Sci, Kumamoto, Japan. [Gavande, Navnath; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Gavande, Navnath; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. EM dasd@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 406-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104621 ER PT J AU Dryga, A Marchler-Bauer, A Lanczycki, CJ Bolton, E Geer, LY Bryant, SH AF Dryga, Anatoly Marchler-Bauer, Aron Lanczycki, Christopher J. Bolton, Evan Geer, Lewis Y. Bryant, Stephen H. TI Exhaustive clustering of similar binding pockets formed by ligands and proteins found in 3D protein structures SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Dryga, Anatoly; Marchler-Bauer, Aron; Lanczycki, Christopher J.; Bolton, Evan; Geer, Lewis Y.; Bryant, Stephen H.] NIH, NCBI, NLM, Bethesda, MD 20894 USA. EM anatoly.dryga@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 340-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104563 ER PT J AU Gangjee, A Mohan, R Bai, RL Hamel, E AF Gangjee, Aleem Mohan, Rishabh Bai, Ruoli Hamel, Ernest TI Design, synthesis, and biological evaluation of substituted monocyclic pyrimidines with potential antitubulin activities as antitumor agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Gangjee, Aleem; Mohan, Rishabh] Duquesne Univ, Sch Pharm, Div Med Chem, Pittsburgh, PA 15282 USA. [Bai, Ruoli; Hamel, Ernest] NCI, Div Canc Treatment & Diag, Frederick Natl Lab Canc Res, Screening Technol Branch,Dev Therapeut Program, Frederick, MD 21702 USA. EM mohanr@duq.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 485-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402278 ER PT J AU Gao, Y Berciu, C Nicastro, D Xu, B Horkay, F AF Gao, Yuan Berciu, Cristina Nicastro, Daniela Xu, Bing Horkay, Ferenc TI Supramolecular self-assembly for fluorescence imaging inside living cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Gao, Yuan; Horkay, Ferenc] NIH, Bethesda, MD 20892 USA. [Gao, Yuan] NIST, Gaithersburg, MD USA. [Gao, Yuan; Xu, Bing] Brandeis Univ, Dept Chem, Waltham, MA 02453 USA. [Berciu, Cristina; Nicastro, Daniela] Brandeis Univ, Dept Biol, Waltham, MA 02453 USA. EM yuan.gao@nih.gov NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 354-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103782 ER PT J AU Gao, Y Xu, B Hammouda, B Douglas, J Horkay, F AF Gao, Yuan Xu, Bing Hammouda, Boualem Douglas, Jack Horkay, Ferenc TI Mechanism of temperature dependent supramolecular fibrillization of small molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Gao, Yuan; Horkay, Ferenc] NIH, Bethesda, MD 20892 USA. [Gao, Yuan; Hammouda, Boualem; Douglas, Jack] NIST, Boulder, CO USA. [Gao, Yuan; Xu, Bing] Brandeis Univ, Waltham, MA 02453 USA. EM yuan.gao@nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 174-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103614 ER PT J AU Glowinski, IB AF Glowinski, Irene B. TI Before DNA was a household word: My journey from bioscience to biopolicy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Glowinski, Irene B.] NIAID, Div Microbiol & Infect Dis, Bethesday, MD USA. EM iglowinski@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 7-PROF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167406112 ER PT J AU Guha, R AF Guha, Rajarshi TI Bridging chemistry and biology with data SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Guha, Rajarshi] NCATS, Rockville, MD 20850 USA. EM guhar@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 114-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403719 ER PT J AU He, SS Li, KL Hu, ZY Ferrer, M Southall, N Lin, B Xiao, JB Hu, X Zheng, W Marugan, JJ Aube, J Schoenen, FJ Frankowski, KJ Liang, TJ AF He, Shanshan Li, Kelin Hu, Zongyi Ferrer, Marc Southall, Noel Lin, Billy Xiao, Jingbo Hu, Xin Zheng, Wei Marugan, Juan J. Aube, Jeffrey Schoenen, Frank J. Frankowski, Kevin J. Liang, T. Jake TI Discovery of inhibitors of the hepatitis C virus using a cell-based infection assay SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [He, Shanshan; Hu, Zongyi; Lin, Billy; Liang, T. Jake] NIDDK, NIH, Bethesda, MD 20892 USA. [Li, Kelin; Aube, Jeffrey; Schoenen, Frank J.; Frankowski, Kevin J.] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA. [Ferrer, Marc; Southall, Noel; Xiao, Jingbo; Hu, Xin; Zheng, Wei; Marugan, Juan J.] NIH, Chem Genom Ctr, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 13-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167401719 ER PT J AU Horkay, F Basser, PJ AF Horkay, Ferenc Basser, Peter J. TI Supramolecular organization of cartilage proteoglycans in salt solutions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Horkay, Ferenc; Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 74-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167405210 ER PT J AU Horkay, F Horkayne-Szakaly, I Dimitriados, EK Basser, PJ AF Horkay, Ferenc Horkayne-Szakaly, Iren Dimitriados, Emilios K. Basser, Peter J. TI Effect of osmotic stress on the structure and biomechanical properties of cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Horkay, Ferenc; Horkayne-Szakaly, Iren; Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. [Dimitriados, Emilios K.] NIBIB, NIH, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 22-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101837 ER PT J AU Huang, XF Yin, ZJ Baniel, C Bentley, P Finn, MG Gildersleeve, JC BenMohamed, L AF Huang, Xuefei Yin, Zhaojun Baniel, Claire Bentley, Philip Finn, M. G. Gildersleeve, Jeffrey C. BenMohamed, Lbachir TI "To click or not to click": The design of a carbohydrate based anticancer vaccine for effective and long term antitumor immunity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Huang, Xuefei; Yin, Zhaojun; Baniel, Claire; Bentley, Philip] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Finn, M. G.] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA. [Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [BenMohamed, Lbachir] Univ Calif Irvine, Cellular & Mol Immunol Lab, Irvine, CA 92697 USA. EM xuefei@chemistry.msu.edu RI Huang, Xuefei/G-3371-2014 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 18-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165102182 ER PT J AU Jang, H Arce, FT Ramachandran, S Lal, R Kagan, BL Nussinov, R AF Jang, Hyunbum Arce, Fernando Teran Ramachandran, Srinivasan Lal, Ratnesh Kagan, Bruce L. Nussinov, Ruth TI Membrane insertion of Alzheimer's amyloid-beta (A beta) peptides and their assembly into common cyclic structural motifs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jang, Hyunbum; Nussinov, Ruth] Leidos Biomed Res Inc, Natl Canc Inst Frederick, Canc & Inflammat Program, Frederick, MD 21702 USA. [Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. EM nussinor@helix.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 61-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104303 ER PT J AU Jiang, JK McCoy, JG Li, JH Vootukuri, S Shen, M Shang, Y LeClair, CA Huang, WW Negri, A Blue, R Harrington, A Naini, S David, G Choi, WS Volpi, E Fernandez, J Babayeva, M Nedelman, MA Diacovo, TG Filizola, M Coller, BS Thomas, CJ AF Jiang, Jian-Kang McCoy, Joshua G. Li, Jihong Vootukuri, Spandana Shen, Min Shang, Yi LeClair, Christopher A. Huang, Wenwei Negri, Ana Blue, Robert Harrington, Amanda Naini, Sarasija David, George, III Choi, Won-Seok Volpi, Elisabetta Fernandez, Joseph Babayeva, Mariana Nedelman, Mark A. Diacovo, Thomas G. Filizola, Marta Coller, Barry S. Thomas, Craig J. TI Development of a novel class alpha IIb beta 3 receptor antagonist RUC-4 as anti-platelet aggregation agent for myocardial infarction SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jiang, Jian-Kang; McCoy, Joshua G.; Shen, Min; LeClair, Christopher A.; Huang, Wenwei; Thomas, Craig J.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Shang, Yi; Negri, Ana; Filizola, Marta] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA. [Li, Jihong; Vootukuri, Spandana; Blue, Robert; Harrington, Amanda; Naini, Sarasija; David, George, III; Choi, Won-Seok; Volpi, Elisabetta; Fernandez, Joseph; Coller, Barry S.] Rockefeller Univ, Allen & Frances Adler Lab Blood & Vasc Biol, New York, NY 10021 USA. [Babayeva, Mariana] Touro Coll Pharm, New York, NY USA. [Nedelman, Mark A.] Ekam Imaging, Boston, MA USA. [Diacovo, Thomas G.] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA. [Diacovo, Thomas G.] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA. EM jiankangj@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 365-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402169 ER PT J AU Jordan, SM AF Jordan, Shannon M. TI Hazardous substances data bank: A tool for natural product information and research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jordan, Shannon M.] NIH, Natl Lib Med, Bethesda, MD 20894 USA. EM shannon.jordan1@nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 3-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103291 ER PT J AU Kim, S Bolton, EE Bryant, SH AF Kim, Sunghwan Bolton, Evan E. Bryant, Stephen H. TI Complementarity between PubChem 2D and 3D neighbors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Kim, Sunghwan; Bolton, Evan E.; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 77-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104319 ER PT J AU Kobayashi, H AF Kobayashi, Hisataka TI Activatable fluorescent imaging probes for cancer detection and diagnosis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Kobayashi, Hisataka] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 74-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101530 ER PT J AU Konig, G Hudson, P Boresch, S Woodcock, HL AF Konig, Gerhard Hudson, Phillip Boresch, Stefan Woodcock, Henry Lee TI Affordable multiscale free energy simulations: A novel method that efficiently connects low level sampling to QM/MM via non-Boltzmann Bennett reweighting SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Hudson, Phillip; Woodcock, Henry Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Konig, Gerhard] NIH, Lab Computat Biol, Bethesda, MD 20892 USA. [Boresch, Stefan] Univ Vienna, Dept Computat Biol Chem, A-1090 Vienna, Austria. EM hlw@usf.edu RI Boresch, Stefan/F-3467-2014 OI Boresch, Stefan/0000-0002-2793-6656 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 236-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104470 ER PT J AU LeClair, CA Louer, CT Leister, W AF LeClair, Christopher A. Louer, C. Thomas Leister, William TI Utilizing a SMART approach to compound processing and management SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [LeClair, Christopher A.; Louer, C. Thomas; Leister, William] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM leclairc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 506-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402298 ER PT J AU Marsden, MD Loy, BA DeChristopher, BA Beans, EJ Heumann, LV Fournogerakis, D Schrier, AJ Chun, TW Zack, JA Wender, PA AF Marsden, Matthew D. Loy, Brian A. DeChristopher, Brian A. Beans, Elizabeth J. Heumann, Lars V. Fournogerakis, Dennis Schrier, Adam J. Chun, Tae-Wook Zack, Jerome A. Wender, Paul A. TI Toward HIV eradication strategies: Designed, synthetically accessible bryostatin and prostratin analogs potently induce activation of latent HIV reservoirs in vitro and ex vivo SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Loy, Brian A.; DeChristopher, Brian A.; Beans, Elizabeth J.; Heumann, Lars V.; Fournogerakis, Dennis; Schrier, Adam J.; Wender, Paul A.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. [Loy, Brian A.; DeChristopher, Brian A.; Beans, Elizabeth J.; Heumann, Lars V.; Fournogerakis, Dennis; Schrier, Adam J.; Wender, Paul A.] Stanford Univ, Stanford, CA 94305 USA. [Marsden, Matthew D.; Zack, Jerome A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Chun, Tae-Wook] NIAID, NIH, Bethesda, MD 20892 USA. EM wenderp@stanford.edu NR 0 TC 0 Z9 0 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 4-YCC PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167406327 ER PT J AU Nicklaus, MC AF Nicklaus, Marc C. TI NCI/CADD Group's InChI usage and analysis of tautomerism for InChI V2 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Nicklaus, Marc C.] NCI, CADD Grp, CBL, CCR,NIH, Frederick, MD 21702 USA. EM mn1@helix.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 56-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103340 ER PT J AU Opina, ACL Matsumoto, S Vasalatiy, O Swenson, RE Mitchell, JB Krishna, MC AF Opina, Ana Christina L. Matsumoto, Shingo Vasalatiy, Olga Swenson, Rolf E. Mitchell, James B. Krishna, Murali C. TI Synthesis of metabolic C-13-labeled tracers for hyperpolarization SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Opina, Ana Christina L.; Vasalatiy, Olga; Swenson, Rolf E.] NHLBI, NIH, Bethesda, MD USA. [Matsumoto, Shingo; Mitchell, James B.; Krishna, Murali C.] NCI, NIH, Bethesda, MD 20892 USA. EM ana.opina@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 642-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403226 ER PT J AU Perera, L AF Perera, Lalith TI Metal ion binding at the active site of DNA plymerases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Perera, Lalith] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM pereraL2@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 446-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103869 ER PT J AU Pickard, FC Simmonett, A Brooks, BR AF Pickard, Frank C. Simmonett, Andrew Brooks, Bernard R. TI Efficient high-accuracy non-bonded interactions in the CHARMM simulation package SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Pickard, Frank C.; Simmonett, Andrew; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM pickard81@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 116-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403721 ER PT J AU Robertson, JWF Balijepalli, A Reiner, JE Kasianowicz, JJ AF Robertson, Joseph W. F. Balijepalli, Arvind Reiner, Joseph E. Kasianowicz, John J. TI Effects of equilibrium chemistry on the selectivity of nanopore biosensors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc ID MOLECULE MASS-SPECTROMETRY; CHANNEL; DYNAMICS C1 [Robertson, Joseph W. F.; Kasianowicz, John J.] NIST, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Balijepalli, Arvind] NIH, Heart Lung & Blood Inst, Bethesda, MD 20892 USA. [Reiner, Joseph E.] Virginia Commonwealth Univ, Dept Phys, Richmond, VA 23220 USA. EM joseph.robertson@nist.gov NR 8 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 331-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101770 ER PT J AU Schneekloth, JS Kim, YS AF Schneekloth, John S., Jr. Kim, Yeong Sang TI Chemical approaches for studying protein sumoylation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Schneekloth, John S., Jr.; Kim, Yeong Sang] NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM schneeklothjs@mail.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 502-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403092 ER PT J AU Shao, YH Sodt, A Koenig, G Tao, P Mei, Y Brooks, B AF Shao, Yihan Sodt, Alex Koenig, Gerhard Tao, Peng Mei, Ye Brooks, Bernard TI Multiple-environment same-system quantum mechanical molecular mechanical (MESS-QM/MM) calculations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Shao, Yihan] Q Chem Inc, Pleasanton, CA 94588 USA. [Sodt, Alex; Koenig, Gerhard; Mei, Ye; Brooks, Bernard] NHLBI, NIH, Bethesda, MD 20852 USA. [Tao, Peng] So Methodist Univ, Dallas, TX 75275 USA. EM yihan.shao@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 226-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403828 ER PT J AU Shaytan, A Panchenko, A AF Shaytan, Alexey Panchenko, Anna TI Water mediated interactions in nucleosomes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Shaytan, Alexey; Panchenko, Anna] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD USA. EM panch@ncbi.nlm.nih.gov RI Shaytan, Alexey/D-7306-2012 OI Shaytan, Alexey/0000-0003-0312-938X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 174-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104411 ER PT J AU Shcherbakova, DM Pletnev, S Piatkevich, KD Verkhusha, VV AF Shcherbakova, Daria M. Pletnev, Sergei Piatkevich, Kiryl D. Verkhusha, Vladislav V. TI Red-shifted fluorescent proteins with a large Stokes shift: Chemical mechanism and imaging applications of LSSmOrange SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Shcherbakova, Daria M.; Piatkevich, Kiryl D.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. [Shcherbakova, Daria M.; Piatkevich, Kiryl D.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA. [Pletnev, Sergei] Leidos Biomedical Res Inc, Basic Res Program, Argonne Natl Lab, Argonne, IL 60439 USA. [Pletnev, Sergei] NCI, Macromol Crystallog Lab, Argonne Natl Lab, Argonne, IL 60439 USA. EM daria.shcherbakova@einstein.yu.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 15-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403621 ER PT J AU Shi, ZD Xu, BY Vasalatiy, O Griffiths, GL Zheng, W Swenson, RE AF Shi, Zhen-Dan Xu, Biying Vasalatiy, Olga Griffiths, Gary L. Zheng, Wei Swenson, Rolf E. TI Design and syntheses of multiple fluorescent tocopherol probes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Shi, Zhen-Dan; Xu, Biying; Vasalatiy, Olga; Griffiths, Gary L.; Swenson, Rolf E.] NHLBI, Imaging Probe Dev Ctr, Rockville, MD 20850 USA. [Zheng, Wei] Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM shizh@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 92-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167401795 ER PT J AU Simeon, FG Lu, SY Morse, C Culligan, W Wook, A Zoghbi, SS Liow, JS Gladding, R Innis, R Pike, VW AF Simeon, Fabrice G. Lu, Shuiyu Morse, Cheryl Culligan, William Wook, Alicia Zoghbi, Sami S. Liow, Jeih-San Gladding, Robert Innis, Robert Pike, Victor W. TI Synthesis of a candidate C-11-labeled brain histamine subtype 3 receptor radioligand for evaluation in monkey SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Simeon, Fabrice G.; Lu, Shuiyu; Morse, Cheryl; Culligan, William; Wook, Alicia; Zoghbi, Sami S.; Liow, Jeih-San; Gladding, Robert; Innis, Robert; Pike, Victor W.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. EM simeonf@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 452-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402246 ER PT J AU Simmonett, AC Pickard, FC Brooks, BR AF Simmonett, Andrew C. Pickard, Frank C. Brooks, Bernard R. TI Efficient algorithms for evaluating multipole interactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Simmonett, Andrew C.; Pickard, Frank C.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM andy.simmonett@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 2-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403609 ER PT J AU Sulima, A Hall, M Gottesman, MM Swenson, RE AF Sulima, Agnieszka Hall, Matthew Gottesman, Michael M. Swenson, Rolf E. TI Synthesis of new fluorescent analogs of cisplatin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Sulima, Agnieszka; Swenson, Rolf E.] NIH, Imaging Probe Dev Ctr, Rockville, MD 20850 USA. [Hall, Matthew; Gottesman, Michael M.] NCI, NIH, Bethesda, MD 20892 USA. EM agnieszs@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 629-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167403214 ER PT J AU Teske, KA Bogart, JW Sanchez, L Bantukallu, G Simeonov, A Jadhav, A Yasgar, A Maloney, D Arnold, LA AF Teske, Kelly A. Bogart, Jon W. Sanchez, Luis Bantukallu, Ganesha Simeonov, Anton Jadhav, Ajit Yasgar, Adam Maloney, David Arnold, Leggy A. TI Development of selective non-secosteroidal vitamin D receptor inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Teske, Kelly A.; Bogart, Jon W.; Sanchez, Luis; Arnold, Leggy A.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53201 USA. [Bantukallu, Ganesha; Simeonov, Anton; Jadhav, Ajit; Yasgar, Adam; Maloney, David] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. EM kateske@uwm.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 357-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402162 ER PT J AU Tofoleanu, F Brooks, B AF Tofoleanu, Florentina Brooks, Bernard TI Determining the apo state structure of the HCN2 ion channel through collaboration between computational simulations and transition metal ion FRET SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Tofoleanu, Florentina; Brooks, Bernard] NHLBI, NIH, Bethesda, MD 20852 USA. EM florentina.tofoleanu@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 12-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104257 ER PT J AU Torres, OB Jalah, R Rice, KC Li, FY Antoline, JFG Iyer, MR Cheng, KJ Jacobson, AE Beck, Z Alving, CR Matyas, GR AF Torres, Oscar B. Jalah, Rashmi Rice, Kenner C. Li, Fuying Antoline, Joshua F. G. Iyer, Malliga R. Cheng, Kejun Jacobson, Arthur E. Beck, Zoltan Alving, Carl R. Matyas, Gary R. TI Development of a vaccine for the treatment of heroin addiction: Determination of the optimal heroin hapten-carrier density SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Torres, Oscar B.; Jalah, Rashmi; Beck, Zoltan; Alving, Carl R.; Matyas, Gary R.] US Mil HIV Res Program, Walter Reed Army Inst Res, Lab Adjuvant & Antigen Res, Silver Spring, MD 20910 USA. [Rice, Kenner C.; Li, Fuying; Antoline, Joshua F. G.; Cheng, Kejun; Jacobson, Arthur E.] NIDA, Dept Hlth & Human Serv, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.; Li, Fuying; Antoline, Joshua F. G.; Iyer, Malliga R.; Cheng, Kejun; Jacobson, Arthur E.] NIAAA, NIH, Bethesda, MD 20892 USA. [Torres, Oscar B.; Jalah, Rashmi; Beck, Zoltan] US Mil HIV Res Program, Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. EM otorres@hivresearch.org NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 428-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402224 ER PT J AU Turganbayeva, A Scott, TM Wolt, JD AF Turganbayeva, Assiya Scott, Trisha M. Wolt, Jeffrey D. TI Assessing quality DNA extraction and detection for GMO compliance monitoring SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Turganbayeva, Assiya] Natl Biotechnol Ctr, Astana, Kazakhstan. [Scott, Trisha M.; Wolt, Jeffrey D.] Iowa State Univ, Biosafety Inst Genet Modified Agr Prod, Ames, IA 50011 USA. EM assiyat@iastate.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 303-AGRO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100668 ER PT J AU Vann, WF Lee, RC Kovac, P Ryan, ET McCarthy, PC LaForce, M Alderson, M Maisonneuve, J Banoub, JH An, YM Cipollo, JF AF Vann, Willie F. Lee, Robert C. Kovac, Pavol Ryan, Edward T. McCarthy, Pumtiwitt C. LaForce, Marc Alderson, Mark Maisonneuve, Jeff Banoub, Joseph H. An, Yanming Cipollo, John F. TI Alternate technology for preparation of glycoconjugate vaccines SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Vann, Willie F.; Lee, Robert C.; An, Yanming; Cipollo, John F.] US FDA, Lab Bacterial Polysaccharides, CBER, Bethesda, MD 20892 USA. [Kovac, Pavol] NIDDK, NIH, Bethesda, MD 20892 USA. [Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McCarthy, Pumtiwitt C.] Morgan State Univ, Dept Chem, Baltimore, MD 21239 USA. [LaForce, Marc; Alderson, Mark; Maisonneuve, Jeff] PATH, Seattle, WA USA. [Banoub, Joseph H.] Fisheries & Oceans Canada, St John, NF, Canada. EM wvann@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 9-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165102174 ER PT J AU Wang, YL AF Wang, Yanli TI PubChem BioAssay, a public information resource for drug discovery: A bibliometric analysis on PubChem application SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Wang, Yanli] Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 41-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104285 ER PT J AU Wang, ZX Marchler-Bauer, A Bryant, S AF Wang, Zhouxi Marchler-Bauer, Aron Bryant, Steve TI Testing the consistency of protein sequence classification with protein 3D-structure similarity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Wang, Zhouxi; Marchler-Bauer, Aron; Bryant, Steve] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM josie.wang@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 258-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104491 ER PT J AU Wilson, SH Freudenthal, BD Beard, WA Perera, L Pedersen, LG AF Wilson, Samuel H. Freudenthal, Bret D. Beard, Willaim A. Perera, Lalith Pedersen, Lee G. TI DNA polymerase dynamics involving the mutagenic and non-mutagenic 8-oxoG lesion SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Wilson, Samuel H.; Freudenthal, Bret D.; Beard, Willaim A.; Perera, Lalith; Pedersen, Lee G.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 141-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167406291 ER PT J AU Wu, XW Brooks, BR AF Wu, Xiongwu Brooks, Bernard R. TI Virtual mixture simulation approach to study multistate equilibrium: Application to constant pH simulation in explicit water SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, Bethesda, MD 20852 USA. EM wuxw@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 413-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104625 ER PT J AU Wu, XW Vanden-Eijnden, E Brooks, BR AF Wu, Xiongwu Vanden-Eijnden, Eric Brooks, Bernard R. TI Generalization of the self-guided Langevin dynamic simulation method SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20852 USA. [Vanden-Eijnden, Eric] NYU, Courant Inst Math Sci, New York, NY 10012 USA. EM wuxw@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 4 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 282-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104512 ER PT J AU Zhao, XZ Smith, SJ Metifiot, M Marchand, C Pommier, Y Hughes, SH Burke, TR AF Zhao, Xue Zhi Smith, Steven J. Metifiot, Mathieu Marchand, Christophe Pommier, Yves Hughes, Stephen H. Burke, Terrence R., Jr. TI Bicyclic 4-amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing compounds having high potency against Raltegravir-resistant integrase mutants of HIV-1 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Frederick Natl Lab Canc Res, Ctr Canc Res, NIH,Chem Biol Lab, Frederick, MD 21702 USA. [Smith, Steven J.; Hughes, Stephen H.] NCI, Frederick Natl Lab Canc Res, Ctr Canc Res, NIH,HIV Drug Resistance Program, Frederick, MD 21702 USA. [Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Ctr Canc Res, NIH, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Ctr Canc Res, NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM xuezhi.zhao@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 402-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402202 ER PT J AU Abrams, JS Mooney, M Zwiebel, J Friedman, S AF Abrams, Jeffrey S. Mooney, Margaret Zwiebel, James Friedman, Steve TI Improving the Protocol Implementation Process: The National Cancer Institute's Response SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID COOPERATIVE-ONCOLOGY-GROUP; CLINICAL-TRIALS; IMPACT; COSTS C1 [Abrams, Jeffrey S.; Mooney, Margaret; Zwiebel, James; Friedman, Steve] NCI, Bethesda, MD 20892 USA. RP Abrams, JS (reprint author), NCI, Bethesda, MD 20892 USA. NR 9 TC 1 Z9 1 U1 0 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 AUG 10 PY 2014 VL 32 IS 23 BP 2515 EP U164 DI 10.1200/JCO.2014.55.5912 PG 2 WC Oncology SC Oncology GA AN4KK UT WOS:000340556400024 PM 25002734 ER PT J AU Lynch, DR Fischbeck, KH AF Lynch, David R. Fischbeck, Kenneth H. TI Nicotinamide in Friedreich's ataxia: useful or not? SO LANCET LA English DT Editorial Material ID HISTONE DEACETYLASE INHIBITORS C1 [Lynch, David R.] Childrens Hosp Philadelphia, Div Neurol & Pediat, Philadelphia, PA 19104 USA. [Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD USA. RP Lynch, DR (reprint author), Childrens Hosp Philadelphia, Div Neurol & Pediat, Philadelphia, PA 19104 USA. EM lynchd@mail.med.upenn.edu FU Intramural NIH HHS [ZIA NS003037-08] NR 8 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 9 PY 2014 VL 384 IS 9942 BP 474 EP 475 DI 10.1016/S0140-6736(14)60573-0 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM9JR UT WOS:000340198300006 PM 24794818 ER PT J AU Louis, JM Aniana, A Lohith, K Sayer, JM Roche, J Bewley, CA Clore, GM AF Louis, John M. Aniana, Annie Lohith, Katheryn Sayer, Jane M. Roche, Julien Bewley, Carole A. Clore, G. Marius TI Binding of HIV-1 gp41-Directed Neutralizing and Non-Neutralizing Fragment Antibody Binding Domain (Fab) and Single Chain Variable Fragment (ScFv) Antibodies to the Ectodomain of gp41 in the Pre-Hairpin and Six-Helix Bundle Conformations SO PLOS ONE LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; MEDIATED CELL-FUSION; TRIMERIC COILED-COIL; 44 KDA ECTODOMAIN; IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN; PHAGE LIBRARY; POTENT INHIBITORS; ATOMIC-STRUCTURE; STRUCTURAL BASIS AB We previously reported a series of antibodies, in fragment antigen binding domain (Fab) formats, selected from a human non-immune phage library, directed against the internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41. Broadly neutralizing antibodies from that series bind to both the fully exposed N-HR trimer, representing the pre-hairpin intermediate state of gp41, and to partially-exposed N-HR helices within the context of the gp41 six-helix bundle. While the affinities of the Fabs for pre-hairpin intermediate mimetics vary by only 2 to 20-fold between neutralizing and non-neutralizing antibodies, differences in inhibition of viral entry exceed three orders of magnitude. Here we compare the binding of neutralizing (8066) and non-neutralizing (8062) antibodies, differing in only four positions within the CDR-H2 binding loop, in Fab and single chain variable fragment (ScFv) formats, to several pre-hairpin intermediate and six-helix bundle constructs of gp41. Residues 56 and 58 of the mini-antibodies are shown to be crucial for neutralization activity. There is a large differential (>= 150-fold) in binding affinity between neutralizing and non-neutralizing antibodies to the six-helix bundle of gp41 and binding to the six-helix bundle does not involve displacement of the outer C-terminal helices of the bundle. The binding stoichiometry is one six-helix bundle to one Fab or three ScFvs. We postulate that neutralization by the 8066 antibody is achieved by binding to a continuum of states along the fusion pathway from the pre-hairpin intermediate all the way to the formation of the six-helix bundle, but prior to irreversible fusion between viral and cellular membranes. C1 [Louis, John M.; Aniana, Annie; Sayer, Jane M.; Roche, Julien; Clore, G. Marius] NIDDK, Labs Chem Phys, NIH, Bethesda, MD 20892 USA. [Lohith, Katheryn; Bewley, Carole A.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Louis, JM (reprint author), NIDDK, Labs Chem Phys, NIH, Bethesda, MD 20892 USA. EM johnl@niddk.nih.gov; mariusc@mail.nih.gov RI Roche, Julien/O-3204-2013 OI Roche, Julien/0000-0003-3892-0200 FU Intramural Research Program of the NIDDK, National Institutes of Health; Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH FX This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH (to G. M. C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 4 Z9 4 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 8 PY 2014 VL 9 IS 8 AR e104683 DI 10.1371/journal.pone.0104683 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0CG UT WOS:000343231900079 PM 25105806 ER PT J AU Kim, KK Adelstein, RS Kawamoto, S AF Kim, Kee K. Adelstein, Robert S. Kawamoto, Sachiyo TI Isoform-specific proteasomal degradation of Rbfox3 during chicken embryonic development SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Rbfox3; Rbfox family; Alternative splicing; RNA recognition motif; Proteasome degradation; Neural development ID PROTEIN; FOX-1; DIFFERENTIATION; EXPRESSION; UBIQUITIN; HOMOLOGS; BRAIN; CODE AB Rbfox3, a neuron-specific RNA-binding protein, plays an important role in neuronal differentiation during development. An isoform Rbfox3-d31, which excludes the 93-nucleotide cassette exon within the RNA recognition motif of chicken Rbfox3, has been previously identified. However, the cellular functions of Rbfox3-d31 remain largely unknown. Here we find that Rbfox3-d31 mRNA is highly expressed during the early developmental stages of the chicken embryo, while Rbfox3-d31 protein is barely detected during the same stage due to its rapid degradation mediated by the ubiquitin-proteasome pathway. Importantly, this degradation is specific to the Rbfox3-d31 isoform and it does not occur with full-length Rbfox3. Furthermore, suppression of Rbfox3-d31 protein degradation with the proteasome inhibitor MG132 attenuates the splicing activity of another Rbfox family member Rbfox2 by altering the subcellular localization of Rbfox2. These results suggest that Rbfox3-d31 functions as a repressor for the splicing activity of the Rbfox family and its protein level is regulated in an isoform-specific manner in vivo. Published by Elsevier Inc. C1 [Kim, Kee K.; Adelstein, Robert S.; Kawamoto, Sachiyo] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Kawamoto, S (reprint author), NHLBI, Mol Cardiol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 6C209, Bethesda, MD 20892 USA. EM kawamots@mail.nih.gov RI Kim, Kee/F-8784-2011; OI Adelstein, Robert/0000-0002-8683-2144 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, United States FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, United States. NR 22 TC 5 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 8 PY 2014 VL 450 IS 4 BP 1662 EP 1667 DI 10.1016/j.bbrc.2014.07.057 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AO4UY UT WOS:000341338100070 PM 25044120 ER PT J AU Pildervasser, JVN Abrahao, KP Souza-Formigoni, MLO AF Pildervasser, Joao V. N. Abrahao, Karina P. Souza-Formigoni, Maria L. O. TI Distinct behavioral phenotypes in ethanol-induced place preference are associated with different extinction and reinstatement but not behavioral sensitization responses SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE behavioral sensitization; CPP; different phenotypes; ethanol; extinction; individual variability ID NUCLEUS-ACCUMBENS; MEASURING REWARD; COCAINE SEEKING; ADDICTION; DOPAMINE; ALCOHOL; RELAPSE; MICE; RATS; RECONSOLIDATION AB Conditioned place preference (CPP) is a model to study the role of drug conditioning properties. In outbred strains, individual variability may affect some behavioral measures. However, there are few studies focusing on understanding how different phenotypes of ethanol conditioned behavior may influence its extinction, reinstatement, and behavioral adaptation measures. We used male Swiss Webster mice to study different phenotypes related to ethanol conditioning strength, reinstatement and behavioral sensitization. Mice went through a CPP procedure with ethanol (2.2 g/kg, i.p.). After that, one group of mice was submitted to repeated extinction sessions, while another group remained in their home cages without any drug treatment. Mice went through environmental and ethanol priming (1.0 g/kg, i.p.) reinstatement tests. Ethanol priming test reinstated the conditioned behavior only in the animals kept in the home-cage during the abstinence period. Besides, the ethanol conditioned behavior strength was positively correlated with the time required to be extinguished. In the second set of experiments, some mice went through a CPP protocol followed by behavioral sensitization (five i.p. administrations of ethanol 2.2 g/kg or saline per week, for 3 weeks) and another group of mice went through sensitization followed by CPR No positive correlation was observed between ethanol CPP strength and the intensity of behavioral sensitization. Considering that different phenotypes observed in CPP strength predicted the variability in other CPP measures, we developed a statistics-based method to classify mice according to CPP strength to be used in the evaluation of ethanol conditioning properties. C1 [Pildervasser, Joao V. N.; Souza-Formigoni, Maria L. O.] Univ Fed Sao Paulo, Dept Psicobiol, Unidade Dependencia Drogas, Sao Paulo, Brazil. [Abrahao, Karina P.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Souza-Formigoni, MLO (reprint author), Univ Fed Sao Paulo UNIFESP, Dept Psicobiol, Rua Napoleao de Barros 950, BR-04024002 Sao Paulo, Brazil. EM mlosformigoni@unifesp.br RI Souza-Formigoni, Maria Lucia/B-5736-2011 OI Souza-Formigoni, Maria Lucia/0000-0002-6361-5630 FU CAPES; AFIP; FAPESP; FAPESP (Sao Paulo Research Foundation-FAPESP) [2011/15258-8] FX The research was supported by funds from CAPES, AFIP, and FAPESP. Joao V. N. Pildervasser received a Masters fellowship from FAPESP (grant #2011/15258-8, Sao Paulo Research Foundation-FAPESP). NR 44 TC 1 Z9 1 U1 0 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD AUG 8 PY 2014 VL 8 AR 267 DI 10.3389/fnbeh.2014.00267 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AN9CH UT WOS:000340903100001 PM 25152719 ER PT J AU Friis, S Sales, KU Schafer, JM Vogel, LK Kataoka, H Bugge, TH AF Friis, Stine Sales, Katiuchia Uzzun Schafer, Jeffrey Martin Vogel, Lotte K. Kataoka, Hiroaki Bugge, Thomas H. TI The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BOUND SERINE-PROTEASE; NEURAL-TUBE CLOSURE; MOLECULAR-CLONING; EPITHELIAL-CELLS; EPIDERMAL DIFFERENTIATION; CELLULAR-LOCALIZATION; PLACENTAL DEVELOPMENT; PROTEOLYTIC CASCADE; ZYMOGEN ACTIVATION; BARRIER FUNCTION AB The membrane-anchored serine proteases, matriptase and prostasin, and the membrane-anchored serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2, are critical effectors of epithelial development and postnatal epithelial homeostasis. Matriptase and prostasin form a reciprocal zymogen activation complex that results in the formation of active matriptase and prostasin that are targets for inhibition by HAI-1 and HAI-2. Conflicting data, however, have accumulated as to the existence of auxiliary functions for both HAI-1 and HAI-2 in regulating the intracellular trafficking and activation of matriptase. In this study, we, therefore, used genetically engineered mice to determine the effect of ablation of endogenous HAI-1 and endogenous HAI-2 on endogenous matriptase expression, subcellular localization, and activation in polarized intestinal epithelial cells. Whereas ablation of HAI-1 did not affect matriptase in epithelial cells of the small or large intestine, ablation of HAI-2 resulted in the loss of matriptase from both tissues. Gene silencing studies in intestinal Caco-2 cell monolayers revealed that this loss of cell-associated matriptase was mechanistically linked to accelerated activation and shedding of the protease caused by loss of prostasin regulation by HAI-2. Taken together, these data indicate that HAI-1 regulates the activity of activated matriptase, whereas HAI-2 has an essential role in regulating prostasin-dependent matriptase zymogen activation. C1 [Friis, Stine; Sales, Katiuchia Uzzun; Schafer, Jeffrey Martin; Bugge, Thomas H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Sales, Katiuchia Uzzun] NIDCR, Clin Res Core, NIH, Bethesda, MD 20892 USA. [Friis, Stine; Vogel, Lotte K.] Univ Copenhagen, Dept Cellular & Mol Med, Fac Hlth Sci, DK-2200 Copenhagen N, Denmark. [Schafer, Jeffrey Martin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Kataoka, Hiroaki] Miyazaki Univ, Sect Oncopathol & Regenerat Biol, Dept Pathol, Fac Med, Miyazaki 8891692, Japan. RP Bugge, TH (reprint author), NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 320, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU Harboe Foundation; Lundbeck Foundation; Foundation of 17.12.1981; NIDCR; National Institutes of Health FX This work was supported by the NIDCR, National Institutes of Health, Intramural Research Program (to T. H. B.), by The Harboe Foundation, The Lundbeck Foundation, and The Foundation of 17.12.1981 (to S. F.), and by The Lundbeck Foundation (to L. V.). NR 56 TC 10 Z9 10 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 8 PY 2014 VL 289 IS 32 BP 22319 EP 22332 DI 10.1074/jbc.M114.574400 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4XQ UT WOS:000340593500043 PM 24962579 ER PT J AU Ibekwe, NN Nvau, JB Oladosu, PO Usman, AM Ibrahim, K Boshoff, HI Dowd, CS Orisadipe, AT Aiyelaagbe, O Adesomoju, AA Barry, CE Okogun, JI AF Ibekwe, Nneka N. Nvau, John B. Oladosu, Peters O. Usman, Auwal M. Ibrahim, Kolo Boshoff, Helena I. Dowd, Cynthia S. Orisadipe, Abayomi T. Aiyelaagbe, Olapeju Adesomoju, Akinbo A. Barry, Clifton E., III Okogun, Joseph I. TI Some Nigerian anti-tuberculosis ethnomedicines: A preliminary efficacy assessment SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE African ethnomedicines; Cough; Anti-Mycobacterium activity; M.tb.; M.bovis (BCG) ID MYCOBACTERIUM-TUBERCULOSIS; NATURAL-PRODUCTS; KHAYA-GRANDIFOLIOLA; MEDICINAL-PLANTS; DRUG DISCOVERY; ANTIMYCOBACTERIAL ACTIVITY; GARCINIA-KOLA; CONSTITUENTS; POLYPHENOLS; THERAPY AB Ethnopharmacological significance: Nigerian herbalists possess indigenous ethnomedicinal recipes for the management of tuberculosis and related ailments. A collaborative preliminary modern scientific evaluation of the efficacy of some Nigerian ethnomedicines used by traditional medicine practitioners (TMPs) in the management of tuberculosis and related ailments has been carried out. Materials and methods: Ethnomedicinal recipes (ETMs) were collected from TMPs from locations in various ecological zones of Nigeria under a collaborative understanding. The aqueous methanolic extracts of the ETMs were screened against Mycobacterium bovis, BCG and Mycobacterium tuberculosis strain H(37)Rv using the broth microdilution method. Results: Extracts of ETMs screened against BCG showed 69% activity against the organism. The activities varied from weak, <= 2500 mu g/mL to highly active, 33 mu g/mL 64% of the extracts were active against Mycobacterium tuberculosis The activities of the extracts against Mycobacterium tuberculosis varied from weak, <= 2500 mu g/mL to highly active, 128 mu g/mL. There was 77% agreement in results obtained using BCG or Mycobacterium tuberculosis as test organisms. Conclusion: The results show clear evidence for the efficacy of the majority of indigenous Nigerian herbal recipes in the ethnomedicinal management of tuberculosis and related ailments. BCG may be effectively used, to a great extent, as the organism for screening for potential anti-Mycobacterium tuberculosis agents. A set of prioritization criteria for the selection of plants for initial further studies for the purpose of antituberculosis drug discovery research is proposed. (C) 2014 Published by Elsevier Ireland Ltd. C1 [Ibekwe, Nneka N.; Nvau, John B.; Oladosu, Peters O.; Usman, Auwal M.; Ibrahim, Kolo; Orisadipe, Abayomi T.; Okogun, Joseph I.] Natl Inst Pharmaceut Res & Dev, Abuja, Nigeria. [Ibekwe, Nneka N.; Nvau, John B.; Aiyelaagbe, Olapeju; Adesomoju, Akinbo A.] Univ Ibadan, Dept Chem, Ibadan, Nigeria. [Dowd, Cynthia S.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Okogun, Joseph I.] Benedictine Monastery, Pax Herbal Clin & Res Labs, Ewu Esan, Edo State, Nigeria. [Dowd, Cynthia S.] George Washington Univ, Chem 1Dept, Washington, DC 20052 USA. [Orisadipe, Abayomi T.] Sheda Sci & Technol Complex, Div Chem, Sheda, Abuja, Nigeria. [Okogun, Joseph I.] Univ Ibadan, Dept Chem, Ibadan, Nigeria. RP Okogun, JI (reprint author), Natl Inst Pharmaceut Res & Dev, Abuja, Nigeria. EM jokogun@yahoo.com RI Barry, III, Clifton/H-3839-2012 FU NIAID-NIH [AI000693-22] FX We thank the NIAID-NIH for support on grant project number AI000693-22 and for the award of postgraduate fellowships to N. lbekwe and J. Nvau. Engineer B. Dogonyaro and M. Tsado and members of the NIAID-NIH IT team gave instrument and information technology supports. Bitrus Pam drove the vehicle that took the team safely to various parts of Nigeria to visit the TMPs. We appreciate his contributions to the success of the project. We thank Dr. Jemilat Ibrahim and Grace Ugbabe of the Herbarium, National Institute For Pharmaceutical Research And Development, Abuja, Nigeria who assisted in the identification of plant specimen samples. We acknowledge the administrative and logistics support enthusiastically given to the project by the then Director General of the National Institute for Pharmaceutical Research and Development, Dr. Uford S. Inyang. We thank the management and staff of NIPRD for their support. We are grateful to Katherine M. Perry who was the project manager and a source of strength and encouragement to the team. NR 62 TC 4 Z9 4 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD AUG 8 PY 2014 VL 155 IS 1 BP 524 EP 532 DI 10.1016/j.jep.2014.05.059 PG 9 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AN8KV UT WOS:000340854000051 PM 24911338 ER PT J AU Gerber, LH Narber, CG Vishnoi, N Johnson, SL Chan, L Duric, Z AF Gerber, Lynn H. Narber, Cody G. Vishnoi, Nalini Johnson, Sidney L. Chan, Leighton Duric, Zoran TI The feasibility of using haptic devices to engage people with chronic traumatic brain injury in virtual 3D functional tasks SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Traumatic brain injury; Virtual reality; Haptic devices; Fine motor; Cognitive performance ID EUROPEAN COUNTRIES; REHABILITATION; ENVIRONMENT; STROKE; COMPLAINTS; ATTENTION; FEEDBACK; DEFICITS; THERAPY; SKILLS AB Background: The primary aim of this study was to assess the level of engagement in computer-based simulations of functional tasks, using a haptic device for people with chronic traumatic brain injury. The objectives were to design functional tasks using force feedback device and determine if it could measure motor performance improvement. Methods: A prospective crosssectional study was performed in a biomedical research facility. The testing environment consisted of a single, interactive, stylus-driven computer session navigating virtual scenes in 3D space. Subjects had a haptic training session (TRAIN) and then had three chances to perform each virtual task: (i) remove tools from a workbench (TOOL), (ii) compose 3 letter words (SPELL), (iii) manipulate utensils to prepare a sandwich (SAND), and (iv) tool use (TUSE). Main Outcome Measures included self-report of engagement in the activities, improved performance on simulated tasks and observer estimate as measured by time to completion or number of words completed from baseline, correlations among performance measures and self-reports of boredom, neuropsychological symptom inventory (NSI), and The Purdue Peg Motor Test (PPT). Results: Participants were 19 adults from the community with a 1 year history of non-penetrating traumatic brain injury (TBI) and were able to use computers. Seven had mild, 3 moderate and 9 severe TBIs. Mean score on the Boredom Proneness Scale (BPS): 107 (normal range 81-117); mean NSI: 32; mean PPT 54 (normal range for assembly line workers > 67). Responses to intervention: 3 (15%)subjects did not repeat all three trials of the tasks; 100% reported they were highly engaged in the interactions; 6 (30%) reported they had a high level of frustration with the tasks, but completed them with short breaks. Performance measures: Comparison of baseline to post training: TOOL time decreased by (mean) 60 sec; SPELL increased by 2.7 words; TUSE time decreased by (mean) 68 sec; and SAND time decreased by (mean) 72 sec. PPT correlated with TOOL (r = -0.65, p = 0.016) and TUSE time (r = -0.6, p = 0.014). SPELL correlated with Boredom score (r = 0.41, p = 0.08) and NSI (r = -.49, p = 0.05). Conclusion: People with chronic TBI of various ages and severity report being engaged in using haptic devices that interact with 3D virtual environments. Haptic devices are able to capture objective data that provide useful information about fine motor and cognitive performance. C1 [Gerber, Lynn H.; Johnson, Sidney L.] George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Narber, Cody G.; Vishnoi, Nalini; Duric, Zoran] George Mason Univ, Dept Comp Sci, Fairfax, VA 22030 USA. [Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Gerber, LH (reprint author), George Mason Univ, Ctr Study Chron Illness & Disabil, 4400 Univ Dr, Fairfax, VA 22030 USA. EM ngerber1@gmu.edu FU Henry Jackson Foundation [HJF-678233] FX Student support is gratefully acknowledged from: Sinead Gil and Petar Z Duric. This study was supported by a grant from the Henry Jackson Foundation (HJF-678233). NR 44 TC 0 Z9 0 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD AUG 8 PY 2014 VL 11 AR 117 DI 10.1186/1743-0003-11-117 PG 15 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA AO0ZA UT WOS:000341040300001 PM 25103113 ER PT J AU Wang, XD Mendelsohn, L Rogers, H Leitman, S Raghavachari, N Yang, YQ Yau, YY Tallack, M Perkins, A Taylor, JG Noguchi, CT Kato, GJ AF Wang, Xunde Mendelsohn, Laurel Rogers, Heather Leitman, Susan Raghavachari, Nalini Yang, Yanqin Yau, Yu Ying Tallack, Michael Perkins, Andrew Taylor, James G. Noguchi, Constance Tom Kato, Gregory J. TI Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Kruppel-like factor SO BLOOD LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; RIGHT HEART CATHETERIZATION; PLASMA ENDOTHELIN-1 LEVELS; GLOBIN GENE-EXPRESSION; ACUTE CHEST SYNDROME; PRIMITIVE ERYTHROPOIESIS; RECEPTOR ANTAGONISTS; ANGIOGENIC FACTORS; DISEASE; TRANSCRIPTION AB In adults with sickle cell disease (SCD), markers of iron burden are associated with excessive production of the angiogenic protein placenta growth factor (PlGF) and high estimated pulmonary artery pressure. Enforced PlGF expression in mice stimulates production of the potent vasoconstrictor endothelin-1, producing pulmonary hypertension. We now demonstrate heme-bound iron (hemin) induces PlGF mRNA >200-fold in a dose-and time-dependent fashion. In murine and human erythroid cells, expression of erythroid Kruppel-like factor (EKLF) precedes PlGF, and its enforced expression in human erythroid progenitor cells induces PlGF mRNA. Hemin-induced expression of PlGF is abolished in EKLF-deficient murine erythroid cells but rescued by conditional expression of EKLF. Chromatin immunoprecipitation reveals that EKLF binds to the PlGF promoter region. SCD patients show higher level expression of both EKLF and PlGF mRNA in circulating blood cells, and markers of iron overload are associated with high PlGF and early mortality. Finally, PlGF association with iron burden generalizes to other human diseases of iron overload. Our results demonstrate a specific mechanistic pathway induced by excess iron that is linked in humans with SCD and in mice to markers of vasculopathy and pulmonary hypertension. These trials were registered at www.clinicaltrials.gov as #NCT00007150, #NCT00023296, #NCT00081523, and #NCT00352430. C1 [Wang, Xunde; Mendelsohn, Laurel; Yang, Yanqin; Taylor, James G.] NHLBI, NIH, Bethesda, MD 20892 USA. [Rogers, Heather; Noguchi, Constance Tom] NIDDK, NIH, Bethesda, MD 20892 USA. [Leitman, Susan; Yau, Yu Ying] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Raghavachari, Nalini] NIA, NIH, Bethesda, MD 20892 USA. [Tallack, Michael; Perkins, Andrew] Mater Hosp, Mater Med Res Inst, Brisbane, Qld, Australia. [Kato, Gregory J.] Univ Pittsburgh, Div Hematol Oncol, Dept Med, Pittsburgh, PA 15261 USA. [Kato, Gregory J.] Univ Pittsburgh, Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA 15261 USA. RP Kato, GJ (reprint author), Univ Pittsburgh, Div Hematol Oncol, Dept Med, 200 Lothrop St,BST E1240, Pittsburgh, PA 15261 USA. EM katogj@upmc.edu RI Tallack, Michael/A-4760-2010; Perkins, Andrew/M-3216-2014; Kato, Gregory/I-7615-2014; OI Perkins, Andrew/0000-0003-3644-7093; Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU National Heart, Lung and Blood Institute Division of Intramural Research; National Institutes of Health Clinical Center [1 ZIA HL006162-01, 1 ZIA HL006013-03, CL002107-12] FX This research was funded by the National Heart, Lung and Blood Institute Division of Intramural Research and National Institutes of Health Clinical Center (grants 1 ZIA HL006162-01, 1 ZIA HL006013-03, and CL002107-12). NR 66 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD AUG 7 PY 2014 VL 124 IS 6 BP 946 EP 954 DI 10.1182/blood-2013-11-539718 PG 9 WC Hematology SC Hematology GA AQ2MK UT WOS:000342620400023 PM 24916507 ER PT J AU Sundborger, AC Fang, SM Heymann, JA Ray, P Chappie, JS Hinshaw, JE AF Sundborger, Anna C. Fang, Shunming Heymann, Juergen A. Ray, Pampa Chappie, Joshua S. Hinshaw, Jenny E. TI A Dynamin Mutant Defines a Superconstricted Prefission State SO CELL REPORTS LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAIN; MEMBRANE FISSION; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; GTPASE ACTIVITY; CONSTRICTION; ENDOPHILIN; MODEL; RECONSTRUCTION; MICROSCOPY AB Dynamin is a 100 kDa GTPase that organizes into helical assemblies at the base of nascent clathrin-coated vesicles. Formation of these oligomers stimulates the intrinsic GTPase activity of dynamin, which is necessary for efficient membrane fission during endocytosis. Recent evidence suggests that the transition state of dynamin's GTP hydrolysis reaction serves as a key determinant of productive fission. Here, we present the structure of a transition-state-defective dynamin mutant K44A trapped in a prefission state at 12.5 angstrom resolution. This structure constricts to 3.7 nm, reaching the theoretical limit required for spontaneous membrane fission. Computational docking indicates that the ground-state conformation of the dynamin polymer is sufficient to achieve this superconstricted prefission state and reveals how a two-start helical symmetry promotes the most efficient packing of dynamin tetramers around the membrane neck. These data suggest a model for the assembly and regulation of the minimal dynamin fission machine. C1 [Sundborger, Anna C.; Fang, Shunming; Heymann, Juergen A.; Ray, Pampa; Hinshaw, Jenny E.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Chappie, Joshua S.] Cornell Univ, Coll Vet Med, Dept Mol Med, Ithaca, NY 14850 USA. RP Chappie, JS (reprint author), Cornell Univ, Coll Vet Med, Dept Mol Med, Ithaca, NY 14850 USA. EM chappie@cornell.edu; jennyh@helix.nih.gov RI Sundborger, Anna/J-6590-2014 OI Sundborger, Anna/0000-0003-4696-7543 FU National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. J.S.C. is a Nancy and Peter Meinig Family Investigator in the Life Sciences. We thank Drs. Naiqian Cheng and Dennis Winkler for technical assistance on the FEI Polara; Drs. Jeanne Morin-Leisk, Paula Flicker, and Toshi Kawate for insightful discussions; and Dr. Fred Dyda for his continued support and generosity. NR 38 TC 12 Z9 12 U1 1 U2 13 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 7 PY 2014 VL 8 IS 3 BP 734 EP 742 DI 10.1016/j.celrep.2014.06.054 PG 9 WC Cell Biology SC Cell Biology GA AO7ZR UT WOS:000341572200011 PM 25088425 ER PT J AU de Vries, J Abayomi, A Brandful, J Littler, K Madden, E Marshall, P Oukem-Boyer, OOM Seeley, J AF de Vries, Jantina Abayomi, Akin Brandful, James Littler, Katherine Madden, Ebony Marshall, Patricia Oukem-Boyer, Odile Ouwe Missi Seeley, Janet TI A perpetual source of DNA or something really different: ethical issues in the creation of cell lines for African genomics research SO BMC MEDICAL ETHICS LA English DT Article DE Cell lines; H3Africa; Africa; Ethics; Consent; Sample ownership; Immortalisation ID SUB-SAHARAN AFRICA; INFORMED-CONSENT; VOLUNTARY PARTICIPATION; NIGERIA; MAP AB Background: The rise of genomic studies in Africa - not least due to projects funded under H3Africa - is associated with the development of a small number of biorepositories across Africa. For the ultimate success of these biorepositories, the creation of cell lines including those from selected H3Africa samples would be beneficial. In this paper, we map ethical challenges in the creation of cell lines. Discussion: The first challenge we identified relates to the moral status of cells living in culture. There is no doubt that cells in culture are alive, and the question is how this characteristic is relevant to ethical decision-making. The second challenge relates to the fact that cells in culture are a source of cell products and mitochondrial DNA. In combination with other technologies, cells in culture could also be used to grow human tissue. Whilst on the one hand, this feature increases the potential utility of the sample and promotes science, on the other it also enables further scientific work that may not have been specifically consented to or approved. The third challenge relates to ownership over samples, particularly in cases where cell lines are created by a biobank, and in a different country than where samples were collected. Relevant questions here concern the export of samples, approval of secondary use and the acceptability of commercialisation. A fourth challenge relates to perceptions of blood and bodily integrity, which may be particularly relevant for African research participants from certain cultures or backgrounds. Finally, we discuss challenges around informed consent and ethical review. Summary: In this paper, we sought to map the myriad of ethical challenges that need to be considered prior to making cell line creation a reality in the H3Africa project. Considering the relative novelty of this practice in Africa, such challenges will need to be considered, discussed and potentially be resolved before cell line creation in Africa becomes financially feasible and sustainable. We suggest that discussions need to be undertaken between stakeholders internationally, considering the international character of the H3Africa project. We also map out avenues for empirical research. C1 [de Vries, Jantina] Univ Cape Town, Groote Schuur Hosp, UCT Ctr Clin Res, Dept Med,Off J52 16, ZA-7925 Cape Town, South Africa. [Abayomi, Akin] Univ Stellenbosch, Fac Med & Hlth Sci, NSB Biobank H3A, ZA-7602 Stellenbosch, South Africa. [Abayomi, Akin] Univ Stellenbosch, Fac Med & Hlth Sci, Natl Hlth Lab Serv South Africa, ZA-7602 Stellenbosch, South Africa. [Brandful, James] Univ Ghana, Noguchi Mem Inst Med Res, Legon, Ghana. [Littler, Katherine] Wellcome Trust Res Labs, London NW1 2BE, England. [Madden, Ebony] NHGRI, Div Genom Med, Durham, NC 27713 USA. [Marshall, Patricia] Case Western Reserve Univ, Sch Med, Dept Bioeth, Cleveland, OH 44106 USA. [Oukem-Boyer, Odile Ouwe Missi] CERMES, Niamey, Niger. [Oukem-Boyer, Odile Ouwe Missi] Cameroun Bioeth Initiat CAMBIN, Yaounde, Cameroon. [Seeley, Janet] MRC UVRI Uganda Res Unit AIDS, Entebbe, Uganda. RP de Vries, J (reprint author), Univ Cape Town, Groote Schuur Hosp, UCT Ctr Clin Res, Dept Med,Off J52 16, Old Main Bldg, ZA-7925 Cape Town, South Africa. EM Jantina.devries@uct.ac.za RI De Vries, Jantina/I-2752-2014; OI De Vries, Jantina/0000-0001-7192-2633; Seeley, Janet/0000-0002-0583-5272 FU wider H3Africa Consortium; Wellcome Trust [WT099313MA]; NIH as part of the H3Africa Consortium [1UH2HG007092]; NSB-H3Africa; NIH [P50-HG-003390-06]; H3A Bionet through the NHGRI of the NIH [1U41HG006941-01]; MRC (UK) FX We would like to thank our colleagues from the H3Africa Working Group on Ethics for their contributions to our discussions. We are also grateful to the wider H3Africa Consortium for contributions and support. JdV acknowledges support from the Wellcome Trust (WT099313MA). AA would like to acknowledge support for the NSB-H3A biobank located at Stellenbosch University, National Health Laboratory Services of South Africa which is supported by a grant from the NIH as part of the H3Africa Consortium (1UH2HG007092). AA would also like to acknowledge the support of the NSB-H3Africa biobank team and members of the Governance and Advisory panel (GAP) for insights in important ethical issues relating to modern biobanking. PM acknowledges support from the NIH (grant number P50-HG-003390-06). JB and OOMOB received support from H3A Bionet (funded through the NHGRI of the NIH under grant number NIH#1U41HG006941-01 REVISED. JS acknowledges support from the MRC (UK) Unit core funding. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding bodies. NR 33 TC 3 Z9 3 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6939 J9 BMC MED ETHICS JI BMC Med. Ethics PD AUG 7 PY 2014 VL 15 AR 60 DI 10.1186/1472-6939-15-60 PG 7 WC Ethics; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Biomedical Social Sciences GA AN9FY UT WOS:000340912900001 PM 25104115 ER PT J AU Berezhkovskii, AM Dagdug, L Bezrukov, SM AF Berezhkovskii, Alexander M. Dagdug, Leonardo Bezrukov, Sergey M. TI From normal to anomalous diffusion in comb-like structures in three dimensions SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID BRAIN EXTRACELLULAR-SPACE; FACILITATED MEMBRANE-TRANSPORT; BOUNDARY-CONDITIONS; POROUS-MEDIA; HOMOGENIZATION; TORTUOSITY; SURFACES; CHANNEL; MICRODOMAINS; CELLS AB Diffusion in a comb-like structure, formed by a main cylindrical tube with identical periodic dead ends of cylindrical shape, occurs slower than that in the same system without dead ends. The reason is that the particle, entering a dead end, interrupts its propagation along the tube axis. The slowdown becomes stronger and stronger as the dead end length increases, since the particle spends more and more time in the dead ends. In the limiting case of infinitely long dead ends, diffusion becomes anomalous with the exponent equal to 1/2. We develop a formalism which allows us to study the mean square displacement of the particle along the tube axis in such systems. The formalism is applicable for an arbitrary dead end length, including the case of anomalous diffusion in a tube with infinitely long dead ends. In particular, we demonstrate how intermediate anomalous diffusion arises when the dead ends are long enough. C1 [Berezhkovskii, Alexander M.; Dagdug, Leonardo; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.; Dagdug, Leonardo] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Phys, Mexico City 09340, DF, Mexico. RP Berezhkovskii, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIH, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Consejo Nacional de Ciencia y Tecnologia (CONACyT) [176452] FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. L. D. thanks Consejo Nacional de Ciencia y Tecnologia (CONACyT) for partial support under Grant No. 176452. NR 28 TC 4 Z9 4 U1 0 U2 9 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 7 PY 2014 VL 141 IS 5 AR 054907 DI 10.1063/1.4891566 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AN6OC UT WOS:000340713100056 PM 25106613 ER PT J AU Liu, Y Jesus, AA Marrero, B Yang, D Ramsey, SE Sanchez, GAM Tenbrock, K Wittkowski, H Jones, OY Kuehn, HS Lee, CCR DiMattia, MA Cowen, EW Gonzalez, B Palmer, I DiGiovanna, JJ Biancotto, A Kim, H Tsai, WL Trier, AM Huang, Y Stone, DL Hill, S Kim, HJ St Hilaire, C Gurprasad, S Plass, N Chapelle, D Horkayne-Szakaly, I Foell, D Barysenka, A Candotti, F Holland, SM Hughes, JD Mehmet, H Issekutz, AC Raffeld, M McElwee, J Fontana, JR Minniti, CP Moir, S Kastner, DL Gadina, M Steven, AC Wingfield, PT Brooks, SR Rosenzweig, SD Fleisher, TA Deng, Z Boehm, M Paller, AS Goldbach-Mansky, R AF Liu, Y. Jesus, A. A. Marrero, B. Yang, D. Ramsey, S. E. Sanchez, G. A. Montealegre Tenbrock, K. Wittkowski, H. Jones, O. Y. Kuehn, H. S. Lee, C. -C. R. DiMattia, M. A. Cowen, E. W. Gonzalez, B. Palmer, I. DiGiovanna, J. J. Biancotto, A. Kim, H. Tsai, W. L. Trier, A. M. Huang, Y. Stone, D. L. Hill, S. Kim, H. J. St Hilaire, C. Gurprasad, S. Plass, N. Chapelle, D. Horkayne-Szakaly, I. Foell, D. Barysenka, A. Candotti, F. Holland, S. M. Hughes, J. D. Mehmet, H. Issekutz, A. C. Raffeld, M. McElwee, J. Fontana, J. R. Minniti, C. P. Moir, S. Kastner, D. L. Gadina, M. Steven, A. C. Wingfield, P. T. Brooks, S. R. Rosenzweig, S. D. Fleisher, T. A. Deng, Z. Boehm, M. Paller, A. S. Goldbach-Mansky, R. TI Activated STING in a Vascular and Pulmonary Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AICARDI-GOUTIERES-SYNDROME; MONOGENIC AUTOINFLAMMATORY DISEASES; FAMILIAL CHILBLAIN LUPUS; CYCLIC GMP-AMP; I INTERFERON; CYTOSOLIC DNA; PROTEASOME SUBUNIT; INTRACELLULAR DNA; INBORN-ERRORS; IMMUNITY AB BACKGROUND The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-beta, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. C1 [Liu, Y.; Jesus, A. A.; Marrero, B.; Sanchez, G. A. Montealegre; DiMattia, M. A.; Palmer, I.; Kim, H.; Tsai, W. L.; Trier, A. M.; Huang, Y.; Plass, N.; Chapelle, D.; Gadina, M.; Steven, A. C.; Wingfield, P. T.; Brooks, S. R.; Deng, Z.; Goldbach-Mansky, R.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Lee, C. -C. R.; Cowen, E. W.; DiGiovanna, J. J.; Raffeld, M.] NCI, NIH, Bethesda, MD 20892 USA. [Yang, D.; Biancotto, A.; St Hilaire, C.; Fontana, J. R.; Minniti, C. P.; Boehm, M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Kuehn, H. S.; Gurprasad, S.; Rosenzweig, S. D.; Fleisher, T. A.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Stone, D. L.; Candotti, F.; Kastner, D. L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Hill, S.] NIH, Dept Radiol & Imaging Serv, Bethesda, MD 20892 USA. [Kim, H. J.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Holland, S. M.; Moir, S.] NIAID, NIH, Bethesda, MD 20892 USA. [Jones, O. Y.; Horkayne-Szakaly, I.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Ramsey, S. E.; Issekutz, A. C.] Dalhousie Univ, Halifax, NS, Canada. [Tenbrock, K.] Rhein Westfal TH Aachen, D-52062 Aachen, Germany. [Wittkowski, H.; Foell, D.; Barysenka, A.] Univ Hosp Muenster, Munster, Germany. [Gonzalez, B.] Hosp Ninos Luis Calvo Mackenna, Santiago, Chile. [Hughes, J. D.; Mehmet, H.; McElwee, J.] Merck Res Labs, Boston, MA USA. [Paller, A. S.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Goldbach-Mansky, R (reprint author), NIAMSD, NIH Bldg 10,Rm 6D-47B,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldbacr@mail.nih.gov OI Kim, Hanna/0000-0002-0595-6533; St. Hilaire, Cynthia/0000-0003-1871-6915 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases FX Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 42 TC 150 Z9 152 U1 10 U2 37 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 7 PY 2014 VL 371 IS 6 BP 507 EP 518 DI 10.1056/NEJMoa1312625 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AM5LE UT WOS:000339899100005 PM 25029335 ER PT J AU Orru, CD Bongianni, M Tonoli, G Ferrari, S Hughson, AG Groveman, BR Fiorini, M Pocchiari, M Monaco, S Caughey, B Zanusso, G AF Orru, Christina D. Bongianni, Matilde Tonoli, Giovanni Ferrari, Sergio Hughson, Andrew G. Groveman, Bradley R. Fiorini, Michele Pocchiari, Maurizio Monaco, Salvatore Caughey, Byron Zanusso, Gianluigi TI A Test for Creutzfeldt-Jakob Disease Using Nasal Brushings SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID QUAKING-INDUCED CONVERSION; RECOMBINANT PRION PROTEIN; CHRONIC WASTING DISEASE; CEREBROSPINAL-FLUID; OLFACTORY EPITHELIUM; MAMMALIAN PRIONS; DIAGNOSIS; TRANSMISSION; CRITERIA; SCRAPIE AB BACKGROUND Definite diagnosis of sporadic Creutzfeldt-Jakob disease in living patients remains a challenge. A test that detects the specific marker for Creutzfeldt-Jakob disease, the prion protein (PrPCJD), by means of real-time quaking-induced conversion (RT-QuIC) testing of cerebrospinal fluid has a sensitivity of 80 to 90% for the diagnosis of sporadic Creutzfeldt-Jakob disease. We have assessed the accuracy of RT-QuIC analysis of nasal brushings from olfactory epithelium in diagnosing sporadic Creutzfeldt-Jakob disease in living patients. METHODS We collected olfactory epithelium brushings and cerebrospinal fluid samples from patients with and patients without sporadic Creutzfeldt-Jakob disease and tested them using RT-QuIC, an ultrasensitive, multiwell plate-based fluorescence assay involving PrPCJD-seeded polymerization of recombinant PrP into amyloid fibrils. RESULTS The RT-QuIC assays seeded with nasal brushings were positive in 30 of 31 patients with Creutzfeldt-Jakob disease (15 of 15 with definite sporadic Creutzfeldt-Jakob disease, 13 of 14 with probable sporadic Creutzfeldt-Jakob disease, and 2 of 2 with inherited Creutzfeldt-Jakob disease) but were negative in 43 of 43 patients without Creutzfeldt-Jakob disease, indicating a sensitivity of 97% (95% confidence interval [CI], 82 to 100) and specificity of 100% (95% CI, 90 to 100) for the detection of Creutzfeldt-Jakob disease. By comparison, testing of cerebrospinal fluid samples from the same group of patients had a sensitivity of 77% (95% CI, 57 to 89) and a specificity of 100% (95% CI, 90 to 100). Nasal brushings elicited stronger and faster RT-QuIC responses than cerebrospinal fluid (P<0.001 for the between-group comparison of strength of response). Individual brushings contained approximately 105 to 107 prion seeds, at concentrations several logs 10 greater than in cerebrospinal fluid. CONCLUSIONS In this preliminary study, RT-QuIC testing of olfactory epithelium samples obtained from nasal brushings was accurate in diagnosing Creutzfeldt-Jakob disease and indicated substantial prion seeding activity lining the nasal vault. C1 [Orru, Christina D.; Bongianni, Matilde; Hughson, Andrew G.; Groveman, Bradley R.; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Orru, Christina D.] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Bongianni, Matilde; Ferrari, Sergio; Fiorini, Michele; Monaco, Salvatore; Zanusso, Gianluigi] Univ Verona, Dept Neurol & Movement Sci, I-37100 Verona, Italy. [Tonoli, Giovanni] Azienda Osped Univ Integrata, Policlin GB Rossi, Clin Otorinolaringoiatr, Verona, Italy. [Pocchiari, Maurizio] Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM bcaughey@nih.gov; gianluigi.zanusso@univr.it OI ZANUSSO, Gianluigi/0000-0001-5199-6264; Monaco, Salvatore/0000-0003-3191-8597 FU National Institute of Allergy and Infectious Diseases (NIAID); Fondazione Cariverona (Disabilita cognitiva e comportamentale nelle demenze e nelle psicosi); Italian Ministry of Health [RF2009-1474758]; Creutzfeldt-Jakob Disease Foundation; Programma Master and Back-Percorsi di rientro [PRR-MAB-A2011-19199] FX Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), by a grant from Fondazione Cariverona (Disabilita cognitiva e comportamentale nelle demenze e nelle psicosi, to Dr. Monaco), by a grant from the Italian Ministry of Health (RF2009-1474758, to Drs. Zanusso and Pocchiari), by a grant from the Creutzfeldt-Jakob Disease Foundation (to Dr. Orru), by a fellowship from Programma Master and Back-Percorsi di rientro (PRR-MAB-A2011-19199, to Dr. Orru), and by donations to the NIAID Gift Fund from Mary Hilderman Smith, Zoe Smith Jaye, and Jenny Smith Unruh, in memory of Jeffrey Smith. NR 37 TC 64 Z9 66 U1 1 U2 10 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 7 PY 2014 VL 371 IS 6 BP 519 EP 529 DI 10.1056/NEJMoa1315200 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AM5LE UT WOS:000339899100006 PM 25099576 ER PT J AU Evans, MK Longo, DL AF Evans, Michele K. Longo, Dan L. TI PALB2 Mutations and Breast-Cancer Risk SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID REPAIR C1 [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. FU Intramural NIH HHS [Z01 AG000513-08] NR 10 TC 6 Z9 6 U1 0 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 7 PY 2014 VL 371 IS 6 BP 566 EP 568 DI 10.1056/NEJMe1405784 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AM5LE UT WOS:000339899100013 PM 25099582 ER PT J AU Ciarapica, R De Salvo, M Carcarino, E Bracaglia, G Adesso, L Leoncini, PP Dall'Agnese, A Walters, ZS Verginelli, F De Sio, L Boldrini, R Inserra, A Bisogno, G Rosolen, A Alaggio, R Ferrari, A Collini, P Locatelli, M Stifani, S Screpanti, I Rutella, S Yu, Q Marquez, VE Shipley, J Valente, S Mai, A Miele, L Puri, PL Locatelli, F Palacios, D Rota, R AF Ciarapica, R. De Salvo, M. Carcarino, E. Bracaglia, G. Adesso, L. Leoncini, P. P. Dall'Agnese, A. Walters, Z. S. Verginelli, F. De Sio, L. Boldrini, R. Inserra, A. Bisogno, G. Rosolen, A. Alaggio, R. Ferrari, A. Collini, P. Locatelli, M. Stifani, S. Screpanti, I. Rutella, S. Yu, Q. Marquez, V. E. Shipley, J. Valente, S. Mai, A. Miele, L. Puri, P. L. Locatelli, F. Palacios, D. Rota, R. TI The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx) SO ONCOGENE LA English DT Article DE EZH2; FBXO32; histone methyltransferases; PAX3-FOXO1; rhabdomyosarcoma; Polycomb proteins ID SKELETAL-MUSCLE DIFFERENTIATION; COMBINED EPIGENETIC THERAPY; CHILDRENS ONCOLOGY GROUP; STEM-CELLS; HISTONE METHYLATION; GENE-EXPRESSION; INHIBITOR 3-DEAZANEPLANOCIN; UBIQUITIN LIGASE; DNA METHYLATION; PROSTATE-CANCER AB The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS. C1 [Ciarapica, R.; De Salvo, M.; Bracaglia, G.; Adesso, L.; Leoncini, P. P.; Verginelli, F.; De Sio, L.; Stifani, S.; Locatelli, F.; Rota, R.] IRCCS, Osped Pediat Bambino Gesu, Dept Oncohematol, Rome, Italy. [Carcarino, E.; Dall'Agnese, A.; Puri, P. L.; Palacios, D.] IRCCS Fdn Santa Lucia, Rome, Italy. [Walters, Z. S.; Shipley, J.] Inst Canc Res, Div Mol Pathol & Canc Therapeut, Sutton, Surrey, England. [Boldrini, R.] IRCCS, Osped Pediat Bambino Gesu, Dept Pathol, Rome, Italy. [Inserra, A.] IRCCS, Osped Pediat Bambino Gesu, Dept Surg, Rome, Italy. [Bisogno, G.; Rosolen, A.] Univ Padua, Dept Pediat, Oncohematol Unit, Padua, Italy. [Alaggio, R.] Univ Padua, Med DIMED, Pathol Unit, Padua, Italy. [Ferrari, A.] Fdn IRCCS Ist Nazl Tumori, Pediat Oncol Unit, Milan, Italy. [Collini, P.] Fdn IRCCS Ist Nazl Tumori, Anat Pathol Unit 2, Milan, Italy. [Locatelli, M.] IRCCS, Osped Pediat Bambino Gesu, Sci Directorate, Rome, Italy. [Stifani, S.] McGill Univ, Ctr Neuronal Survival, Montreal Neurol Inst, Montreal, PQ, Canada. [Screpanti, I.] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy. [Yu, Q.] Genome Inst Singapore, Agcy Sci Technol & Res, Singapore, Singapore. [Marquez, V. E.] Natl Canc Inst, CCR, Frederick Natl Lab Canc Res, Chem Biol Lab, Frederick, MD USA. [Valente, S.; Mai, A.] Univ Roma La Sapienza, Fdn Cenci Bolognetti, Ist Pasteur, Dipartimento Chim & Tecnol Farmaco, Rome, Italy. [Miele, L.] Univ Mississippi, Med Ctr, Inst Canc, Jackson, MS 39216 USA. [Puri, P. L.] Sanford Burnham Med Res Inst, Muscle Dev & Regenerat Program, La Jolla, CA USA. [Locatelli, F.] Univ Pavia, Dipartimento Sci Pediat, I-27100 Pavia, Italy. RP Rota, R (reprint author), IRCCS, Osped Pediat Bambino Gesu, Dept Oncohematol, Rome, Italy. EM d.palacios@hsantalucia.it; rossella.rota@opbg.net RI Valente, Sergio/K-2198-2016; Palacios, Daniela/K-4698-2016; Collini, Paola/K-7354-2016; OI Valente, Sergio/0000-0002-2241-607X; Palacios, Daniela/0000-0002-2207-2369; Mai, Antonello/0000-0001-9176-2382; Collini, Paola/0000-0002-6158-210X; Ferrari, Andrea/0000-0002-4724-0517; Rutella, Sergio/0000-0003-1970-7375 FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [10338]; Italian Ministry of Health Ricerca Corrente; Association for International Cancer Research (AICR-UK) [12-0168]; AIRC 5 per mille; NIH Intramural Research Program, National Cancer Institute, CCR; Cancer Research UK [C5066/A10399]; Sarcoma UK; Progetto IIT-Sapienza [A2]; FIRB [RBFR10ZJQT]; FP7 Project [BLUEPRINT/282510] FX We thank E Giorda for fluorescence-activated cell sorting analysis. Myogenin (Wright WE) and MHC (Fishman DA) antibodies were obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242, USA. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC, 10338) and Italian Ministry of Health Ricerca Corrente (RR); Association for International Cancer Research (AICR-UK, 12-0168) (DP); AIRC 5 per mille (FL); NIH Intramural Research Program, National Cancer Institute, CCR (VEM); Cancer Research UK (C5066/A10399) (ZSW); Sarcoma UK (ZSW, JS); Progetto IIT-Sapienza A2, FIRB RBFR10ZJQT and FP7 Project BLUEPRINT/282510 (AM). SS is a Chercheur National of the Fonds de la Recherche en Sante du Quebec. NR 73 TC 18 Z9 18 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD AUG 7 PY 2014 VL 33 IS 32 BP 4173 EP 4184 DI 10.1038/onc.2013.471 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AN4YK UT WOS:000340595700008 PM 24213577 ER PT J AU Tabor, HK Auer, PL Jamal, SM Chong, JX Yu, JH Gordon, AS Graubert, TA O'Donnell, CJ Rich, SS Nickerson, DA Bamshad, MJ AF Tabor, Holly K. Auer, Paul L. Jamal, Seema M. Chong, Jessica X. Yu, Joon-Ho Gordon, Adam S. Graubert, Timothy A. O'Donnell, Christopher J. Rich, Stephen S. Nickerson, Deborah A. Bamshad, Michael J. CA NHLBI Exome Sequencing Project TI Pathogenic Variants for Mendelian and Complex Traits in Exomes of 6,517 European and African Americans: Implications for the Return of Incidental Results SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENETIC-VARIANTS; GENOME; INDIVIDUALS; MUTATIONS; FRAMEWORK; RECOMMENDATIONS; ASSOCIATION; PREVALENCE; CHALLENGES; MANAGEMENT AB Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of. incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results. C1 [Tabor, Holly K.] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA 98101 USA. [Tabor, Holly K.; Jamal, Seema M.; Chong, Jessica X.; Yu, Joon-Ho; Bamshad, Michael J.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Auer, Paul L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Gordon, Adam S.; Nickerson, Deborah A.; Bamshad, Michael J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Graubert, Timothy A.] Harvard Univ, Dept Med, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Div Intramural Res, Framingham, MA 01702 USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. RP Bamshad, MJ (reprint author), Univ Washington, Dept Pediat, Seattle, WA 98195 USA. EM mbamshad@u.washington.edu RI Hardy, John/C-2451-2009; de Bakker, Paul/B-8730-2009; Singleton, Andrew/C-3010-2009; Johnson, Andrew/G-6520-2013; OI Graubert, Timothy/0000-0002-7710-1171; Assimes, Themistocles/0000-0003-2349-0009; de Bakker, Paul/0000-0001-7735-7858; Quinlan, Aaron/0000-0003-1756-0859; Seshadri, Sudha/0000-0001-6135-2622; Chong, Jessica/0000-0002-1616-2448; Turner, Emily/0000-0001-9040-9229; Shendure, Jay/0000-0002-1516-1865 FU National Heart, Lung, and Blood Institute (NHLBI) [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926] FX We acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI), the contributions of the many research institutions that participated in this study, the study investigators, field staff, and the study participants who created the Exome Sequencing Project (ESP) resource for biomedical research. Funding for the NHLBI Grand Opportunity (GO) ESP was provided by NHLBI grants RC2 HL-103010 (Heart GO), RC2 HL-102923 (Lung GO), and RC2 HL-102924 (Women's Health Initiative Sequencing Project). Exome sequencing was supported by NHLBI grants RC2 HL-102925 (Broad GO) and RC2 HL-102926 (Seattle GO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 48 TC 30 Z9 31 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 7 PY 2014 VL 95 IS 2 BP 183 EP 193 DI 10.1016/j.ajhg.2014.07.006 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AM7VE UT WOS:000340076000005 PM 25087612 ER PT J AU Drobizhev, M Stoltzfus, C Topol, I Collins, J Wicks, G Mikhaylov, A Barnett, L Hughes, TE Rebane, A AF Drobizhev, Mikhail Stoltzfus, Caleb Topol, Igor Collins, Jack Wicks, Geoffrey Mikhaylov, Alexander Barnett, Lauren Hughes, Thomas E. Rebane, Aleksander TI Multiphoton Photochemistry of Red Fluorescent Proteins in Solution and Live Cells SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID LARGE STOKES SHIFT; MONOMERIC RED; MICROSCOPY; CHROMOPHORE; DARK; PHOTOCONVERSION; COLOR; DECARBOXYLATION; ISOMERIZATION; SPECTROSCOPY AB Genetically encoded fluorescent proteins (FPs), and biosensors based on them, provide new insights into how living cells and tissues function. Ultimately, the goal of the bioimaging community is to use these probes deep in tissues and even in entire organisms, and this will require two-photon laser scanning microscopy (TPLSM), with its greater tissue penetration, lower autofluorescence background, and minimum photodamage in the out-of-focus volume. However, the extremely high instantaneous light intensities of femtosecond pulses in the focal volume dramatically increase the probability of further stepwise resonant photon absorption, leading to highly excited, ionizable and reactive states, often resulting in fast bleaching of fluorescent proteins in TPLSM. Here, we show that the femtosecond multiphoton excitation of red FPs (DsRed2 and mFruits), both in solution and live cells, results in a chain of consecutive, partially reversible reactions, with individual rates driven by a high-order (3-5 photon) absorption. The first step of this process corresponds to a three- (DsRed2) or four-photon (mFruits) induced fast isomerization of the chromophore, yielding intermediate fluorescent forms, which then subsequently transform into nonfluorescent products. Our experimental data and model calculations are consistent with a mechanism in which ultrafast electron transfer from the chromophore to a neighboring positively charged amino acid residue triggers the first step of multiphoton chromophore transformations in DsRed2 and mFruits, consisting of decarboxylation of a nearby deprotonated glutamic acid residue. C1 [Drobizhev, Mikhail; Stoltzfus, Caleb; Wicks, Geoffrey; Mikhaylov, Alexander; Rebane, Aleksander] Montana State Univ, Dept Phys, Bozeman, MT 59717 USA. [Barnett, Lauren; Hughes, Thomas E.] Montana State Univ, Dept Cell Biol & Neurosci, Bozeman, MT 59717 USA. [Topol, Igor; Collins, Jack] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Drobizhev, M (reprint author), Montana State Univ, Dept Phys, Bozeman, MT 59717 USA. EM drobizhev@physics.montana.edu RI Stoltzfus, Caleb/H-3278-2014; OI Stoltzfus, Caleb/0000-0002-0543-345X; Hughes, Thomas/0000-0001-5880-9951 FU NIH [R01 GM 098083, 1 R01 NS083875-01]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by NIH grants R01 GM 098083 and 1 R01 NS083875-01. We thank Pat Callis and Anton Vorontsov for very stimulating discussions. I.T. and J.C. thank the staff and administration of the Advanced Biomedical Computing Center for their support of this project. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. government. NR 46 TC 6 Z9 6 U1 3 U2 47 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 7 PY 2014 VL 118 IS 31 BP 9167 EP 9179 DI 10.1021/jp502477c PG 13 WC Chemistry, Physical SC Chemistry GA AM9TD UT WOS:000340223000005 PM 25004113 ER PT J AU Miranda, PC Mekonnen, A Salvador, R Basser, PJ AF Miranda, Pedro C. Mekonnen, Abeye Salvador, Ricardo Basser, Peter J. TI Predicting the electric field distribution in the brain for the treatment of glioblastoma SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE electric field; tumor treating fields; glioblastoma; finite element method ID TRANSCRANIAL CURRENT STIMULATION; DIELECTRIC-PROPERTIES; MAGNETIC STIMULATION; CEREBRAL CORTEX; CONDUCTIVITY; TISSUE; FREQUENCY; IMPEDANCE; MODELS; BONE AB The use of alternating electric fields has been recently proposed for the treatment of recurrent glioblastoma. In order to predict the electric field distribution in the brain during the application of such tumor treating fields (TTF), we constructed a realistic head model from MRI data and placed transducer arrays on the scalp to mimic an FDA-approved medical device. Values for the tissue dielectric properties were taken from the literature; values for the device parameters were obtained from the manufacturer. The finite element method was used to calculate the electric field distribution in the brain. We also included a 'virtual lesion' in the model to simulate the presence of an idealized tumor. The calculated electric field in the brain varied mostly between 0.5 and 2.0 V cm(-1) and exceeded 1.0 V cm(-1) in 60% of the total brain volume. Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces. These increases were strongest near the ventricles but were also present outside the tumor's necrotic core and in some parts of the gray matter-white matter interface. The electric field values predicted in this model brain are in reasonably good agreement with those that have been shown to reduce cancer cell proliferation in vitro. The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties. This could explain some of the variability in treatment outcomes. The proposed modeling framework could be used to better understand the physical basis of TTF efficacy through retrospective analysis and to improve TTF treatment planning. C1 [Miranda, Pedro C.; Mekonnen, Abeye; Salvador, Ricardo] Univ Lisbon, Fac Ciencias, IBEB, P-1749016 Lisbon, Portugal. [Basser, Peter J.] NICHD, STBB, PPITS, NIH, Bethesda, MD 20892 USA. RP Miranda, PC (reprint author), Univ Lisbon, Fac Ciencias, IBEB, P-1749016 Lisbon, Portugal. EM pcmiranda@fc.ul.pt RI Miranda, Pedro/A-5643-2013; Salvador, Ricardo/K-2301-2015 OI Miranda, Pedro/0000-0002-6793-8111; Salvador, Ricardo/0000-0003-1235-6533 FU Foundation for Science and Technology (FCT), Portugal; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health, USA; Seventh Framework Programme for Research of the European Commission [222079] FX This work was supported by the Foundation for Science and Technology (FCT), Portugal; the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA; the Seventh Framework Programme for Research of the European Commission (project HIVE, FET-Open grant 222079). NR 45 TC 16 Z9 16 U1 2 U2 20 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 7 PY 2014 VL 59 IS 15 BP 4137 EP 4147 DI 10.1088/0031-9155/59/15/4137 PG 11 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AM7OI UT WOS:000340056800010 PM 25003941 ER PT J AU Bal, H Guerin, L Casey, ME Conti, M Eriksson, L Michel, C Fanti, S Pettinato, C Adler, S Choyke, P AF Bal, H. Guerin, L. Casey, M. E. Conti, M. Eriksson, L. Michel, C. Fanti, S. Pettinato, C. Adler, S. Choyke, P. TI Improving PET spatial resolution and detectability for prostate cancer imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE prostate cancer; PET; TOF PET; spatial resolution ID TIME-OF-FLIGHT; POSITRON-EMISSION-TOMOGRAPHY; MODEL OBSERVERS; SCATTER CORRECTION; C-11-CHOLINE PET; TUMOR-DETECTION; IMPACT; C-11-ACETATE; PERFORMANCE; NOISE AB Prostate cancer, one of the most common forms of cancer among men, can benefit from recent improvements in positron emission tomography (PET) technology. In particular, better spatial resolution, lower noise and higher detectability of small lesions could be greatly beneficial for early diagnosis and could provide a strong support for guiding biopsy and surgery. In this article, the impact of improved PET instrumentation with superior spatial resolution and high sensitivity are discussed, together with the latest development in PET technology: resolution recovery and time-of-flight reconstruction. Using simulated cancer lesions, inserted in clinical PET images obtained with conventional protocols, we show that visual identification of the lesions and detectability via numerical observers can already be improved using state of the art PET reconstruction methods. This was achieved using both resolution recovery and time-of-flight reconstruction, and a high resolution image with 2 mm pixel size. Channelized Hotelling numerical observers showed an increase in the area under the LROC curve from 0.52 to 0.58. In addition, a relationship between the simulated input activity and the area under the LROC curve showed that the minimum detectable activity was reduced by more than 23%. C1 [Bal, H.; Guerin, L.; Casey, M. E.; Conti, M.; Eriksson, L.; Michel, C.] Siemens Healthcare Mol Imaging, Knoxville, TN 37932 USA. [Fanti, S.] Univ Bologna, Policlin S Orsola Malpighi, Bologna, Italy. [Pettinato, C.] St Orsola Marcello Malpighi Hosp, Med Phys Unit, Bologna, Italy. [Adler, S.] NCI Leidos Biomed Res Inc, Bethesda, MD USA. [Choyke, P.] NCI, Bethesda, MD 20892 USA. RP Bal, H (reprint author), Siemens Healthcare Mol Imaging, Knoxville, TN 37932 USA. EM harshali.bal@siemens.com NR 41 TC 8 Z9 8 U1 1 U2 11 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 7 PY 2014 VL 59 IS 15 BP 4411 EP 4426 DI 10.1088/0031-9155/59/15/4411 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AM7OI UT WOS:000340056800027 PM 25049221 ER PT J AU Muller, JR Waldmann, TA Dubois, S AF Mueller, Juergen R. Waldmann, Thomas A. Dubois, Sigrid TI Loss of Cytotoxicity and Gain of Cytokine Production in Murine Tumor-Activated NK Cells SO PLOS ONE LA English DT Article ID NATURAL-KILLER-CELLS; PERIPHERAL-BLOOD; MULTIPLE-SCLEROSIS; DENDRITIC CELLS; DIFFERENTIAL EXPRESSION; INHIBITORY RECEPTORS; CLASS-I; SUBSETS; IL-15; CD56(BRIGHT) AB NK cells are able to form a functional memory suggesting that some NK cells are surviving the activation process. We hypothesized that NK cell activation causes the development of a distinct NK cell subset and studied the fate of murine post-activation NK cells. Activation was achieved by in vivo and in vitro exposures to the melanoma tumor cell line B16 that was followed by differentiation in IL-2. When compared with control NK cells, post-activation CD25(+) NK cells expressed little granzyme B or perforin and had low lysis activity. Post-activation NK cells expressed CD27, CD90, CD127, and were low for CD11b suggesting that tumor-induced activation is restricted to an early NK cell subset. Activation of NK cells led to decreases of CD16, CD11c and increases of CD62L and the IL-18 receptor. In vivo activated but not control NK cells expressed a variety of cytokines that included IFN gamma, TNF alpha, GM-CSF and IL-10. These data suggest that the exposure of a subset of peripheral NK cells to the B16 tumor environment caused an exhaustion of their cytolytic capacity but also a gain in their ability to produce cytokines. C1 [Mueller, Juergen R.; Waldmann, Thomas A.; Dubois, Sigrid] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dubois, S (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM duboiss@mail.nih.gov FU National Cancer Institute, NIH FX This research is supported by the intramural research program of the National Cancer Institute, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 1 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2014 VL 9 IS 8 AR e102793 DI 10.1371/journal.pone.0102793 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM6SB UT WOS:000339993900006 PM 25101668 ER PT J AU Ioannidis, JPA Khoury, MJ AF Ioannidis, John P. A. Khoury, Muin J. TI Assessing Value in Biomedical Research The PQRST of Appraisal and Reward SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Humanities & Sci, Dept Stat, Palo Alto, CA 94304 USA. [Ioannidis, John P. A.] Stanford Univ, Meta Res Innovat Ctr Stanford METRICS, Palo Alto, CA 94304 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Khoury, Muin J.] NCI, NIH, Bethesda, MD 20892 USA. RP Ioannidis, JPA (reprint author), Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. EM jioannid@stanford.edu FU Intramural CDC HHS [CC999999] NR 8 TC 24 Z9 25 U1 0 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 6 PY 2014 VL 312 IS 5 BP 483 EP 484 DI 10.1001/jama.2014.6932 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM4FL UT WOS:000339808600013 PM 24911291 ER PT J AU Hingson, R Compton, WM AF Hingson, Ralph Compton, Wilson M. TI Screening and Brief Intervention and Referral to Treatment for Drug Use in Primary Care Back to the Drawing Board SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ALCOHOL; METAANALYSIS; RISK C1 [Hingson, Ralph] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. [Compton, Wilson M.] NIDA, Rockville, MD USA. RP Hingson, R (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Ln, Bethesda, MD 20892 USA. EM rhingson@mail.nih.gov NR 15 TC 25 Z9 25 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 6 PY 2014 VL 312 IS 5 BP 488 EP 489 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM4FL UT WOS:000339808600016 PM 25096687 ER PT J AU Lute, B Jou, W Lateef, DM Goldgof, M Xiao, CY Pinol, RA Kravitz, AV Miller, NR Huang, YG Girardet, C Butler, AA Gavrilova, O Reitman, ML AF Lute, Beth Jou, William Lateef, Dalya M. Goldgof, Margalit Xiao, Cuiying Pinol, Ramon A. Kravitz, Alexxai V. Miller, Nicole R. Huang, Yuning George Girardet, Clemence Butler, Andrew A. Gavrilova, Oksana Reitman, Marc L. TI Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature SO CELL METABOLISM LA English DT Article ID MELANOCYTE-STIMULATING HORMONE; ALPHA-MSH; FOOD-INTAKE; CARDIOVASCULAR FUNCTION; FRAMESHIFT MUTATION; INDUCED HYPOTHERMIA; ENERGY HOMEOSTASIS; NERVOUS-SYSTEM; ONSET OBESITY; FAT MASS AB The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r)-mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists, and MTII selectively activated arcuate nucleus dopaminergic neurons, suggesting that these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress. C1 [Lute, Beth; Jou, William; Gavrilova, Oksana] NIDDK, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. [Lateef, Dalya M.; Goldgof, Margalit; Xiao, Cuiying; Pinol, Ramon A.; Kravitz, Alexxai V.; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Miller, Nicole R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Huang, Yuning George] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Girardet, Clemence; Butler, Andrew A.] Scripps Res Inst, Dept Metab & Aging, Jupiter, FL 33458 USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH [DK075062, DK075063, DK073189] FX We thank Jurgen Schnermann and David R. Sibley for insightful discussions and Anna Panyutin for technical assistance. This research was supported by the Intramural Research Program (DK075062, DK075063) and DK073189 of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH. NR 82 TC 7 Z9 7 U1 3 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD AUG 5 PY 2014 VL 20 IS 2 BP 333 EP 345 DI 10.1016/j.cmet.2014.05.021 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5RJ UT WOS:000341402500018 PM 24981835 ER PT J AU Carver, J Dexheimer, TS Hsu, D Weng, MT Smith, JL Guha, R Jadhav, A Simeonov, A Luo, J AF Carver, Joseph Dexheimer, Thomas S. Hsu, Dennis Weng, Meng-Tzu Smith, Jordan L. Guha, Rajarshi Jadhav, Ajit Simeonov, Anton Luo, Ji TI A High-Throughput Assay for Small Molecule Destabilizers of the KRAS Oncoprotein SO PLOS ONE LA English DT Article ID RAS ONCOGENES; IN-VITRO; K-RAS; INHIBITION; PROTEIN; DEGRADATION; CANCER; LOCALIZATION; TRAFFICKING; ACTIVATION AB Mutations in the Ras family of small GTPases, particularly KRAS, occur at high frequencies in cancer and represent a major unmet therapeutic need due to the lack of effective targeted therapies. Past efforts directed at inhibiting the activity of the Ras oncoprotein have proved difficult. We propose an alternative approach to target Ras by eliminating Ras protein from cells with pharmacological means. In this study, we developed a cell-based, high-content screening platform to identify small molecules that could promote the degradation of the KRAS oncoprotein. We generated an EGFP-KRAS(G12V) fluorescence reporter system and implemented it for automated screening in 1536-well plates using high-throughput cellular imaging. We screened a library of clinically relevant compounds at wide dose range and identified Ponatinib and AMG-47a as two candidate compounds that selectively reduced the levels of EGFP-KRAS(G12V) protein but did not affect EGFP protein in cells. This proof-of-principle study demonstrates that it is feasible to use a high-throughput screen to identify compounds that promote the degradation of the Ras oncoprotein as a new approach to target Ras. C1 [Carver, Joseph; Hsu, Dennis; Weng, Meng-Tzu; Smith, Jordan L.; Luo, Ji] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Dexheimer, Thomas S.; Guha, Rajarshi; Jadhav, Ajit; Simeonov, Anton] Natl Ctr Adv Translat Sci, Div Preclin Innovat, Natl Inst Hlth Chem Genom Ctr, Bethesda, MD 20894 USA. RP Simeonov, A (reprint author), Natl Ctr Adv Translat Sci, Div Preclin Innovat, Natl Inst Hlth Chem Genom Ctr, Bethesda, MD 20894 USA. EM asimeono@mail.nih.gov; ji.luo@nih.gov OI Smith , Jordan /0000-0003-0460-0647 FU National Cancer Institute (NCI) Center for Cancer Research-Johns Hopkins University Master in Biotechnology Fellowship; Howard Hughes Medical Institute-National Institutes of Health Research Scholar Fellowship; Liver Disease Prevention and Treatment Research Foundation (Taiwan) Fellowship; NCI Intramural Program; Division of Preclinical Innovation at the National Center for Advancing Translational Sciences FX This work was supported by an National Cancer Institute (NCI) Center for Cancer Research-Johns Hopkins University Master in Biotechnology Fellowship to J.C.; by a Howard Hughes Medical Institute-National Institutes of Health Research Scholar Fellowship to D. H.; by a Liver Disease Prevention and Treatment Research Foundation (Taiwan) Fellowship to M. T. W.; by the NCI Intramural Program to J.L.; and by the Division of Preclinical Innovation at the National Center for Advancing Translational Sciences to T. S. D., R. G., A.J. and A. S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 6 Z9 6 U1 0 U2 11 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 5 PY 2014 VL 9 IS 8 AR e103836 DI 10.1371/journal.pone.0103836 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BW UT WOS:000341357200034 PM 25093678 ER PT J AU Paldurai, A Xiao, S Kim, SH Kumar, S Nayak, B Samal, S Collins, PL Samal, SK AF Paldurai, Anandan Xiao, Sa Kim, Shin-Hee Kumar, Sachin Nayak, Baibaswata Samal, Sweety Collins, Peter L. Samal, Siba K. TI Effects of Naturally Occurring Six- and Twelve-Nucleotide Inserts on Newcastle Disease Virus Replication and Pathogenesis SO PLOS ONE LA English DT Article ID COMPLETE GENOME SEQUENCE; COMPLETE NUCLEOTIDE-SEQUENCE; LIVE-BIRD MARKETS; PARAMYXOVIRUS TYPE-1; GENETIC DIVERSITY; FUSION PROTEIN; WEST-AFRICA; STRAIN; EXISTENCE; VIRULENCE AB Newcastle disease virus (NDV) isolates contain genomes of 15,186, 15,192 or 15,198 nucleotides (nt). The length differences reflect a 6-nt insert in the 5' (downstream) non-translated region (NTR) of the N gene (15,192-nt genome) or a 12-nt insert in the ORF encoding the P and V proteins (causing a 4-amino acid insert; 15,198-nt genome). We evaluated the role of these inserts in the N and P genes on viral replication and pathogenicity by inserting them into genomes of two NDV strains that have natural genome lengths of 15,186 nt and represent two different pathotypes, namely the mesogenic strain Beaudette C (BC) and the velogenic strain GB Texas (GBT). Our results showed that the 6-nt and 12-nt inserts did not detectably affect N gene expression or P protein function. The inserts had no effect on the replication or virulence of the highly virulent GBT strain but showed modest degree of attenuation in mesogenic strain BC. We also deleted a naturally-occurring 6-nt insertion in the N gene from a highly virulent 15,192-nt genome-length virus, strain Banjarmasin. This resulted in reduced replication in vitro and reduced virulence in vivo. Thus, although these inserts had no evident effect on gene expression, protein function, or replication in vivo, they did affect virulence in two of the three tested strains. C1 [Paldurai, Anandan; Xiao, Sa; Kim, Shin-Hee; Kumar, Sachin; Nayak, Baibaswata; Samal, Sweety; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] Natl Inst Allergy & Infect Dis, Infect Dis Lab, Bethesda, MD USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009]; NIAID NIH FX This research was supported by NIAID contract N01A060009 (85% support) and the NIAID NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services, and the mention of trade names, commercial practices, or organizations does not imply endorsement by the U. S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 4 Z9 4 U1 1 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 5 PY 2014 VL 9 IS 8 AR e103951 DI 10.1371/journal.pone.0103951 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BW UT WOS:000341357200048 PM 25093330 ER PT J AU Bashford-Rogers, RJM Palser, AL Idris, SF Carter, L Epstein, M Callard, RE Douek, DC Vassiliou, GS Follows, GA Hubank, M Kellam, P AF Bashford-Rogers, Rachael J. M. Palser, Anne L. Idris, Saad F. Carter, Lisa Epstein, Michael Callard, Robin E. Douek, Daniel C. Vassiliou, George S. Follows, George A. Hubank, Mike Kellam, Paul TI Capturing needles in haystacks: a comparison of B-cell receptor sequencing methods SO BMC IMMUNOLOGY LA English DT Article ID CONCERTED ACTION BHM4-CT98-3936; POLYMERASE-CHAIN-REACTION; IMMUNOGLOBULIN; CLONALITY; REPERTOIRE; ANTIBODY; PCR; LYMPHOMA; LYMPHOPROLIFERATIONS; MALIGNANCIES AB Background: Deep-sequencing methods are rapidly developing in the field of B-cell receptor (BCR) and T-cell receptor (TCR) diversity. These promise to revolutionise our understanding of adaptive immune dynamics, identify novel antibodies, and allow monitoring of minimal residual disease. However, different methods for BCR and TCR enrichment and amplification have been proposed. Here we perform the first systematic comparison between different methods of enrichment, amplification and sequencing for generating BCR and TCR repertoires using large sample numbers. Results: Resampling from the same RNA or cDNA pool results in highly correlated and reproducible repertoires, but resampling low frequency clones leads to stochastic variance. Repertoires generated by different sequencing methods (454 Roche and Illumina MiSeq) and amplification methods (multiplex PCR, 5' Rapid amplification of cDNA ends (5' RACE), and RNA-capture) are highly correlated, and resulting IgHV gene frequencies between the different methods were not significantly different. Read length has an impact on captured repertoire structure, and ultimately full-length BCR sequences are most informative for repertoire analysis as diversity outside of the CDR is very useful for phylogenetic analysis. Additionally, we show RNA-based BCR repertoires are more informative than using DNA. Conclusions: Repertoires generated by different sequencing and amplification methods are consistent, but we show that read lengths, depths and error profiles should be considered in experimental design, and multiple sampling approaches could be employed to minimise stochastic sampling variation. This detailed investigation of immune repertoire sequencing methods is essential for informing basic and clinical research. C1 [Bashford-Rogers, Rachael J. M.; Palser, Anne L.; Idris, Saad F.; Vassiliou, George S.; Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Carter, Lisa; Epstein, Michael; Callard, Robin E.; Hubank, Mike] UCL Inst Child Hlth, Mol Haematol & Canc Biol Unit, London WC1N 1EH, England. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Follows, George A.] Addenbrookes Hosp, Dept Hematol, Cambridge CB2 0QQ, England. [Kellam, Paul] UCL, Div Infect & Immun, Res Dept Infect, London WC1E 6BT, England. RP Kellam, P (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. EM pk5@sanger.ac.uk OI Vassiliou, George/0000-0003-4337-8022 FU Wellcome Trust FX This work was supported by the Wellcome Trust. We would like to thank the Cambridge Cancer Trials Centre and nurse specialists Gwyn Stafford, Rosie Tween, Lisa Walbridge and Joanna Baxter, and the patients and staff of Addenbrooke's Haematology Translational Research Laboratory. NR 44 TC 8 Z9 8 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD AUG 5 PY 2014 VL 15 AR 29 DI 10.1186/s12865-014-0029-0 PG 9 WC Immunology SC Immunology GA AO2NT UT WOS:000341161800001 PM 25189176 ER PT J AU Lin, YJ Chen, CY Jeang, KT Liu, X Wang, JH Hung, CH Tsang, H Lin, TH Liao, CC Huang, SM Lin, CW Ho, MW Chien, WK Chen, JH Ho, TJ Tsai, FJ AF Lin, Ying-Ju Chen, Chia-Yen Jeang, Kuan-Teh Liu, Xiang Wang, Jen-Hsien Hung, Chien-Hui Tsang, Hsinyi Lin, Ting-Hsu Liao, Chiu-Chu Huang, Shao-Mei Lin, Cheng-Wen Ho, Mao-Wang Chien, Wen-Kuei Chen, Jin-Hua Ho, Tsung-Jung Tsai, Fuu-Jen TI Ring finger protein 39 genetic variants associate with HIV-1 plasma viral loads and its replication in cell culture SO CELL AND BIOSCIENCE LA English DT Article DE HIV-1 viral load; RNF39; Single nucleotide polymorphism; Viral replication ID TRIM5-ALPHA SPRY DOMAIN; HAPLOTYPE RECONSTRUCTION; MAJOR DETERMINANTS; HOST CONTROL; GENOME-WIDE; MCF-7 CELLS; RESTRICTION; RETROVIRUSES; INFECTION; DATABASE AB Background: The human immunodeficiency virus (HIV-1) exploits host proteins to complete its life cycle. Genome-wide siRNA approaches suggested that host proteins affect HIV-1 replication. However, the results barely overlapped. RING finger protein 39 (RNF39) has been identified from genome-wide association studies. However, its function during HIV-1 replication remains unclear. Methods and results: We investigated the relationship between common RNF39 genetic variants and HIV-1 viral loads. The effect of RNF39 protein knockdown or overexpression on HIV-1 replication was then investigated in different cell lines. Two genetic variants were associated with HIV-1 viral loads. Patients with the ht1-GG/GG haplotype presented lower RNF39 expression levels and lower HIV-1 viral load. RNF39 knockdown inhibited HIV-1 expression. Conclusions: RNF39 protein may be involved in HIV-1 replication as observed in genetic studies on patients with HIV-1 and in in vitro cell cultures. C1 [Lin, Ying-Ju; Lin, Ting-Hsu; Liao, Chiu-Chu; Huang, Shao-Mei; Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Res, Genet Ctr, Taichung, Taiwan. [Lin, Ying-Ju; Ho, Tsung-Jung; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Chen, Chia-Yen] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Jeang, Kuan-Teh; Liu, Xiang] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Jen-Hsien; Ho, Mao-Wang] China Med Univ Hosp, Dept Internal Med, Infect Dis Sect, Taichung, Taiwan. [Hung, Chien-Hui] Chang Gung Univ, Grad Inst Clin Med Sci, Chiayi, Taiwan. [Tsang, Hsinyi] NIAID, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Lin, Cheng-Wen] China Med Univ, Dept Med Lab Sci & Biotechnol, Taichung, Taiwan. [Chien, Wen-Kuei] China Med Univ, Ctr Biostat, Taichung, Taiwan. [Chien, Wen-Kuei; Chen, Jin-Hua] Taipei Med Univ, Ctr Biostat, Taipei, Taiwan. [Ho, Tsung-Jung] China Med Univ, Beigang Hosp, Div Chinese Med, Shenyang, Yunlin County, Peoples R China. [Ho, Tsung-Jung] China Med Univ, Tainan Municipal An Nan Hosp, Div Chinese Med, Tainan, Taiwan. [Tsai, Fuu-Jen] Asia Univ, Dept Biotechnol, Taichung, Taiwan. RP Ho, TJ (reprint author), China Med Univ, Sch Chinese Med, Taichung, Taiwan. EM jeron888@gmail.com; d0704@mail.cmuh.org.tw RI Liu, Xiang/F-5731-2014; Tsai, Fuu-Jen/J-4140-2015 FU CMU [CMU100-S-01]; CMUH [DMR-103-039, DMR-103-100]; Republic of China National Science Council [NSC100-2320-B-039-012-MY3] FX Financial support for this research was provided by CMU (CMU100-S-01), CMUH (DMR-103-039; DMR-103-100), and the Republic of China National Science Council (NSC100-2320-B-039-012-MY3). NR 34 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD AUG 5 PY 2014 VL 4 AR 40 DI 10.1186/2045-3701-4-40 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO1WX UT WOS:000341107300002 PM 25126410 ER PT J AU Duki, SF Mathur, H AF Duki, Solomon F. Mathur, Harsh TI Nonexponential tunneling and control of microwave absorption lineshapes via Fano resonance for electrons on helium SO PHYSICAL REVIEW B LA English DT Article ID MAGNETIC-FIELD; SYSTEM AB We consider the application of a small in-planemagnetic field to electrons on a helium surface in a perpendicular magnetic field. Certain states that were bound to the helium surface then dissolve into the continuum, turning into long-lived resonances. As a result microwave absorption lines acquire an asymmetric Fano lineshape that is tunable by varying the microwave polarization or the in-plane magnetic field. Electrons trapped in a formerly bound state will tunnel off the surface of helium; we show that under suitable circumstances this "radioactive decay" can show damped oscillations rather than a simple exponential decay. The mechanism for oscillatory exponential decay is not specific to electrons on helium and this effect may also be relevant elsewhere in physics. C1 [Duki, Solomon F.; Mathur, Harsh] Case Western Reserve Univ, Dept Phys, Cleveland, OH 44106 USA. [Duki, Solomon F.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Duki, SF (reprint author), Case Western Reserve Univ, Dept Phys, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM dukisf@ncbi.nlm.nih.gov OI Duki, Solomon/0000-0003-3042-0252 NR 11 TC 0 Z9 0 U1 1 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 EI 1550-235X J9 PHYS REV B JI Phys. Rev. B PD AUG 5 PY 2014 VL 90 IS 8 AR 085404 DI 10.1103/PhysRevB.90.085404 PG 5 WC Physics, Condensed Matter SC Physics GA AO3SV UT WOS:000341257100004 ER PT J AU Kim, SYH Marson, DC AF Kim, Scott Y. H. Marson, Daniel C. TI Assessing decisional capacity in patients with brain tumors SO NEUROLOGY LA English DT Editorial Material ID MALIGNANT GLIOMA C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Marson, Daniel C.] Univ Alabama Birmingham, Alzheimers Dis Ctr, Dept Neurol, Birmingham, AL USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 5 PY 2014 VL 83 IS 6 BP 482 EP 483 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AN1XV UT WOS:000340378200006 PM 24991036 ER PT J AU Boyd, CD Tierney, M Wassermann, EM Spina, S Oblak, AL Ghetti, B Grafman, J Huey, E AF Boyd, Clara D. Tierney, Michael Wassermann, Eric M. Spina, Salvatore Oblak, Adrian L. Ghetti, Bernardino Grafman, Jordan Huey, Edward TI Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome SO NEUROLOGY LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; FRONTOTEMPORAL DEMENTIA; NEUROPATHOLOGIC CRITERIA; DEPTH-PERCEPTION; DEGENERATION; SENSITIVITY; FEATURES; CORTEX AB Objective: To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from non-AD pathology in corticobasal syndrome (CBS). Methods: This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) vs patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. Results: Patients with CBS-AD had younger onset (54.5 vs 63.6 years, p = 0.001) and lower memory scores on the Mattis Dementia Rating Scale-2 (16 vs 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBS-nonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). Conclusions: In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBS-AD. Classification of evidence: This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%). C1 [Boyd, Clara D.; Huey, Edward] Columbia Univ, Dept Neurol, Med Ctr, New York, NY 10027 USA. [Tierney, Michael; Wassermann, Eric M.] NINDS, Behav Neurol Unit, Bethesda, MD 20892 USA. [Spina, Salvatore; Oblak, Adrian L.; Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Grafman, Jordan] Northwestern Univ, Dept Phys Med & Rehabil, Feinberg Sch Med, Chicago, IL 60611 USA. RP Boyd, CD (reprint author), Columbia Univ, Dept Neurol, Med Ctr, New York, NY 10027 USA. EM cdboyd@fastmail.us FU T32 Neuroepidemiology Training Program NIH/National Institute of Neurological Disorders and Stroke (NINDS) [5T32NS007153-29]; Charles and Ann Lee Brown Fellowship, Intramural Research Program of the NINDS, NIH/NINDS [R00NS060766, R01NS076837]; Columbia University's CTSA grant from NCATS-NCRR/NIH [UL1RR024156]; PHS [P30 AG10133] FX Supported by T32 Neuroepidemiology Training Program 5T32NS007153-29 NIH/National Institute of Neurological Disorders and Stroke (NINDS) (E. L.), Charles and Ann Lee Brown Fellowship, Intramural Research Program of the NINDS, NIH/NINDS grants R00NS060766 and R01NS076837 (E. H.), Columbia University's CTSA grant UL1RR024156 from NCATS-NCRR/NIH (E. H.), and PHS P30 AG10133 (B.G.). NR 32 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 5 PY 2014 VL 83 IS 6 BP 510 EP 519 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AN1XV UT WOS:000340378200011 PM 24991033 ER PT J AU Hu, W Downward, GS Reiss, B Xu, J Bassig, BA Hosgood, HD Zhang, LL Seow, WJ Wu, GP Chapman, RS Tian, LW Wei, FS Vermeulen, R Lan, Q AF Hu, Wei Downward, George S. Reiss, Boris Xu, Jun Bassig, Bryan A. Hosgood, H. Dean, III Zhang, Linlin Seow, Wei Jie Wu, Guoping Chapman, Robert S. Tian, Linwei Wei, Fusheng Vermeulen, Roel Lan, Qing TI Personal and Indoor PM2.5 Exposure from Burning Solid Fuels in Vented and Unvented Stoves in a Rural Region of China with a High Incidence of Lung Cancer SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID FINE PARTICULATE MATTER; HOUSEHOLD AIR-POLLUTION; XUAN-WEI; RETROSPECTIVE COHORT; CARBON-MONOXIDE; BIOMASS FUELS; COAL USE; RISK; IMPROVEMENT; POLLUTANTS AB The combustion of biomass and coal is the dominant source of household air pollution (HAP) in China, and contributes significantly to the total burden of disease in the Chinese population. To characterize HAP exposure related to solid fuel use and ventilation patterns, an exposure assessment study of 163 nonsmoking female heads of households enrolled from 30 villages was conducted in Xuanwei and Fuyuan, two neighboring rural counties with high incidence of lung cancer due to the burning of smoky coal (a bituminous coal, which in health evaluations is usually compared to smokeless coal-an anthracite coal available in some parts of the area). Personal and indoor 24-h PM2.5 samples were collected over two consecutive days in each household, with approximately one-third of measurements retaken in a second season. The overall geometric means (GM) of personal PM2.5 concentrations in Xuanwei and Fuyuan were 166 [Geometric Standard Deviation (GSD):2.0] and 146 (GSD:1.9) mu g/m(3), respectively, which were similar to the indoor PM2.(5) air concentrations [GM(GSD):162 (2.1) and 136 (2.0) mu g/m(3), respectively]. Personal PM2.5 was moderately highly correlated with indoor PM2.5 (Spearman r = 0.70, p < 0.0001). Burning wood or plant materials (tobacco stems, corncobs etc.) resulted in the highest personal PM2.5 concentrations (GM:289 and 225 mu g/m(3), respectively), followed by smoky coal, and smokeless coal (GM:148 and 115 mu g/m(3), respectively). PM2.5 levels of vented stoves were 34-80% lower than unvented stoves and firepits across fuel types. Mixed effect models indicated that fuel type, ventilation, number of windows, season, and burning time per stove were the main factors related to personal PM2.5 exposure. Lower PM2.5 among vented stoves compared with unvented stoves and firepits is of interest as it parallels the observation of reduced risks of malignant and nonmalignant lung diseases in the region. C1 [Hu, Wei; Xu, Jun; Bassig, Bryan A.; Hosgood, H. Dean, III; Seow, Wei Jie; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Downward, George S.; Reiss, Boris; Vermeulen, Roel] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. [Zhang, Linlin; Wu, Guoping; Wei, Fusheng] China Natl Environm Monitoring Ctr, Beijing 100029, Peoples R China. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok 10330, Thailand. [Tian, Linwei] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. RP Vermeulen, R (reprint author), Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. EM r.c.h.vermeulen@uu.nl RI Tian, Linwei/A-9736-2009; Vermeulen, Roel/F-8037-2011 OI Tian, Linwei/0000-0002-4739-1534; Vermeulen, Roel/0000-0003-4082-8163 FU National Institutes of Health intramural research program FX This project was supported by the National Institutes of Health intramural research program. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors would like to acknowledge Jackie King from BioReliance and Peter Hui and Nathan Appel from Information Management Systems, Inc. for their support. NR 33 TC 27 Z9 31 U1 8 U2 82 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD AUG 5 PY 2014 VL 48 IS 15 SI SI BP 8456 EP 8464 DI 10.1021/es502201s PG 9 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA AM7WY UT WOS:000340080600018 PM 25003800 ER PT J AU Rotroff, DM Martin, MT Dix, DJ Filer, DL Houck, KA Knudsen, TB Sipes, NS Reif, DM Xia, MH Huang, RL Judson, RS AF Rotroff, Daniel M. Martin, Matt T. Dix, David J. Filer, Dayne L. Houck, Keith A. Knudsen, Thomas B. Sipes, Nisha S. Reif, David M. Xia, Menghang Huang, Ruili Judson, Richard S. TI Predictive Endocrine Testing in the 21st Century Using in Vitro Assays of Estrogen Receptor Signaling Responses SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID MOLECULAR-MECHANISMS; BETA; DISRUPTORS; CANCER; CELLS; CHEMICALS; ALPHA; US AB Thousands of environmental chemicals are subject to regulatory review for their potential to be endocrine disruptors (ED). In vitro high-throughput screening (HTS) assays have emerged as a potential tool for prioritizing chemicals for ED-related whole-animal tests. In this study, 1814 chemicals including pesticide active and inert ingredients, industrial chemicals, food additives, and pharmaceuticals were evaluated in a panel of 13 in vitro HTS assays. The panel of in vitro assays interrogated multiple end points related to estrogen receptor (ER) signaling, namely binding, agonist, antagonist, and cell growth responses. The results from the in vitro assays were used to create an ER Interaction Score. For 36 reference chemicals, an ER Interaction Score >0 showed 100% sensitivity and 87.5% specificity for classifying potential ER activity. The magnitude of the ER Interaction Score was significantly related to the potency classification of the reference chemicals (p < 0.0001). ER alpha/ER beta selectivity was also evaluated, but relatively few chemicals showed significant selectivity for a specific isoform. When applied to a broader set of chemicals with in vivo uterotrophic data, the ER Interaction Scores showed 91% sensitivity and 65% specificity. Overall, this study provides a novel method for combining in vitro concentration response data from multiple assays and, when applied to a large set of ER data, accurately predicted estrogenic responses and demonstrated its utility for chemical prioritization. C1 [Rotroff, Daniel M.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27514 USA. [Rotroff, Daniel M.; Martin, Matt T.; Dix, David J.; Filer, Dayne L.; Houck, Keith A.; Knudsen, Thomas B.; Sipes, Nisha S.; Reif, David M.; Judson, Richard S.] US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Xia, Menghang; Huang, Ruili] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Judson, RS (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27514 USA. EM judson.richard@epa.gov OI Judson, Richard/0000-0002-2348-9633; Reif, David/0000-0001-7815-6767 NR 32 TC 23 Z9 24 U1 11 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD AUG 5 PY 2014 VL 48 IS 15 SI SI BP 8706 EP 8716 DI 10.1021/es502676e PG 11 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA AM7WY UT WOS:000340080600047 PM 24960280 ER PT J AU Ceribelli, M Kelly, PN Shaffer, AL Wright, GW Xiao, WM Yang, YB Griner, LAM Guha, R Shinn, P Keller, JM Liu, DB Patel, PR Ferrer, M Joshi, S Nerle, S Sandy, P Normant, E Thomas, CJ Staudt, LM AF Ceribelli, Michele Kelly, Priscilla N. Shaffer, Arthur L. Wright, George W. Xiao, Wenming Yang, Yibin Griner, Lesley A. Mathews Guha, Rajarshi Shinn, Paul Keller, Jonathan M. Liu, Dongbo Patel, Paresma R. Ferrer, Marc Joshi, Shivangi Nerle, Sujata Sandy, Peter Normant, Emmanuel Thomas, Craig J. Staudt, Louis M. TI Blockade of oncogenic I kappa B kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer therapy; drug synergism ID GENE-EXPRESSION; SELECTIVE-INHIBITION; BET BROMODOMAINS; SUPER-ENHANCERS; MYC; TRANSCRIPTION; LEUKEMIA; DISCOVERY; TARGET; BRD4 AB In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-kappa B activity is essential for viability of the malignant cells and is sustained by constitutive activity of I kappa B kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-kappa B-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling. C1 [Ceribelli, Michele; Kelly, Priscilla N.; Shaffer, Arthur L.; Xiao, Wenming; Yang, Yibin; Staudt, Louis M.] Natl Canc Inst, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Wright, George W.] Natl Canc Inst, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Griner, Lesley A. Mathews; Guha, Rajarshi; Shinn, Paul; Keller, Jonathan M.; Liu, Dongbo; Patel, Paresma R.; Ferrer, Marc; Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bethesda, MD 20892 USA. [Joshi, Shivangi; Nerle, Sujata; Sandy, Peter; Normant, Emmanuel] Constellat Pharmaceut Inc, Cambridge, MA 02142 USA. RP Staudt, LM (reprint author), Natl Canc Inst, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Intramural Research Programs of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Human Genome Research Institute; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E, U54CA143930]; Division of Preclinical Innovation, National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research FX We thank Kathleen Meyer for help with the Gene Expression Omnibus (GEO) database submission. This research was supported by the Intramural Research Programs of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the National Human Genome Research Institute; the Frederick National Laboratory for Cancer Research, National Institutes of Health, including Contract HHSN261200800001E and Grant U54CA143930; the Division of Preclinical Innovation, National Center for Advancing Translational Sciences; and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research. NR 28 TC 49 Z9 51 U1 0 U2 20 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2014 VL 111 IS 31 BP 11365 EP 11370 DI 10.1073/pnas.1411701111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200035 PM 25049379 ER PT J AU Boele, J Persson, H Shin, JW Ishizu, Y Newie, IS Sokilde, R Hawkins, SM Coarfa, C Ikeda, K Takayama, K Horie-Inoue, K Ando, Y Burroughs, AM Sasaki, C Suzuki, C Sakai, M Aoki, S Ogawa, A Hasegawa, A Lizio, M Kaida, K Teusink, B Carninci, P Suzuki, H Inoue, S Gunaratne, PH Rovira, C Hayashizaki, Y de Hoon, MJL AF Boele, Joost Persson, Helena Shin, Jay W. Ishizu, Yuri Newie, Inga S. Sokilde, Rolf Hawkins, Shannon M. Coarfa, Cristian Ikeda, Kazuhiro Takayama, Ken-ichi Horie-Inoue, Kuniko Ando, Yoshinari Burroughs, A. Maxwell Sasaki, Chihiro Suzuki, Chizuru Sakai, Mizuho Aoki, Shintaro Ogawa, Ayumi Hasegawa, Akira Lizio, Marina Kaida, Kaoru Teusink, Bas Carninci, Piero Suzuki, Harukazu Inoue, Satoshi Gunaratne, Preethi H. Rovira, Carlos Hayashizaki, Yoshihide de Hoon, Michiel J. L. TI PAPD5-mediated 3 ' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nucleotidyl transferase; microRNA processing ID EMBRYONIC STEM-CELLS; MICRORNA BIOGENESIS; SMALL RNAS; CARDIOVASCULAR-DISEASE; PRECURSOR MICRORNA; POLY(A) POLYMERASE; NEXT-GENERATION; HUMAN DICER; CANCER; LIN28 AB Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases. C1 [Boele, Joost; Shin, Jay W.; Ishizu, Yuri; Ando, Yoshinari; Burroughs, A. Maxwell; Sasaki, Chihiro; Suzuki, Chizuru; Sakai, Mizuho; Aoki, Shintaro; Ogawa, Ayumi; Hasegawa, Akira; Lizio, Marina; Kaida, Kaoru; Carninci, Piero; Suzuki, Harukazu; Hayashizaki, Yoshihide; de Hoon, Michiel J. L.] RIKEN, Om Sci Ctr, Yokohama, Kanagawa 2300045, Japan. [Boele, Joost; Teusink, Bas] Vrije Univ Amsterdam, Amsterdam Inst Mol Med & Syst, Dept Syst Bioinformat, NL-1081 HV Amsterdam, Netherlands. [Persson, Helena] Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden. [Shin, Jay W.; Ishizu, Yuri; Sakai, Mizuho; Aoki, Shintaro; Hasegawa, Akira; Lizio, Marina; Kaida, Kaoru; Carninci, Piero; Suzuki, Harukazu; de Hoon, Michiel J. L.] RIKEN, Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa 2300045, Japan. [Newie, Inga S.; Sokilde, Rolf; Rovira, Carlos] Lund Univ, Ctr Canc, Dept Clin Sci, Div Oncol, SE-22381 Lund, Sweden. [Hawkins, Shannon M.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Hawkins, Shannon M.] Baylor Coll Med, Ctr Reprod Med, Houston, TX 77030 USA. [Coarfa, Cristian] Baylor Coll Med, Dept Mol & Cell Biol, Houston, TX 77030 USA. [Gunaratne, Preethi H.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Inoue, Satoshi] Saitama Med Univ, Res Ctr Genom Med, Div Gene Regulat & Signal Transduct, Saitama 3501241, Japan. [Takayama, Ken-ichi; Inoue, Satoshi] Univ Tokyo, Grad Sch Med, Dept Antiaging Med, Bunkyo Ku, Tokyo 1138655, Japan. [Takayama, Ken-ichi; Inoue, Satoshi] Univ Tokyo, Grad Sch Med, Dept Geriatr Med, Bunkyo Ku, Tokyo 1138655, Japan. [Ando, Yoshinari] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [Burroughs, A. Maxwell] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Gunaratne, Preethi H.] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Hayashizaki, Yoshihide] RIKEN, Prevent Med & Diag Innovat Program, Wako, Saitama 3510198, Japan. RP de Hoon, MJL (reprint author), RIKEN, Om Sci Ctr, Yokohama, Kanagawa 2300045, Japan. EM mdehoon@gsc.riken.jp RI Carninci, Piero/K-1568-2014; Hawkins, Shannon/B-7095-2015; Sokilde, Rolf/F-5138-2015; de Hoon, Michiel/N-8006-2015; Suzuki, Harukazu/N-9553-2015; OI Carninci, Piero/0000-0001-7202-7243; Hawkins, Shannon/0000-0002-0727-3971; Sokilde, Rolf/0000-0003-3010-3599; Suzuki, Harukazu/0000-0002-8087-0836; Newie, Inga/0000-0002-6047-6647; Teusink, Bas/0000-0003-3929-0423 FU Ministry of Education, Culture, Sports, Science and Technology (MEXT); Genome Network Project from MEXT; Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from MEXT; MEXT; Hendrik Muller Foundation (Netherlands); Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health [U54HD007495]; Japan Society for the Promotion of Science FX The authors thank Fumi Hori for technical assistance, and Noriko Nakanishi for technical assistance and help with the manuscript. The authors also thank The Institute of Physical and Chemical Research (RIKEN) Genome Network Analysis Support Facility for the sequencing of the MCF7 small-RNA libraries using an Illumina Genome Analyzer, and of the THP1 and MCF7 libraries on an Illumina HiSeq 2000. Additionally the authors thank the The Cancer Genome Atlas (TCGA) Research Network for providing access to the data of TCGA. This work was supported by a research grant for RIKEN Omics Science Centre (which ceased to exist as of April 1, 2013, due to RIKEN reorganization) from Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Y.H.); a grant of the Genome Network Project from MEXT (to Y.H.); a grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from MEXT (to Y.H.); a research grant from MEXT to the RIKEN Center for Life Science Technologies; a research grant from MEXT (to the RIKEN Preventive Medicine and Diagnosis Innovation Program); a grant from the Hendrik Muller Foundation (Netherlands) (to J.B.); a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health through Cooperative Agreements U54HD007495 (to S.M.H.); and a grant from the Japan Society for the Promotion of Science (to M.J.L.d.H.). NR 59 TC 24 Z9 24 U1 0 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 5 PY 2014 VL 111 IS 31 BP 11467 EP 11472 DI 10.1073/pnas.1317751111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200052 PM 25049417 ER PT J AU Trankner, D Hahne, N Sugino, K Hoon, MA Zuker, C AF Traenkner, Dimitri Hahne, Nadeau Sugino, Ken Hoon, Mark A. Zuker, Charles TI Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bronchospasms; airway inflammation ID INFLAMMATION; RECEPTOR; LUNG; EXPRESSION; ABLATION; TRACHEA; FIBERS; REFLEX; VAGAL; TRPA1 AB Asthma is a common debilitating inflammatory lung disease affecting over 200 million people worldwide. Here, we investigated neurogenic components involved in asthmatic-like attacks using the ovalbumin-sensitized murine model of the disease, and identified a specific population of neurons that are required for airway hyperreactivity. We show that ablating or genetically silencing these neurons abolished the hyperreactive broncho-constrictions, even in the presence of a fully developed lung inflammatory immune response. These neurons are found in the vagal ganglia and are characterized by the expression of the transient receptor potential vanilloid 1 (TRPV1) ion channel. However, the TRPV1 channel itself is not required for the asthmatic-like hyperreactive airway response. We also demonstrate that optogenetic stimulation of this population of TRP-expressing cells with channelrhodopsin dramatically exacerbates airway hyperreactivity of inflamed airways. Notably, these cells express the sphingosine-1-phosphate receptor 3 (S1PR3), and stimulation with a S1PR3 agonist efficiently induced broncho-constrictions, even in the absence of ovalbumin sensitization and inflammation. Our results show that the airway hyperreactivity phenotype can be physiologically dissociated from the immune component, and provide a platform for devising therapeutic approaches to asthma that target these pathways separately. C1 [Traenkner, Dimitri; Hahne, Nadeau; Sugino, Ken; Zuker, Charles] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Hoon, Mark A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Zuker, Charles] Columbia Univ, Columbia Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Zuker, Charles] Columbia Univ, Columbia Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA. [Zuker, Charles] Columbia Univ, Columbia Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. RP Zuker, C (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus, Ashburn, VA 20147 USA. EM cz2195@columbia.edu FU Mutant Mouse Regional Resource Center, a National Center for Research Resources, National Institutes of Health; National Institute of Neurological Disorders and Stroke; American Asthma Foundation [09-0257]; National Institute of Dental and Craniofacial Research FX We thank the Sandler Asthma Basic Research Center core facility at the University of California at San Francisco and Xiaozhu Huang for help (and training) with the asthma murine model; Jim Cox and Michael Flynn of Janelia Farm's animal services for help, advice, and support; Iwona Stepniak, Amanda Wardlaw, Miriam Rose, Emily Bowman, and Lihua Wang for expert technical support; Megan Williams, Loren Looger, and Matthew Hockin for helpful comments; and David Anderson and Martyn Goulding for their generous gifts of MrgD-DTR and Rosa-TeNT mice, respectively. The mouse stock Tg(TRPV1-EGFP) was obtained from the Mutant Mouse Regional Resource Center, a National Center for Research Resources, National Institutes of Health-funded strain repository, and was donated to the Mutant Mouse Regional Resource Center by the National Institute of Neurological Disorders and Stroke-funded Gene Expression Nervous System Atlas Bacterial Artificial Chromosome transgenic project. This manuscript resulted from Grant 09-0257 from the American Asthma Foundation (to C.Z.), and was supported in part by the National Institute of Dental and Craniofacial Research (M.A.H.). C.Z. is an Investigator of the Howard Hughes Medical Institute and a Senior Fellow at the Janelia Farm Research Campus, Howard Hughes Medical Institute. NR 37 TC 25 Z9 26 U1 3 U2 16 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 5 PY 2014 VL 111 IS 31 BP 11515 EP 11520 DI 10.1073/pnas.1411032111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200060 PM 25049382 ER PT J AU Phelan, KD Shwe, UT Abramowitz, J Birnbaumer, L Zheng, F AF Phelan, Kevin D. Shwe, U. Thaung Abramowitz, Joel Birnbaumer, Lutz Zheng, Fang TI Critical role of canonical transient receptor potential channel 7 in initiation of seizures SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epilepsy; gamma oscillation; hippocampal circuitry; synaptic plasticity ID STATUS EPILEPTICUS; NMDA RECEPTORS; RAT; OSCILLATIONS; HIPPOCAMPUS; ACTIVATION; MECHANISMS; SYNAPSES; SUBUNITS; CELLS AB Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel. C1 [Phelan, Kevin D.] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Little Rock, AR 72205 USA. [Shwe, U. Thaung; Zheng, Fang] Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Lab Neurobiol, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, L (reprint author), NIEHS, Lab Neurobiol, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov; zhengfang@uams.edu RI Abramowitz, Joel/A-2620-2015; Zheng, Fang/J-1400-2016 OI Zheng, Fang/0000-0002-6626-1938 FU Intramural Research Program of the National Institutes of Health [Z01-ES-101864]; National Institute of Neurological Disorders and Stroke Grant [NS 050381]; University of Arkansas for Medical Sciences Bridging Fund FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (Project Z01-ES-101864, to L.B.), by National Institute of Neurological Disorders and Stroke Grant NS 050381 (to F.Z.), and by the University of Arkansas for Medical Sciences Bridging Fund (F.Z.). NR 19 TC 8 Z9 8 U1 0 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 5 PY 2014 VL 111 IS 31 BP 11533 EP 11538 DI 10.1073/pnas.1411442111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200063 PM 25049394 ER PT J AU Amable, L Fain, J Gavin, E Reed, E AF Amable, Lauren Fain, Jason Gavin, Elaine Reed, Eddie TI Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug SO ONCOLOGY REPORTS LA English DT Article DE cisplatin resistance; Gli1; cisplatin transport; ovarian cancer; DNA repair; DNA adduct ID OVARIAN-CANCER CELLS; SONIC HEDGEHOG; COLON-CANCER; DNA-DAMAGE; REPAIR; SENSITIVITY; GENES; LINES; CIS-DIAMMINEDICHLOROPLATINUM(II); TRANSCRIPTION AB Cellular resistance to platinum anticancer compounds is governed by no less than two molecular processes; DNA repair and cellular accumulation of drug. Gli1 is an upstream regulator of nucleotide excision repair, effecting this process through c-jun. We, therefore, investigated whether Gli1 plays a role in cellular accumulation of cisplatin. Using a Gli1-specific shRNA, we explored the role of Gli1 in the cellular accumulation and efflux of cisplatin, in cisplatin-resistant A2780-CP70 human ovarian cancer cells. When Gli1 is inhibited, cellular uptake of cisplatin was approximately 33% of the level of uptake under control conditions. When Gli1 is inhibited, cellular efflux of cisplatin was completely abrogated, over a 12-h period of observation. We assayed nuclear lysates from these cells, for the ability to bind the DNA sequence that is the Gli-binding site (GBS) in the 5'UTR for each of five known cisplatin transmembrane transporters. Four of these transporters are active in cisplatin uptake; and, one is active in cisplatin efflux. In each case, nuclear lysate from A2780-CP70 cells binds the GBS of the respective cisplatin transport gene. We conclude that Gli1 plays a strong role in total cellular accumulation of cisplatin in these cells; and, that the combined effects on cellular accumulation of drug and on DNA repair may indicate a role for Gli1 in protecting cellular DNA from lethal types of DNA damage. C1 [Amable, Lauren; Reed, Eddie] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. [Fain, Jason; Gavin, Elaine] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36604 USA. RP Reed, E (reprint author), Natl Inst Minor Hlth & Hlth Dispar, NIH, 3 Ctr Dr, Bethesda, MD 20892 USA. EM eddie.reed@nih.gov FU NIH, National Institute on Minority Health and Health Disparities FX The present research was supported by the Intramural Research Program of the NIH, National Institute on Minority Health and Health Disparities. NR 32 TC 4 Z9 4 U1 0 U2 8 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X EI 1791-2431 J9 ONCOL REP JI Oncol. Rep. PD AUG 5 PY 2014 VL 32 IS 2 BP 469 EP 474 DI 10.3892/or.2014.3257 PG 6 WC Oncology SC Oncology GA AL1TJ UT WOS:000338908700004 PM 24926795 ER PT J AU Tamazian, G Simonov, S Dobrynin, P Makunin, A Logachev, A Komissarov, A Shevchenko, A Brukhin, V Cherkasov, N Svitin, A Koepfli, KP Pontius, J Driscoll, CA Blackistone, K Barr, C Goldman, D Antunes, A Quilez, J Lorente-Galdos, B Alkan, C Marques-Bonet, T Menotti-Raymond, M David, VA Narfstrom, K O'Brien, SJ AF Tamazian, Gaik Simonov, Serguei Dobrynin, Pavel Makunin, Alexey Logachev, Anton Komissarov, Aleksey Shevchenko, Andrey Brukhin, Vladimir Cherkasov, Nikolay Svitin, Anton Koepfli, Klaus-Peter Pontius, Joan Driscoll, Carlos A. Blackistone, Kevin Barr, Cristina Goldman, David Antunes, Agostinho Quilez, Javier Lorente-Galdos, Belen Alkan, Can Marques-Bonet, Tomas Menotti-Raymond, Marylin David, Victor A. Narfstroem, Kristina O'Brien, Stephen J. TI Annotated features of domestic cat - Felis catus genome SO GIGASCIENCE LA English DT Article DE Felis catus; Domestic cat; Felis silvestris silvestris; European wildcat; Genome sequence; Annotation; Assembly ID SEQUENCE; MAP AB Background: Domestic cats enjoy an extensive veterinary medical surveillance which has described nearly 250 genetic diseases analogous to human disorders. Feline infectious agents offer powerful natural models of deadly human diseases, which include feline immunodeficiency virus, feline sarcoma virus and feline leukemia virus. A rich veterinary literature of feline disease pathogenesis and the demonstration of a highly conserved ancestral mammal genome organization make the cat genome annotation a highly informative resource that facilitates multifaceted research endeavors. Findings: Here we report a preliminary annotation of the whole genome sequence of Cinnamon, a domestic cat living in Columbia (MO, USA), bisulfite sequencing of Boris, a male cat from St. Petersburg (Russia), and light 30x sequencing of Sylvester, a European wildcat progenitor of cat domestication. The annotation includes 21,865 protein-coding genes identified by a comparative approach, 217 loci of endogenous retrovirus-like elements, repetitive elements which comprise about 55.7% of the whole genome, 99,494 new SNVs, 8,355 new indels, 743,326 evolutionary constrained elements, and 3,182 microRNA homologues. The methylation sites study shows that 10.5% of cat genome cytosines are methylated. An assisted assembly of a European wildcat, Felis silvestris silvestris, was performed; variants between F. silvestris and F. catus genomes were derived and compared to F. catus. Conclusions: The presented genome annotation extends beyond earlier ones by closing gaps of sequence that were unavoidable with previous low-coverage shotgun genome sequencing. The assembly and its annotation offer an important resource for connecting the rich veterinary and natural history of cats to genome discovery. C1 [Tamazian, Gaik; Simonov, Serguei; Dobrynin, Pavel; Makunin, Alexey; Logachev, Anton; Komissarov, Aleksey; Shevchenko, Andrey; Brukhin, Vladimir; Cherkasov, Nikolay; Svitin, Anton; Koepfli, Klaus-Peter; Pontius, Joan; O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199004, Russia. [Driscoll, Carlos A.; Blackistone, Kevin; Barr, Cristina; Goldman, David] NIAAA, Lab Neurogenet, Rockville, MD 20852 USA. [Antunes, Agostinho] Univ Porto, CIIMAR Interdisciplinary Ctr Marine & Environm Re, P-4050123 Oporto, Portugal. [Quilez, Javier] Univ Autonoma Barcelona, Vet Mol Genet Serv, Dept Anim & Food Sci, Barcelona 08003, Catalonia, Spain. [Lorente-Galdos, Belen; Marques-Bonet, Tomas] Univ Pompeu Fabra CSIC, PRBB, Inst Evolutionary Biol, IBE, Barcelona 08003, Catalonia, Spain. [Alkan, Can] Bilkent Univ, Dept Comp Engn, TR-06800 Ankara, Turkey. [Menotti-Raymond, Marylin; David, Victor A.] Frederick Natl Lab Canc Res, Lab Genom Div, Frederick, MD 21702 USA. [Narfstroem, Kristina] Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO 08028 USA. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33004 USA. RP O'Brien, SJ (reprint author), St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199004, Russia. EM lgdchief@gmail.com RI Quilez, Javier/J-7107-2015; Tamazian, Gaik/P-4723-2015; Goldman, David/F-9772-2010; Makunin, Alexey/N-2055-2015; Brukhin, Vladimir/F-9779-2015; Simonov, Serguei/K-3369-2013; Komissarov, Aleksey/A-3594-2009; Alkan, Can/D-2982-2009; OI Quilez, Javier/0000-0002-0108-2672; Tamazian, Gaik/0000-0002-2931-1123; Goldman, David/0000-0002-1724-5405; Makunin, Alexey/0000-0002-9555-5097; Lorente-Galdos, Belen/0000-0001-5390-2452; Marques-Bonet, Tomas/0000-0002-5597-3075; Brukhin, Vladimir/0000-0003-1836-0437; Simonov, Serguei/0000-0002-9104-8004; Komissarov, Aleksey/0000-0001-6981-7316; Alkan, Can/0000-0002-5443-0706; Driscoll, Carlos/0000-0003-2392-505X FU Russian Ministry of Science Mega [11.G34.31.0068]; ERC Starting Grant [260372]; MICINN (Spain) [BFU2011-28549] FX The authors are grateful to Elena Savelyeva (Clinical Biochemistry Laboratory of St. Petersburg Academy of Veterinary Medicine) for preparing samples of Boris the cat. This work was supported, in part, by Russian Ministry of Science Mega-grant no. 11.G34.31.0068; Stephen J. O'Brien, Principal Investigator and ERC Starting Grant (260372) and MICINN (Spain) BFU2011-28549 grants to Tomas Marques-Bonet. NR 10 TC 9 Z9 9 U1 2 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PD AUG 5 PY 2014 VL 3 AR 13 DI 10.1186/2047-217X-3-13 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4FR UT WOS:000365654900001 PM 25143822 ER PT J AU Richard, AC Lyons, PA Peters, JE Biasci, D Flint, SM Lee, JC McKinney, EF Siegel, RM Smith, KGC AF Richard, Arianne C. Lyons, Paul A. Peters, James E. Biasci, Daniele Flint, Shaun M. Lee, James C. McKinney, Eoin F. Siegel, Richard M. Smith, Kenneth G. C. TI Comparison of gene expression microarray data with count-based RNA measurements informs microarray interpretation SO BMC GENOMICS LA English DT Article DE Microarray; NanoString; nCounter; Gene expression ID AFFYMETRIX GENECHIP; PREDICTS PROGNOSIS; OLIGONUCLEOTIDE; PLATFORMS; PERFORMANCE; DISEASE; POWER; PCR AB Background: Although numerous investigations have compared gene expression microarray platforms, preprocessing methods and batch correction algorithms using constructed spike-in or dilution datasets, there remains a paucity of studies examining the properties of microarray data using diverse biological samples. Most microarray experiments seek to identify subtle differences between samples with variable background noise, a scenario poorly represented by constructed datasets. Thus, microarray users lack important information regarding the complexities introduced in real-world experimental settings. The recent development of a multiplexed, digital technology for nucleic acid measurement enables counting of individual RNA molecules without amplification and, for the first time, permits such a study. Results: Using a set of human leukocyte subset RNA samples, we compared previously acquired microarray expression values with RNA molecule counts determined by the nCounter Analysis System (NanoString Technologies) in selected genes. We found that gene measurements across samples correlated well between the two platforms, particularly for high-variance genes, while genes deemed unexpressed by the nCounter generally had both low expression and low variance on the microarray. Confirming previous findings from spike-in and dilution datasets, this "gold-standard" comparison demonstrated signal compression that varied dramatically by expression level and, to a lesser extent, by dataset. Most importantly, examination of three different cell types revealed that noise levels differed across tissues. Conclusions: Microarray measurements generally correlate with relative RNA molecule counts within optimal ranges but suffer from expression-dependent accuracy bias and precision that varies across datasets. We urge microarray users to consider expression-level effects in signal interpretation and to evaluate noise properties in each dataset independently. C1 [Richard, Arianne C.; Lyons, Paul A.; Peters, James E.; Biasci, Daniele; Flint, Shaun M.; Lee, James C.; McKinney, Eoin F.; Smith, Kenneth G. C.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Richard, Arianne C.; Lyons, Paul A.; Peters, James E.; Biasci, Daniele; Flint, Shaun M.; Lee, James C.; McKinney, Eoin F.; Smith, Kenneth G. C.] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England. [Richard, Arianne C.; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, Bethesda, MD 20892 USA. RP Smith, KGC (reprint author), Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. EM kgcs2@cam.ac.uk OI Lee, James/0000-0001-5711-9385 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health; Wellcome Trust [080327/Z/06/Z, 087007/Z/08/Z, 094227/Z/10/Z]; Medical Research Council [G0400929]; NIHR Cambridge Biomedical Research Centre; NIH-Oxford-Cambridge Scholars Program; Wellcome Trust Clinical PhD Programme; Marie Curie Research Fellowship Programme; GSK through the TMAT programme; Wellcome Clinical Training Fellowship; Wellcome Trust Strategic Award [Wellcome Trust Strategic Award (079895] FX We thank all individuals who contributed samples to this study. This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health, the Wellcome Trust (080327/Z/06/Z, 087007/Z/08/Z, and 094227/Z/10/Z), the Medical Research Council (G0400929), and the NIHR Cambridge Biomedical Research Centre. The nCounter Analysis System was available through the Translational Immunology Section of the Office of Science and Technology in NIAMS. ACR was funded by the NIH-Oxford-Cambridge Scholars Program. JEP and JCL were funded by the Wellcome Trust Clinical PhD Programme. DB was funded by the Marie Curie Research Fellowship Programme. SMF was funded by the Wellcome Trust and GSK through the TMAT programme. EFM was funded by a Wellcome Clinical Training Fellowship. We would also like to thank Alex Wessel for assistance with the nCounter Analysis System, and Alexander Hatton and Huzefa Ratlamwala for peripheral blood sample processing and RNA extraction. Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). NR 41 TC 9 Z9 9 U1 0 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 4 PY 2014 VL 15 AR 649 DI 10.1186/1471-2164-15-649 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AN5OM UT WOS:000340641000005 PM 25091430 ER PT J AU Byrd, AL Perez-Rogers, JF Manimaran, S Castro-Nallar, E Toma, I McCaffrey, T Siegel, M Benson, G Crandall, KA Johnson, WE AF Byrd, Allyson L. Perez-Rogers, Joseph F. Manimaran, Solaiappan Castro-Nallar, Eduardo Toma, Ian McCaffrey, Tim Siegel, Marc Benson, Gary Crandall, Keith A. Johnson, William Evan TI Clinical PathoScope: rapid alignment and filtration for accurate pathogen identification in clinical samples using unassembled sequencing data SO BMC BIOINFORMATICS LA English DT Article ID SHORT READ ALIGNMENT; VIRAL PATHOGENS; HUMAN TISSUE; MICROBIOLOGY; OUTBREAK; MODELS; STRAIN; TOOL; CLASSIFICATION; DISCOVERY AB Background: The use of sequencing technologies to investigate the microbiome of a sample can positively impact patient healthcare by providing therapeutic targets for personalized disease treatment. However, these samples contain genomic sequences from various sources that complicate the identification of pathogens. Results: Here we present Clinical PathoScope, a pipeline to rapidly and accurately remove host contamination, isolate microbial reads, and identify potential disease-causing pathogens. We have accomplished three essential tasks in the development of Clinical PathoScope. First, we developed an optimized framework for pathogen identification using a computational subtraction methodology in concordance with read trimming and ambiguous read reassignment. Second, we have demonstrated the ability of our approach to identify multiple pathogens in a single clinical sample, accurately identify pathogens at the subspecies level, and determine the nearest phylogenetic neighbor of novel or highly mutated pathogens using real clinical sequencing data. Finally, we have shown that Clinical PathoScope outperforms previously published pathogen identification methods with regard to computational speed, sensitivity, and specificity. Conclusions: Clinical PathoScope is the only pathogen identification method currently available that can identify multiple pathogens from mixed samples and distinguish between very closely related species and strains in samples with very few reads per pathogen. Furthermore, Clinical PathoScope does not rely on genome assembly and thus can more rapidly complete the analysis of a clinical sample when compared with current assembly-based methods. Clinical PathoScope is freely available at: http://sourceforge.net/projects/pathoscope/. C1 [Byrd, Allyson L.; Perez-Rogers, Joseph F.; Benson, Gary; Johnson, William Evan] Boston Univ, Dept Bioinformat, Boston, MA 02215 USA. [Byrd, Allyson L.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Perez-Rogers, Joseph F.; Manimaran, Solaiappan; Johnson, William Evan] Boston Univ, Sch Med, Div Computat Biomed, Boston, MA 02118 USA. [Castro-Nallar, Eduardo; Crandall, Keith A.] George Washington Univ, Computat Biol Inst, Ashburn, VA 20147 USA. [Toma, Ian; McCaffrey, Tim] George Washington Univ, Div Genom Med, Washington, DC USA. [Siegel, Marc] George Washington Univ, Div Infect Dis, Washington, DC USA. [Benson, Gary] Boston Univ, Dept Comp Sci, Boston, MA 02215 USA. [Benson, Gary] Boston Univ, Dept Biol, Boston, MA 02215 USA. RP Crandall, KA (reprint author), George Washington Univ, Computat Biol Inst, Ashburn, VA 20147 USA. EM kcrandall@gwu.edu; wej@bu.edu OI Castro-Nallar, Eduardo/0000-0003-4384-8661; Crandall, Keith/0000-0002-0836-3389; Toma, Ian/0000-0002-9637-5899 FU NSF IGERT grant [DGE 0654108]; Boston University Bioinformatics program; NIH [R01 HG005692] FX This research was conducted using the Linux Clusters for Genetic Analysis (LinGA) computing resources at Boston University Medical Campus. This research was supported by an NSF IGERT grant (DGE 0654108) in support of the Boston University Bioinformatics program and the NIH (R01 HG005692). NR 57 TC 14 Z9 14 U1 2 U2 14 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 4 PY 2014 VL 15 AR 262 DI 10.1186/1471-2105-15-262 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AM7QE UT WOS:000340061700001 PM 25091138 ER PT J AU Uchida, N Hsieh, MM Platner, C Saunthararajah, Y Tisdale, JF AF Uchida, Naoya Hsieh, Matthew M. Platner, Charlotte Saunthararajah, Yogen Tisdale, John F. TI Decitabine Suspends Human CD34(+) Cell Differentiation and Proliferation during Lentiviral Transduction SO PLOS ONE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; FETAL-HEMOGLOBIN LEVELS; GENE-THERAPY; MYELODYSPLASTIC SYNDROMES; REPOPULATING CELLS; SELF-RENEWAL; IN-VIVO; VECTOR; IMMUNODEFICIENCY; DISEASE AB Efficient ex vivo transduction of hematopoietic stem cells (HSCs) is encumbered by differentiation which reduces engraftment. We hypothesized that inhibiting DNA methyltransferase with decitabine would block differentiation of transduced CD34(+) cells under cytokine stimulation and thus improve transduction efficiency for engrafting HSCs. Human CD34(+) cells in cytokine-containing media were treated with or without decitabine for 24 or 48 hours, and then these cells were transduced with a GFP-expressing lentiviral vector. Utilizing decitabine pre-treatment for 48 hours, we observed an equivalent percentage of successfully transduced cells (GFP-positivity) and a higher percentage of cells that retained CD34 positivity, compared to no decitabine exposure. Cell proliferation was inhibited after decitabine exposure. Similar results were observed among CD34(+) cells from six different donors. Repopulating activity was evaluated by transplantation into NOD/SCID/IL2R gamma(null) mice and demonstrated an equivalent percentage of GFP-positivity in human cells from decitabine-treated samples and a trend for higher human cell engraftment (measured 20-24 weeks after transplantation), compared to no decitabine exposure. In conclusion, ex vivo decitabine exposure inhibits both differentiation and proliferation in transduced human CD34(+) cells and modestly increases the engraftment ability in xenograft mice, while the transduction efficiency is equivalent in decitabine exposure, suggesting improvement of lentiviral transduction for HSCs. C1 [Uchida, Naoya; Hsieh, Matthew M.; Platner, Charlotte; Tisdale, John F.] NIH, NIDDK, NHLBI, Bethesda, MD 20892 USA. [Saunthararajah, Yogen] Cleveland Clin, Taussig Canc Inst, Translat Hematol & Oncol Res, Cleveland, OH 44106 USA. RP Tisdale, JF (reprint author), NIH, NIDDK, NHLBI, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU intramural research program of the National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 1 Z9 1 U1 1 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 4 PY 2014 VL 9 IS 8 AR e104022 DI 10.1371/journal.pone.0104022 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4GX UT WOS:000339812700081 PM 25089909 ER PT J AU Wu, XY Cai, H Kallianpur, A Gao, YT Yang, G Chow, WH Li, HL Zheng, W Shu, XO AF Wu, Xiaoyan Cai, Hui Kallianpur, Asha Gao, Yu-Tang Yang, Gong Chow, Wong-Ho Li, Hong-Lan Zheng, Wei Shu, Xiao-Ou TI Age at Menarche and Natural Menopause and Number of Reproductive Years in Association with Mortality: Results from a Median Follow-Up of 11.2 Years among 31,955 Naturally Menopausal Chinese Women SO PLOS ONE LA English DT Article ID ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE MORTALITY; ISCHEMIC-HEART-DISEASE; LUNG-CANCER; POSTMENOPAUSAL WOMEN; ADVENTIST HEALTH; NORWEGIAN WOMEN; KANGWHA COHORT; RISK; STROKE AB Background: Studies conducted in Western countries suggest that early age at menarche and early age at menopause are both associated with increased total mortality, but limited data are available for Asian populations. We examined associations of age at menarche and natural menopause and duration of the reproductive span with mortality in a population-based cohort study of Chinese women. Methods: We evaluated the effects of age at menarche, age at natural menopause, and number of reproductive years on total and cause-specific mortality among 31,955 naturally menopausal Chinese women who participated in the Shanghai Women's Health Study, a population-based, prospective cohort study. Results: A total of 3,158 deaths occurred during a median follow-up of 11.2 years. Results from Cox proportional hazards models showed that younger age at menopause (<46.64 years) was associated with higher risk of total mortality (P-trend = 0.02). Younger age at menarche (<14 years) was associated with higher risk of mortality from stroke (P-trend = 0.03) and diabetes (P-trend = 0.02) but lower risk of mortality from respiratory system cancer (P-trend = 0.01). Women with a shorter reproductive span had lower risk of mortality from gynecological cancers (P-trend = 0.03). Conclusions: Our study found that menstrual characteristics are important predictors of mortality, suggesting an important role of sex hormones in biological aging. C1 [Wu, Xiaoyan; Cai, Hui; Kallianpur, Asha; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Wu, Xiaoyan; Cai, Hui; Kallianpur, Asha; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Gao, Yu-Tang; Li, Hong-Lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho] NCI, Occupat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. EM Xiao-ou.shu@vanderbilt.edu FU United States National Cancer Institute at the US National Institutes of Health [R37 CA070867] FX This work was supported by a grant from the United States National Cancer Institute at the US National Institutes of Health [grant number R37 CA070867, PI: W. Zheng]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 11 Z9 11 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 4 PY 2014 VL 9 IS 8 DI 10.1371/journal.pone.0103673 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4GX UT WOS:000339812700040 ER PT J AU Bunyavanich, S Schadt, EE Himes, BE Lasky-Su, J Qiu, WL Lazarus, R Ziniti, JP Cohain, A Linderman, M Torgerson, DG Eng, CS Pino-Yanes, M Padhukasahasram, B Yang, JJ Mathias, RA Beaty, TH Li, XN Graves, P Romieu, I Navarro, BD Salam, MT Vora, H Nicolae, DL Ober, C Martinez, FD Bleecker, ER Meyers, DA Gauderman, WJ Gilliland, F Burchard, EG Barnes, KC Williams, LK London, SJ Bin, Z Raby, BA Weiss, ST AF Bunyavanich, Supinda Schadt, Eric E. Himes, Blanca E. Lasky-Su, Jessica Qiu, Weiliang Lazarus, Ross Ziniti, John P. Cohain, Ariella Linderman, Michael Torgerson, Dara G. Eng, Celeste S. Pino-Yanes, Maria Padhukasahasram, Badri Yang, James J. Mathias, Rasika A. Beaty, Terri H. Li, Xingnan Graves, Penelope Romieu, Isabelle del Rio Navarro, Blanca Salam, M. Towhid Vora, Hita Nicolae, Dan L. Ober, Carole Martinez, Fernando D. Bleecker, Eugene R. Meyers, Deborah A. Gauderman, W. James Gilliland, Frank Burchard, Esteban G. Barnes, Kathleen C. Williams, L. Keoki London, Stephanie J. Zhang, Bin Raby, Benjamin A. Weiss, Scott T. TI Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis SO BMC MEDICAL GENOMICS LA English DT Article DE Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy ID BODY-MASS INDEX; AIRWAY INFLAMMATION; SUSCEPTIBILITY LOCI; GENE-EXPRESSION; PERIPHERAL-BLOOD; RISK-FACTORS; DISEASE; METAANALYSIS; ASTHMA; POPULATION AB Background: Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. Methods: We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS. Results: GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value <= 1x10(-6) tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 x 10(-24)) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 x 10(-72)). Conclusions: Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases. C1 [Bunyavanich, Supinda; Schadt, Eric E.; Cohain, Ariella; Linderman, Michael; Zhang, Bin] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Bunyavanich, Supinda; Schadt, Eric E.; Cohain, Ariella; Linderman, Michael; Zhang, Bin] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Bunyavanich, Supinda] Icahn Sch Med Mt Sinai, Dept Pediat, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Bunyavanich, Supinda] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Himes, Blanca E.; Lasky-Su, Jessica; Qiu, Weiliang; Lazarus, Ross; Ziniti, John P.; Raby, Benjamin A.; Weiss, Scott T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Himes, Blanca E.; Lasky-Su, Jessica; Qiu, Weiliang; Lazarus, Ross; Ziniti, John P.; Raby, Benjamin A.; Weiss, Scott T.] Harvard Univ, Sch Med, Boston, MA USA. [Torgerson, Dara G.; Eng, Celeste S.; Pino-Yanes, Maria; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Torgerson, Dara G.; Eng, Celeste S.; Pino-Yanes, Maria; Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA USA. [Pino-Yanes, Maria] Inst Salud Carlos III, IBER Enfermedades Resp, Madrid, Spain. [Padhukasahasram, Badri; Williams, L. Keoki] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA. [Yang, James J.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. [Mathias, Rasika A.; Beaty, Terri H.; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Mathias, Rasika A.; Beaty, Terri H.; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Li, Xingnan; Bleecker, Eugene R.; Meyers, Deborah A.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom, Winston Salem, NC USA. [Graves, Penelope; Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Graves, Penelope; Martinez, Fernando D.] Univ Arizona, BIO5 Inst, Tucson, AZ USA. [Romieu, Isabelle] Int Agcy Res Canc, Lyon, France. [del Rio Navarro, Blanca] Hosp Infantil Federico Gomez, Mexico City, DF, Mexico. [Salam, M. Towhid; Vora, Hita; Gauderman, W. James; Gilliland, Frank] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Nicolae, Dan L.; Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [London, Stephanie J.] NIEHS, Dept Hlth & Human Serv, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Lazarus, Ross] Baker IDI, Med Bioinformat, Melbourne, Australia. RP Bunyavanich, S (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. EM supinda@post.harvard.edu RI Pino-Yanes, Maria/C-8498-2017; OI Pino-Yanes, Maria/0000-0003-0332-437X; lazarus, ross/0000-0003-3939-1961; Lasky-Su, Jessica/0000-0001-6236-4705; London, Stephanie/0000-0003-4911-5290 FU National Institutes of Allergy and Infectious Disease [K08AI093538, AI070503, AI079139, AI061774, AI077439]; National Heart, Lung, and Blood Institute [HL101651, HL087665, HL085197, HL072414, HL49596, HL064307, HL064313, HL075419, HL65899, HL083069, HL066289, HL101543, HL079055, HL087699, HL061768, HL076647, P30ES007048, P01ES011627, HL087680, HL078885, HL088133, HL069167]; National Institute of Diabetes and Digestive and Kidney Diseases [DK064695]; National Institutes of Environmental Health Sciences [ES020801, ES022719, ES007048, ES009581, R826708, RD831861, ES011627, ES015794]; Division of Intramural Research of National Institutes of Health [Z01 ES049019]; American Asthma Foundation; Fund for Henry Ford Hospital; Mary Beryl Patch Turnbull Scholar Program; Flight Attendant Medical Research Institute (FAMRI); RWJF Amos Medical Faculty Development Award; Sandler Foundation; Fundacion Ramon Areces FX We thank all the participants who made this study possible. We appreciate contributions from Brooke Schuemann, Barbara Klanderman, PhD, Jody S. Sylvia, Ute Geigenmuller, PhD, Roxanne Kelly, M. B. A., Jose Rodriguez Santana, M. D, William Rodriguez Cintron, M. D., Rocio Chapela, M. D., Jean Ford, M. D., Shannon Thyne, M. D., and Pedro C. Avila, M. D. This work was supported by grants from the National Institutes of Allergy and Infectious Disease (K08AI093538 to S. B.; AI070503 to C.O.; AI079139 and AI061774 to L. K. W.; and AI077439 to E. G. B.), the National Heart, Lung, and Blood Institute (HL101651 to C.O. and D.L.N.; HL087665 to D.L.N.; HL085197, HL087665, HL072414, and HL49596 to C.O.; HL064307 and HL064313 to F. D. M.; HL075419, HL65899, HL083069, HL066289, HL087680, HL101543, and HL101651 to S. T. W.; HL079055 to L. K. W.; HL087699, to K. C. B.; HL061768, HL076647, P30ES007048, P01ES011627 to F. D. G.; HL087680 to W.J.G.; HL078885 and HL088133 to E. G. B.; HL087665 to D. A. M.; and HL069167 to E. R. B), the National Institute of Diabetes and Digestive and Kidney Diseases to L. K. W. (DK064695); the National Institutes of Environmental Health Sciences (ES020801 and ES022719 to W.J.G.; ES007048, ES009581, R826708, RD831861, and ES011627 to F. D. G.; ES015794 to E. G. B.; and the Division of Intramural Research, Z01 ES049019 to S.J.L.) of the National Institutes of Health. Also supported by the American Asthma Foundation and the Fund for Henry Ford Hospital (to L. K. W.), Mary Beryl Patch Turnbull Scholar Program (to K. C. B.); the Flight Attendant Medical Research Institute (FAMRI), RWJF Amos Medical Faculty Development Award, the American Asthma Foundation, the Sandler Foundation (to E. G. B.), and Fundacion Ramon Areces (to M.P.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 13 Z9 13 U1 1 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD AUG 2 PY 2014 VL 7 AR 48 DI 10.1186/1755-8794-7-48 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AO1BU UT WOS:000341047600001 PM 25085501 ER PT J AU Ghany, MG Gara, N AF Ghany, Marc G. Gara, Naveen TI QUEST for a cure for hepatitis C virus: the end is in sight SO LANCET LA English DT Editorial Material ID HCV GENOTYPE 1; INFECTION; SOFOSBUVIR; RIBAVIRIN; ABT-450/R-OMBITASVIR; BOCEPREVIR; TELAPREVIR; LEDIPASVIR; DASABUVIR; MORTALITY C1 [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Gara, Naveen] Washington Hosp Ctr, Dept Gastroenterol, Washington, DC 20010 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov NR 28 TC 4 Z9 4 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 2 PY 2014 VL 384 IS 9941 BP 381 EP 383 DI 10.1016/S0140-6736(14)60807-2 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AM9IV UT WOS:000340195800006 PM 24907223 ER PT J AU Sadowski, SM Millo, C Cottle-Delisle, C Merkel, R Yang, L Cochran, C Nilubol, N Herscovitch, P Marx, SJ Kebebew, E AF Sadowski, S. M. Millo, C. Cottle-Delisle, C. Merkel, R. Yang, L. Cochran, C. Nilubol, N. Herscovitch, P. Marx, S. J. Kebebew, E. TI Should 68 Gallium-DOTATATE PET/CT be the first-line imaging study to detect neuroendocrine tumors in patients with multiple endocrine neoplasia type 1? SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Sadowski, S. M.; Millo, C.; Cottle-Delisle, C.; Merkel, R.; Yang, L.; Cochran, C.; Nilubol, N.; Herscovitch, P.; Marx, S. J.; Kebebew, E.] NIH, Bethesda, MD 20892 USA. EM samira.sadowskiveuthey@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 EI 1613-7671 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2014 VL 126 SU 3 MA FP3.2 BP S141 EP S141 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CJ1DH UT WOS:000355221700005 ER PT J AU Jonklaas, J Sathasivam, A Wang, H Finigan, D Soldin, OP Burman, KD Soldin, SJ AF Jonklaas, Jacqueline Sathasivam, Anpalakan Wang, Hong Finigan, David Soldin, Offie P. Burman, Kenneth D. Soldin, Steven J. TI 3,3 '-Diiodothyronine Concentrations in Hospitalized or Thyroidectomized Patients: Results from a Pilot Study SO ENDOCRINE PRACTICE LA English DT Article ID TANDEM MASS-SPECTROMETRY; RESTING METABOLIC-RATE; FREE-THYROXINE; SERUM 3,5-DIIODOTHYRONINE; TRIIODOTHYRONINE LEVELS; HORMONE; 3,3-L-DIIODOTHYRONINE; 3,3-DIIODOTHYRONINE; RADIOIMMUNOASSAY; TSH AB Objective: To determine if various medical conditions affect the serum concentrations of 3,3'-diiodothyronine (3,3'-T2). Methods: A total of 100 patients who were recruited from a group of inpatients and outpatients with a diverse range of medical conditions, donated a single blood sample that was assayed for thyroid hormone derivatives using liquid- chromatography tandem mass spectrometry (LC-MS/MS). The associations between 3,3'-T2 concentrations and physiologic data and medical conditions were assessed. Results: Higher quartiles of 3,3'-T2 concentrations (quartile 1: 2.01-7.48, quartile 2: 7.74-12.4, quartile 3: 12.5-17, quartile 4: 17.9-45.8 pg/mL) were associated with decreasing occurrence of critical illness (58%, 11%, 0%, 8%), stroke (29%, 7.7%, 4%, 0%), critical care unit hospitalization (75%, 39%, 8.3 %, 12%), and inpatient status (83%, 42%, 8%, 12%) (all P<.001). The same quartiles were associated with increasing frequency of thyroidectomy (4%, 12%, 17%, 60%). In multivariate analyses, after adjustment for age and sex, inpatient status was associated with decreasing concentrations of 3,3'-T2 (46% decrease for inpatients with 95% confidence interval [CI] 32-57%, P<.0001). Thyroidectomy was associated with increasing concentrations of 3,3'-T2 (29% increase (CI 0.5-66%, P=.049). Conclusion: We observed associations between inpatient status and reduced 3,3'-T2 concentrations. This appears to be a global change associated with illness, rather than an association with specific medical conditions. We also observed higher 3,3'-T2 concentrations in athyreotic outpatients receiving thyroid-stimulating hormone (TSH) suppression therapy. This demonstrates that there is production of 3,3'-T2 from levothyroxine (LT4) in extrathyroidal tissues. Conversion of thyroxine (T4) to 3,3'-T2 via both triiodothyronine (T3) and reverse triiodothyronine (rT3) pathways may prevent excessive T3 concentrations in such patients. C1 [Jonklaas, Jacqueline; Sathasivam, Anpalakan; Finigan, David; Soldin, Offie P.; Soldin, Steven J.] Georgetown Univ, Div Endocrinol, Washington, DC 20007 USA. [Sathasivam, Anpalakan; Burman, Kenneth D.] Medstar Washington Hosp Ctr, Endocrinol Sect, Columbia, MD USA. [Wang, Hong] Medstar Hlth Res Inst, Hyattsville, MD USA. [Soldin, Offie P.] Natl Inst Hlth, Dept Oncol, Bethesda, MD USA. [Soldin, Steven J.] Natl Inst Hlth, Dept Lab Med, Bethesda, MD USA. RP Jonklaas, J (reprint author), Georgetown Univ, Div Endocrinol, Suite 230,Bldg D,4000 Reservoir Rd NW, Washington, DC 20007 USA. EM jonklaaj@georgetown.edu FU National Center for Advancing Translational Sciences (NCATS) [UL1TR000101, UL1RR031975]; National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA) FX This project has been funded in part with federal funds (UL1TR000101 previously UL1RR031975) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, "Re-Engineering the Clinical Research Enterprise." Statistical analyses were provided by the Design, Biostatistics, and Population Studies component of the Georgetown-Howard Universities Center for Clinical and Translational Science. Data in the manuscript were presented in part at the 95th Annual Meeting of the Endocrine Society in San Francisco, California. NR 30 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD AUG PY 2014 VL 20 IS 8 BP 797 EP 807 DI 10.4158/EP13453.OR PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0LF UT WOS:000350026400009 PM 24518182 ER PT J AU Biyikli, HH Arduc, A Isik, S Ozuguz, U Caner, S Dogru, F Shorbagi, AI Erden, G Berker, D Guler, S AF Biyikli, Halil Huseyin Arduc, Ayse Isik, Serhat Ozuguz, Ufuk Caner, Sedat Dogru, Fatma Shorbagi, Ali Ibrahim Erden, Gonul Berker, Dilek Guler, Serdar TI ASSESSING THE RELATIONSHIP BETWEEN SERUM GHRELIN LEVELS AND METABOLIC PARAMETERS AND AUTOIMMUNITY IN PATIENTS WITH EUTHYROID HASHIMOTO'S THYROIDITIS SO ENDOCRINE PRACTICE LA English DT Article ID PLASMA GHRELIN; CIRCULATING GHRELIN; INSULIN-RESISTANCE; PREMENOPAUSAL WOMEN; GLUCOSE-TOLERANCE; DYSFUNCTION; ATHEROSCLEROSIS; HYPERTHYROIDISM; EXPRESSION; DECREASE AB Objective: Hashimoto's thyroiditis (HT) may affect metabolic parameters and increase predisposition to obesity. In this study, we aimed to assess the relationships among serum ghrelin concentrations, metabolic parameters, and thyroid autoimmunity in euthyroid HT patients. Methods: The study included 48 euthyroid HT patients and 41 age-and sex-matched healthy controls. We assessed serum ghrelin, free triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (anti-TPO), thyroglobulin antibody (anti-Tg), fasting blood glucose (FBG), insulin, lipid levels, and homeostasis model assessment insulin resistance (HOMA-IR) in all subjects. Results: Sex distribution, mean age, and body mass index (BMI) were similar in HT patients and controls (female/male, 42/6 vs. 33/8, 46.8 +/- 14.7 vs. 45 +/- 12.5 years, 28.5 +/- 6.1 vs. 28.4 +/- 4.9 kg/m(2), respectively; P>.05 for all). The mean waist circumference (WC) of the HT group was significantly higher than that of the control group (100.6 +/- 14.6 vs. 93.2 +/- 13.2 cm, P = .015). While FBG, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels in the HT group were significantly higher than in the control group, insulin levels and HOMA-IR were similar. Ghrelin levels were lower in HT patients compared to controls (416.9 +/- 224.4 and 689.9 +/- 191.6 pg/mL, respectively; P<.001). Ghrelin levels were similar in patients with low and high anti-TPO titers. Negative correlations were observed between ghrelin levels and BMI, WC, and anti-TPO levels. Regression analysis revealed that HT was the most important predictor of ghrelin levels. Conclusion: Euthyroid HT is associated with a decrease in plasma ghrelin levels. Altered body fat distribution and increased anti-TPO levels do not seem to be directly involved in lower ghrelin levels in euthyroid HT patients. C1 [Biyikli, Halil Huseyin; Dogru, Fatma] Ankara Numune Training & Res Hosp, Dept Internal Med, Minist Hlth, Ankara, Turkey. [Arduc, Ayse] NIDDK, NIH, Endocrine & Obes Branch, Bethesda, MD 20892 USA. [Isik, Serhat; Ozuguz, Ufuk; Berker, Dilek] Ankara Numune Training & Res Hosp, Dept Endocrinol & Metab, Minist Hlth, Ankara, Turkey. [Caner, Sedat] Ataturk Educ & Res Hosp, Dept Endocrinol & Metab, Minist Hlth, Ankara, Turkey. [Shorbagi, Ali Ibrahim] Near East Univ Hosp, Dept Gastroenterol & Hepatol, Nicosia, Cyprus. [Erden, Gonul] Ankara Numune Training & Res Hosp, Dept Biochem, Minist Hlth, Ankara, Turkey. [Guler, Serdar] Hitit Univ, Dept Endocrinol & Metab, Corum, Turkey. RP Arduc, A (reprint author), 1778 Dawson St, Vienna, VA 22182 USA. EM ayse_arduc@yahoo.com NR 32 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD AUG PY 2014 VL 20 IS 8 BP 818 EP 824 DI 10.4158/EP13469.OR PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0LF UT WOS:000350026400011 PM 24518184 ER PT J AU Malide, D Metais, JY Dunbar, CE AF Malide, Daniela Metais, Jean-Yves Dunbar, Cynthia E. TI In vivo Clonal Tracking of Hematopoietic Stem and Progenitor Cells Marked by Five Fluorescent Proteins using Confocal and Multiphoton Microscopy SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Stem Cell Biology; Issue 90; LeGO imaging; clonal tracking; fluorescent proteins; confocal microscopy; multiphoton microscopy; hematopoiesis; lentiviral vectors; hematopoietic stem cells ID ONTOLOGY LEGO VECTORS; MARKING; NICHE AB We developed and validated a fluorescent marking methodology for clonal tracking of hematopoietic stem and progenitor cells (HSPCs) with high spatial and temporal resolution to study in vivo hematopoiesis using the murine bone marrow transplant experimental model. Genetic combinatorial marking using lentiviral vectors encoding fluorescent proteins (FPs) enabled cell fate mapping through advanced microscopy imaging. Vectors encoding five different FPs: Cerulean, EGFP, Venus, tdTomato, and mCherry were used to concurrently transduce HSPCs, creating a diverse palette of color marked cells. Imaging using confocal/two-photon hybrid microscopy enables simultaneous high resolution assessment of uniquely marked cells and their progeny in conjunction with structural components of the tissues. Volumetric analyses over large areas reveal that spectrally coded HSPC-derived cells can be detected non-invasively in various intact tissues, including the bone marrow (BM), for extensive periods of time following transplantation. Live studies combining video-rate multiphoton and confocal time-lapse imaging in 4D demonstrate the possibility of dynamic cellular and clonal tracking in a quantitative manner. C1 [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20824 USA. [Metais, Jean-Yves; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD USA. RP Malide, D (reprint author), NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20824 USA. EM dmalide@nih.gov FU National Heart, Lung, Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health. We thank Boris Fehse (University Medical Center Hamburg-Eppendorf, Hamburg, Germany) for providing the five LeGO vector plasmids; Christian A. Combs and Neal S. Young (NHLBI, NIH) for discussions, support and encouragement throughout this study, and Andre LaRochelle (NHLBI, NIH) for assistance with tail vein injections. NR 12 TC 0 Z9 0 U1 1 U2 4 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD AUG PY 2014 IS 90 AR e51669 DI 10.3791/51669 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0EV UT WOS:000349299200034 PM 25145579 ER PT J AU Beydoun, MA AF Beydoun, May A. TI The Interplay of Gender, Mood, and Stress Hormones in the Association between Emotional Eating and Dietary Behavior SO JOURNAL OF NUTRITION LA English DT Editorial Material ID ELEVATED DEPRESSIVE SYMPTOMS; AFRICAN-AMERICAN WOMEN; ADRENALECTOMIZED RATS; RESTRAINT STRESS; OBESITY; FOOD; QUALITY; WEIGHT; ADULTS; GLUCOCORTICOIDS C1 NIA, Baltimore, MD 21224 USA. RP Beydoun, MA (reprint author), NIA, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov FU Intramural NIH HHS NR 56 TC 2 Z9 4 U1 2 U2 21 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 AUG PY 2014 VL 144 IS 8 BP 1139 EP 1141 DI 10.3945/jn.114.196717 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AX1GU UT WOS:000346696700001 PM 24919688 ER PT J AU Ma, JT Sloan, M Fox, CS Hoffmann, U Smith, CE Saltzman, E Rogers, GT Jacques, PF McKeown, NM AF Ma, Jiantao Sloan, Matthew Fox, Caroline S. Hoffmann, Udo Smith, Caren E. Saltzman, Edward Rogers, Gail T. Jacques, Paul F. McKeown, Nicola M. TI Sugar-Sweetened Beverage Consumption Is Associated with Abdominal Fat Partitioning in Healthy Adults SO JOURNAL OF NUTRITION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; SUBCUTANEOUS ADIPOSE-TISSUE; CARDIOVASCULAR-DISEASE; INSULIN SENSITIVITY; COMPUTED-TOMOGRAPHY; LIPOPROTEIN-LIPASE; VISCERAL ADIPOSITY; METABOLIC SYNDROME; DIABETES-MELLITUS; HEART-DISEASE AB Abdominal adiposity, particularly visceral adipose tissue (VAT), is independently linked to the pathogenesis of diabetes and cardiovascular diseases. Emerging evidence suggests that greater intake of sugar-sweetened beverages (SSBs) may be associated with abnormal fat accumulation in VAT. We examined whether habitual SSB consumption and diet soda intakes are differentially associated with deposition of body fat. We conducted a cross-sectional analysis using previously collected data in 2596 middle-aged adults (1306 men and 1290 women) from the Framingham Heart Study Offspring and Third Generation cohorts. VAT and abdominal subcutaneous adipose tissue (SAT) were measured using multidetector computed tomography. Habitual intake of SSBs and diet soda was assessed by a validated food frequency questionnaire. We observed that SSB consumption was positively associated with VAT after adjustment for SAT and other potential confounders (P-trend < 0.001). We observed an inverse association between SSB consumption and SAT (P-trend = 0.04) that persisted after additional adjustment for VAT (P-trend < 0.001). Higher SSB consumption was positively associated with the VAT-to-SAT ratio (P-trend < 0.001). No significant association was found between diet soda consumption and either VAT or the VAT-to-SAT ratio, but diet soda was positively associated with SAT (P-trend < 0.001). Daily consumers of SSBs had a 10% higher absolute VAT volume and a 15% greater VAT-to-SAT ratio compared with nonconsumers, whereas consumption of diet soda was not associated with either volume or distribution of VAT. C1 [Ma, Jiantao; Rogers, Gail T.; Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Nutr Epidemiol Program, Boston, MA 02111 USA. [Smith, Caren E.] Tufts Univ, Nutr & Genom Lab, Boston, MA 02111 USA. [Saltzman, Edward] Tufts Univ, Energy Metab Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Sloan, Matthew] Univ Massachusetts, Sch Med, Worcester, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol & Metab, Boston, MA 02115 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP McKeown, NM (reprint author), Tufts Univ, Nutr Epidemiol Program, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU NIH/National Heart, Lung, and Blood Institute Framingham Heart Study [N01-HC-25195]; Boston University School of Medicine; USDA [58-1950-0-014] FX Supported by NIH/National Heart, Lung, and Blood Institute Framingham Heart Study under contract N01-HC-25195, the Boston University School of Medicine, and USDA agreement 58-1950-0-014. NR 41 TC 8 Z9 8 U1 0 U2 1 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 AUG PY 2014 VL 144 IS 8 BP 1283 EP 1290 DI 10.3945/jn.113.188599 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AX1GU UT WOS:000346696700022 PM 24944282 ER PT J AU Rohner, F Zimmermann, M Jooste, P Pandav, C Caldwell, K Raghavan, R Raiten, DJ AF Rohner, Fabian Zimmermann, Michael Jooste, Pieter Pandav, Chandrakant Caldwell, Kathleen Raghavan, Ramkripa Raiten, Daniel J. TI Biomarkers of Nutrition for Development-Iodine Review SO JOURNAL OF NUTRITION LA English DT Review ID NUTRIENT INTAKE DISTRIBUTIONS; SCHOOL-AGE-CHILDREN; THYROID-FUNCTION; URINARY IODINE; PREGNANT-WOMEN; DEFICIENCY DISORDERS; POPULATION-LEVEL; PROCESSED FOODS; ENDEMIC GOITER; DIETARY IODINE AB The objective of the Biomarkers of Nutrition for Development (BOND) project is to provide state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. Specifically, the BOND project seeks to develop consensus on accurate assessment methodologies that are applicable to researchers (laboratory/clinical/surveillance), clinicians, programmers, and policy makers (data consumers). The BOND project is also intended to develop targeted research agendas to support the discovery and development of biomarkers through improved understanding of nutrient biology within relevant biologic systems. In phase I of the BOND project, 6 nutrients (iodine, vitamin A, iron, zinc, folate, and vitamin B-12) were selected for their high public health importance because they typify the challenges faced by users in the selection, use, and interpretation of biomarkers. For each nutrient, an expert panel was constituted and charged with the development of a comprehensive review covering the respective nutrient's biology, existing biomarkers, and specific issues of use with particular reference to the needs of the individual user groups. In addition to the publication of these reviews, materials from each will be extracted to support the BOND interactive Web site (http://www.nichd.nih.gov/global_nutrition/programs/bond/pages/index.aspx). This review represents the first in the series of reviews and covers all relevant aspects of iodine biology and biomarkers. The article is organized to provide the reader with a full appreciation of iodine's background history as a public health issue, its biology, and an overview of available biomarkers and specific considerations for the use and interpretation of iodine biomarkers across a range of clinical and population-based uses. The review also includes a detailed research agenda to address priority gaps in our understanding of iodine biology and assessment. C1 [Rohner, Fabian] Groundwork LLC, Crans Pres Celigny, Switzerland. [Rohner, Fabian] Global Alliance Improved Nutr GAIN, Geneva, Switzerland. [Zimmermann, Michael] Swiss Fed Inst Technol, Inst Food Nutr & Hlth, Zurich, Switzerland. [Zimmermann, Michael] Int Council Control Iodine Deficiency Disorders I, Zurich, Switzerland. [Jooste, Pieter] North West Univ, Fac Hlth Sci, Ctr Excellence Nutr, Potchefstroom, South Africa. [Jooste, Pieter] ICCIDD Global Network, Southern Africa Off, Cape Town, South Africa. [Pandav, Chandrakant] All India Inst Med Sci, Ctr Community Med, New Delhi, India. [Pandav, Chandrakant] ICCIDD Global Network, South Asia Off, New Delhi, India. [Caldwell, Kathleen] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Raghavan, Ramkripa; Raiten, Daniel J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov RI Zimmermann, Michael/C-3062-2016 FU Bill and Melinda Gates Foundation; PepsiCo; NIH Division of Nutrition Research Coordination; Office of Dietary Supplements, NIH FX Published in a supplement to The Journal of Nutrition. The Biomarkers of Nutrition for Development (BOND) project was developed by the nutrition program staff of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the NIH within the U.S. Department of Health and Human Services (DHHS). The initial 6 nutrients, iodine, vitamin A, iron, zinc, folate, and vitamin B-12, selected were chosen for their high public health importance. Expert panels on each nutrient were constituted and charged with developing comprehensive reviews for publication in the BOND series. The BOND program received its core funding from the Bill and Melinda Gates Foundation, PepsiCo, the NIH Division of Nutrition Research Coordination, and the Office of Dietary Supplements, NIH. The Supplement Coordinators for this supplement were Daniel J. Raiten and Ramkripa Raghavan (NICHD). Supplement NR 165 TC 30 Z9 31 U1 3 U2 21 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 AUG PY 2014 VL 144 IS 8 BP 1322S EP 1342S DI 10.3945/jn.113.181974 PG 21 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AX1GU UT WOS:000346696700027 PM 24966410 ER PT J AU Weiss, JM Wiltout, RH AF Weiss, Jonathan M. Wiltout, Robert H. TI Multifaceted antitumor responses to activating anti-CD40 antibody therapy combined with immunomodulatory or targeted agents SO ONCOIMMUNOLOGY LA English DT Editorial Material DE biomarkers; immunostimulation; immunotherapy; inflammation; targets; therapeutic antibodies ID TUMOR MICROENVIRONMENT; CD40 EXPRESSION; CELLS; CANCER; IMMUNOTHERAPY; CARCINOMA; APOPTOSIS AB Therapeutic targeting of the CD40 pathway may be efficacious for cancer treatment. Accumulating evidence suggests synergistic and unique antitumor responses may be achieved using CD40-based therapies in combination with other immunomodulators or targeted agents. C1 [Weiss, Jonathan M.; Wiltout, Robert H.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Wiltout, RH (reprint author), NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. EM wiltrour@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD AUG PY 2014 VL 3 IS 8 AR e954483 DI 10.4161/21624011.2014.954483 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA AX4SR UT WOS:000346922100015 ER PT J AU Barclay, VC Kennedy, DA Weaver, VC Sim, D Lloyd-Smith, JO Read, AF AF Barclay, Victoria C. Kennedy, David A. Weaver, Veronika C. Sim, Derek Lloyd-Smith, James O. Read, Andrew F. TI The Effect of Immunodeficiency on the Evolution of Virulence: An Experimental Test with the Rodent Malaria Plasmodium chabaudi SO AMERICAN NATURALIST LA English DT Article DE immune suppression; evolution; virulence ID WITHIN-HOST COMPETITION; PARASITE VIRULENCE; MYXOMA VIRUS; INFECTIONS; DYNAMICS; TRANSMISSION; RESISTANT; MICE; PHAGOCYTOSIS; CONSEQUENCES AB Host immunity plays an important role in the evolution of pathogen virulence and disease emergence. There is increasing theoretical and empirical evidence that enhanced immunity through vaccination may have the unfortunate side effect of selecting for more virulent parasites, but the effect of host immune suppression on pathogen evolution is less clear. Here, we use serial passage experiments in mice to test how immune-suppressed hosts may alter pathogen virulence evolution. We passaged Plasmodium chabaudi through CD4(+) T cell depleted or control mice every 7 days for 20 weeks and then measured virulence differences during infection of immunologically normal mice. We found that those parasites that had been selected through CD4(+) T cell depleted mice were more virulent than parasites selected through control mice. Virulence increases during serial passage are believed to be caused by pathogen adaptation to the passage host. These data suggest that immune-suppressed hosts could provide a within-host environment that lowers the barrier to parasite adaptation and promotes the evolution of virulence. C1 [Barclay, Victoria C.; Kennedy, David A.; Sim, Derek; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Kennedy, David A.; Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Weaver, Veronika C.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Read, Andrew F.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. RP Barclay, VC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM vbarclay@imseinstitute.org RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU Pennsylvania State University FX For discussion during the very long incubation of this project, we thank A. August, M. Boots, M. Cantorna, M. Ferrari, M. Mackinnon, M. Poss, members of the Read-Thomas lab group, and the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. We thank M. Rabba for the configuration of figure 1. The work was funded by Pennsylvania State University (start-up funds to A.F.R.). NR 66 TC 6 Z9 6 U1 0 U2 15 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0003-0147 EI 1537-5323 J9 AM NAT JI Am. Nat. PD AUG PY 2014 VL 184 SU 1 BP S47 EP S57 DI 10.1086/676887 PG 11 WC Ecology; Evolutionary Biology SC Environmental Sciences & Ecology; Evolutionary Biology GA AW6JF UT WOS:000346375100005 PM 25061677 ER PT J AU White, TC Findley, K Dawson, TL Scheynius, A Boekhout, T Cuomo, CA Xu, J Saunders, CW AF White, Theodore C. Findley, Keisha Dawson, Thomas L., Jr. Scheynius, Annika Boekhout, Teun Cuomo, Christina A. Xu, Jun Saunders, Charles W. TI Fungi on the Skin: Dermatophytes and Malassezia SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID CAPITIS CLINICAL-TRIAL; SEBORRHEIC DERMATITIS; PITYRIASIS-VERSICOLOR; ATOPIC-DERMATITIS; TINEA-VERSICOLOR; TRICHOPHYTON-RUBRUM; MOLECULAR-DETECTION; PATHOGENIC FUNGUS; GENUS MALASSEZIA; RIBOSOMAL DNA AB Several human skin diseases and disorders are associated with two groups of fungi, the dermatophytes and Malassezia. Although these skin-related problems are not generally life threatening, they are among the most common diseases and disorders of mankind. These fungi are phylogenetically divergent, with the dermatophytes within the Ascomycota and Malassezia within Basidiomycota. Genome analysis indicates that the adaptations to the skin environment are different in these two groups of fungi. Malassezia are dependent on host lipids and secrete lipases and phospholipases that likely release host fatty acids. The dermatophytes encode multiple enzymes with potential roles in modulating host interactions: polyketide synthases, nonribosomal peptide synthetases, LysM, proteases, kinases, and pseudokinases. These two fungal groups have maximized their interactions with the host using two very different mechanisms. C1 [White, Theodore C.] Univ Missouri, Sch Biol Sci, Kansas City, MO 64110 USA. [Findley, Keisha] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Dawson, Thomas L., Jr.] Procter & Gamble Co, Singapore 138547, Singapore. [Scheynius, Annika] Karolinska Inst, Translat Immunol Unit, Dept Med Solna, SE-14186 Stockholm, Sweden. [Scheynius, Annika] Univ Hosp, SE-14186 Stockholm, Sweden. [Boekhout, Teun] CBS KNAW Fungal Biodivers Ctr, NL-3584 CT Utrecht, Netherlands. [Cuomo, Christina A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Xu, Jun; Saunders, Charles W.] Procter & Gamble Co, Mason, OH 45040 USA. RP Saunders, CW (reprint author), Procter & Gamble Co, Mason, OH 45040 USA. EM saunders.cw@pg.com OI Dawson, Thomas/0000-0003-3878-1722; Cuomo, Christina/0000-0002-5778-960X NR 121 TC 8 Z9 8 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD AUG PY 2014 VL 4 IS 8 AR a019802 DI 10.1101/cshperspect.a019802 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NO UT WOS:000346519300005 ER PT J AU Andrews, PW Cavagnaro, J Deans, R Feigal, E Horowitz, E Keating, A Rao, M Turner, M Wilmut, I Yamanaka, S AF Andrews, Peter W. Cavagnaro, Joy Deans, Robert Feigal, Ellen Horowitz, Ed Keating, Armand Rao, Mahendra Turner, Marc Wilmut, Ian Yamanaka, Shinya TI Harmonizing standards for producing clinical-grade therapies from pluripotent stem cells SO NATURE BIOTECHNOLOGY LA English DT Letter ID CELLULAR THERAPY; INFORMED-CONSENT C1 [Andrews, Peter W.] Univ Sheffield, Dept Biomed Sci, Ctr Stem Cell Biol, Western Bank, Sheffield S10 2TN, S Yorkshire, England. [Andrews, Peter W.] Int Stem Cell Initiat, Harbor, ME USA. [Cavagnaro, Joy] Access BIO, Boyce, VA USA. [Deans, Robert] Alliance Regenerat Med Athersys, Cleveland, OH USA. [Feigal, Ellen] Calif Inst Regenerat Med, San Francisco, CA USA. [Horowitz, Ed] Int Soc Cell Therapy, Vancouver, BC, Canada. [Keating, Armand] Univ Toronto, Amer Soc Hematol, Toronto, ON, Canada. [Keating, Armand] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Turner, Marc] Scottish Natl Blood Transfus Serv Headquarters, Edinburgh, Midlothian, Scotland. [Wilmut, Ian] Univ Edinburgh, Scottish Ctr Regenerat Med, Edinburgh BioQuarter, Edinburgh, Midlothian, Scotland. [Yamanaka, Shinya] Kyoto Univ, Kyoto Ctr iPS Cell Res & Applicat, Sakyo Ku, Kyoto, Japan. [Yamanaka, Shinya] Int Soc Stem Cell Res, Northbrook, IL USA. RP Andrews, PW (reprint author), Univ Sheffield, Dept Biomed Sci, Ctr Stem Cell Biol, Western Bank, Sheffield S10 2TN, S Yorkshire, England. EM mrao@nyscf.org NR 16 TC 19 Z9 19 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2014 VL 32 IS 8 BP 724 EP 726 DI 10.1038/nbt.2973 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AW7PF UT WOS:000346455900009 PM 25093882 ER PT J AU Naumova, AV Modo, M Moore, A Murry, CE Frank, JA AF Naumova, Anna V. Modo, Michel Moore, Anna Murry, Charles E. Frank, Joseph A. TI Clinical imaging in regenerative medicine SO NATURE BIOTECHNOLOGY LA English DT Article ID NEURAL STEM-CELLS; POSITRON-EMISSION-TOMOGRAPHY; PANCREATIC-ISLET CELLS; NONISCHEMIC DILATED CARDIOMYOPATHY; HEMATOPOIETIC PROGENITOR CELLS; REPORTER GENE-EXPRESSION; IRON-OXIDE NANOPARTICLES; MARROW MONONUCLEAR-CELLS; TYPE-1 DIABETES-MELLITUS; NORMAL ORGAN WEIGHTS AB In regenerative medicine, clinical imaging is indispensable for characterizing damaged tissue and for measuring the safety and efficacy of therapy. However, the ability to track the fate and function of transplanted cells with current technologies is limited. Exogenous contrast labels such as nanoparticles give a strong signal in the short term but are unreliable long term. Genetically encoded labels are good both short-and long-term in animals, but in the human setting they raise regulatory issues related to the safety of genomic integration and potential immunogenicity of reporter proteins. Imaging studies in brain, heart and islets share a common set of challenges, including developing novel labeling approaches to improve detection thresholds and early delineation of toxicity and function. Key areas for future research include addressing safety concerns associated with genetic labels and developing methods to follow cell survival, differentiation and integration with host tissue. Imaging may bridge the gap between cell therapies and health outcomes by elucidating mechanisms of action through longitudinal monitoring. C1 [Naumova, Anna V.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Naumova, Anna V.; Murry, Charles E.] Univ Washington, Ctr Cardiovasc Biol, Seattle, WA 98195 USA. [Naumova, Anna V.; Murry, Charles E.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Modo, Michel] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA. [Modo, Michel] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA USA. [Modo, Michel] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Modo, Michel] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Moore, Anna] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Murry, Charles E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Murry, Charles E.] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Murry, Charles E.] Univ Washington, Dept Med Cardiol, Seattle, WA 98195 USA. [Frank, Joseph A.] NIH, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Murry, CE (reprint author), Univ Washington, Ctr Cardiovasc Biol, Seattle, WA 98195 USA. EM murry@uw.edu; jfrank@helix.nih.gov OI Modo, Michel/0000-0003-4436-735X FU Commonwealth of Pennsylvania, Department of Health [4100061184]; NINDS [R01NS082226]; NIBIB [1R01EB016629]; US National Institutes of Health (NIH) [P01HL094374, R01HL084642, U01HL100405, P01GM81619]; intramural research program in the Clinical Center and National Institutes of Biomedical Imaging and Bioengineering at the US National Institutes of Health; NIH [R24 DK096465] FX The authors would like to acknowledge Kristine Evers for proofreading of the manuscript and the following grant support: M.M. was supported by the Commonwealth of Pennsylvania, Department of Health (4100061184), NINDS (R01NS082226) and NIBIB (1R01EB016629). C.E.M. was supported by US National Institutes of Health (NIH) grants P01HL094374, R01HL084642, U01HL100405 and P01GM81619. J.A.F. was supported in part by the intramural research program in the Clinical Center and National Institutes of Biomedical Imaging and Bioengineering at the US National Institutes of Health. A.M. was supported in part by NIH grant R24 DK096465. NR 159 TC 52 Z9 55 U1 7 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2014 VL 32 IS 8 BP 804 EP U121 DI 10.1038/nbt.2993 PG 15 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AW7PF UT WOS:000346455900021 PM 25093889 ER PT J AU Quick, H Groth, C Banerjee, S Carlin, BP Stenzel, MR Stewart, PA Sandler, DP Engel, LS Kwok, RK AF Quick, Harrison Groth, Caroline Banerjee, Sudipto Carlin, Bradley P. Stenzel, Mark R. Stewart, Patricia A. Sandler, Dale P. Engel, Lawrence S. Kwok, Richard K. TI Exploration of the use of Bayesian modeling of gradients for censored spatiotemporal data from the Deepwater Horizon oil spill SO SPATIAL STATISTICS LA English DT Article DE Gaussian process; Gradients; Markov chain Monte Carlo; Censored data; Hierarchical modeling; Spatiotemporal data AB This paper develops a hierarchical framework for identifying spatiotemporal patterns in data with a high degree of censoring using the gradient process. To do this, we impute censored values using a sampling-based inverse CDF method within our Markov chain Monte Carlo algorithm, thereby avoiding burdensome integration and facilitating efficient estimation of other model parameters. We illustrate use of our methodology using a simulated data example, and uncover the danger of simply substituting a space- and time-constant function of the level of detection for all missing values. We then fit our model to area measurement data of volatile organic compound (VOC) air concentrations collected on vessels supporting the response and clean-up efforts of the Deepwater Horizon oil release that occurred starting April 20, 2010. These data contained a high percentage of observations below the detectable limits of the measuring instrument. Despite this, we were still able to make some interesting discoveries, including elevated levels of VOC near the site of the oil well on June 26th. Using the results from this preliminary analysis, we hope to inform future research on the Deepwater Horizon study, including the use of gradient methods for assigning workers to exposure categories. (C) 2014 Elsevier B.V. All rights reserved. C1 [Quick, Harrison] Univ Missouri, Dept Stat, Columbia, MO 65211 USA. [Groth, Caroline; Banerjee, Sudipto; Carlin, Bradley P.] Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. [Stenzel, Mark R.] Exposure Assessments Applicat LLC, Arlington, VA 22207 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA 22207 USA. [Sandler, Dale P.; Kwok, Richard K.] NIEHS, Res Triangle Pk, NC 27709 USA. [Engel, Lawrence S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. RP Banerjee, S (reprint author), Univ Minnesota, Div Biostat, Minneapolis, MN 55455 USA. EM quickh@missouri.edu; baner009@umn.edu RI Kwok, Richard/B-6907-2017; OI Kwok, Richard/0000-0002-6794-8360; Sandler, Dale/0000-0002-6776-0018; Engel, Lawrence/0000-0001-9268-4830 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; Social & Scientific Systems, Inc. [S939000025] FX We would like to thank Wendy McDowell and other members of the GuLF STUDY for their continued efforts. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, as well as a contract with Social & Scientific Systems, Inc. (contract #S939000025). The opinions of this paper are those of the author and not necessarily of any funding body. NR 18 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-6753 J9 SPAT STAT-NETH JI Spat. Stat. PD AUG PY 2014 VL 9 BP 166 EP 179 DI 10.1016/j.spasta.2014.03.002 PG 14 WC Geosciences, Multidisciplinary; Mathematics, Interdisciplinary Applications; Remote Sensing; Statistics & Probability SC Geology; Mathematics; Remote Sensing GA AW9TR UT WOS:000346600800006 PM 25599019 ER PT J AU Krischer, JP Gopal-Srivastava, R Groft, SC Eckstein, DJ AF Krischer, Jeffrey P. Gopal-Srivastava, Rashmi Groft, Stephen. C. Eckstein, David J. CA Rare Dis Clinical Res Network TI The Rare Diseases Clinical Research Network's Organization and Approach to Observational Research and Health Outcomes Research SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE rare diseases network; multi-institutional clinical research; outcomes; patient advocacy groups ID QUALITY-OF-LIFE; CONTACT REGISTRY; VASCULITIS; CHALLENGES; CHILDREN; SYSTEM AB Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio-repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR-governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2 months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases. C1 [Krischer, Jeffrey P.] Univ S Florida, Tampa, FL USA. [Gopal-Srivastava, Rashmi; Groft, Stephen. C.; Eckstein, David J.] NCATS, Off Rare Dis Res, Bethesda, MD USA. RP Krischer, JP (reprint author), 3650 Spectrum Blvd, Tampa, FL 33612 USA. EM jpkrischer@epi.usf.edu FU NCATS NIH HHS [U01 TR001263] NR 27 TC 4 Z9 4 U1 2 U2 10 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 AUG PY 2014 VL 29 SU 3 BP S739 EP S744 DI 10.1007/s11606-014-2894-x PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XU UT WOS:000345411700005 PM 25029976 ER PT J AU Pariser, AR Gahl, WA AF Pariser, Anne R. Gahl, William A. TI Important Role of Translational Science in Rare Disease Innovation, Discovery, and Drug Development SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE rare disease; translational medical research; diagnosis; registries ID UNDIAGNOSED DISEASES; DISORDERS; MUTATION; MELANOMA; CANCER; BRAF AB Rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science. Most rare diseases are genetic disorders or atypical manifestations of infectious, immunologic, or oncologic diseases; they all provide opportunities to study extremes of human pathology and provide insight into both normal and aberrant physiology. Recently, drug development has become increasingly focused on classifying diseases largely on genetic grounds; this has allowed the identification of molecularly defined targets and the development of targeted therapies. Clinical trials are now focusing on progressively smaller subgroups within both common and rare disease populations, often based on genetic tests or biomarkers. Drug developers, researchers, and regulatory agencies face a variety of challenges throughout the life cycle of drug research and development for rare diseases. These include the small numbers of patients available for study, lack of knowledge of the disease's natural history, incomplete understanding of the basic mechanisms causing the disorder, and variability in disease severity, expression, and course. Traditional approaches to rare disease clinical research have not kept pace with advances in basic science, and increased attention to translational science is needed to address these challenges, especially diagnostic testing, registries, and novel trial designs. C1 [Pariser, Anne R.] US FDA, Off New Drugs, Rare Dis Program, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Gahl, William A.] NIH, Undiagnosed Dis Program, Off Director, Bethesda, MD 20892 USA. [Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Pariser, AR (reprint author), US FDA, Off New Drugs, Rare Dis Program, Ctr Drug Evaluat & Res, WO22-6471,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Anne.pariser@fda.hhs.gov FU Intramural NIH HHS NR 20 TC 4 Z9 5 U1 2 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 AUG PY 2014 VL 29 SU 3 BP S804 EP S807 DI 10.1007/s11606-014-2881-2 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XU UT WOS:000345411700014 PM 25029971 ER PT J AU Lui, JLC Nilsson, O Baron, J AF Lui, Julian C. Nilsson, Ola Baron, Jeffrey TI RECENT RESEARCH ON THE GROWTH PLATE Recent insights into the regulation of the growth plate SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Review DE growth hormone; signal transduction; IGF; microarray; skeletal ID PEPTIDE RECEPTOR-B; FACTOR 21 FGF21; IDIOPATHIC SHORT STATURE; GENOME-WIDE ASSOCIATION; NATRIURETIC PEPTIDE; POSTNATAL-GROWTH; GENE-EXPRESSION; BONE-GROWTH; HETEROZYGOUS MUTATIONS; METABOLIC REGULATOR AB For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth. C1 [Lui, Julian C.; Nilsson, Ola; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, CRC, Bethesda, MD 20892 USA. [Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Mol Med, SE-17176 Stockholm, Sweden. [Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, SE-17176 Stockholm, Sweden. [Nilsson, Ola] Karolinska Univ Hosp, SE-17176 Stockholm, Sweden. RP Lui, JLC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM luichunk@mail.nih.gov RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), US National Institutes of Health (NIH); European Society for Paediatric Endocrinology Research Fellowship Grant; Swedish Research Council [K2012-99X-21998-01-3]; Swedish Society of Medicine; Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care; Wera Ekstrom's Foundation for Pediatric Research; Marta och Gunnar V Philipson's Foundation; Sallskapet Barnavard; Stiftelsen Frimurare Barnhuset i Stockholm; Karolinska Institutet FX J C L and J B were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), US National Institutes of Health (NIH). O N was supported by an European Society for Paediatric Endocrinology Research Fellowship Grant and grants from the Swedish Research Council (K2012-99X-21998-01-3), the Swedish Society of Medicine, Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care, Wera Ekstrom's Foundation for Pediatric Research, Marta och Gunnar V Philipson's Foundation, Sallskapet Barnavard, Stiftelsen Frimurare Barnhuset i Stockholm, and Karolinska Institutet. NR 83 TC 12 Z9 12 U1 2 U2 9 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD AUG PY 2014 VL 53 IS 1 BP T1 EP T9 DI 10.1530/JME-14-0022 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU4ZX UT WOS:000345617800004 PM 24740736 ER PT J AU Wang, XY Chrysovergis, K Kosak, J Kissling, G Streicker, M Moser, G Li, RF Eling, TE AF Wang, Xingya Chrysovergis, Kali Kosak, Justin Kissling, Grace Streicker, Mike Moser, Glenda Li, Ruifang Eling, Thomas E. TI hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling SO AGING-US LA English DT Article DE hNAG-1/GDF15; lifespan; metabolism; insulin/IGF-1/mTOR ID MACROPHAGE INHIBITORY CYTOKINE-1; MICE; LONGEVITY; WEIGHT; MECHANISMS; EXPRESSION; MODULATOR; C57BL/6J; CANCER; DIET AB Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) or GDF15 is a divergent member of the transforming growth factor beta (TGF-beta) superfamily and mice expressing hNAG-1/hGDF15 have been shown to be resistant to HFD-induced obesity and inflammation. This study investigated if hNAG-1 increases lifespan in mice and its potential mechanisms. Here we report that female hNAG-1 mice had significantly increased both mean and median life spans in two transgenic lines, with a larger difference in life spans in mice on a HFD than on low fat diet. hNAG-1 mice displayed significantly reduced body and adipose tissue weight, lowered serum IGF-1, insulin and glucose levels, improved insulin sensitivity, and increased oxygen utilization, oxidative metabolism and energy expenditure. Gene expression analysis revealed significant differences in conserved gene pathways that are important regulators of longevity, including IGF-1, p70S6K, and PI3K/Akt signaling cascades. Phosphorylation of major components of IGF-1/mTOR signaling pathway was significantly lower in hNAG-1mice. Collectively, hNAG-1 is an important regulator of mammalian longevity and may act as a survival factor. Our study suggests that hNAG-1 has potential therapeutic uses in obesity-related diseases where life span is frequently shorter. C1 [Wang, Xingya; Chrysovergis, Kali; Kosak, Justin; Li, Ruifang; Eling, Thomas E.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Kissling, Grace] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Streicker, Mike; Moser, Glenda] Integrated Syst Lab Inc, Morrisville, NC 27560 USA. [Wang, Xingya] Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 310053, Zhejiang, Peoples R China. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov FU NIH, NIEHS [Z01-ES010016-14] FX We thank Drs. Xiaoling Li and Paul Wade for critical reading of this manuscript. We wish to thank Laura Wharey, Kevin Gerrish, and Ruchir Shah at NIEHS Microarray core for performing microarray experiment and data analysis. This research was supported by NIH, NIEHS Intramural Research Program (Eling) Z01-ES010016-14. NR 36 TC 13 Z9 13 U1 0 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD AUG PY 2014 VL 6 IS 8 BP 690 EP 704 PG 15 WC Cell Biology SC Cell Biology GA AU2FE UT WOS:000345431000006 PM 25239873 ER PT J AU Kristal, AR Till, C Song, XL Tangen, CM Goodman, PJ Neuhauser, ML Schenk, JM Thompson, IM Meyskens, FL Goodman, GE Minasian, LM Parnes, HL Klein, EA AF Kristal, Alan R. Till, Cathee Song, Xiaoling Tangen, Catherine M. Goodman, Phyllis J. Neuhauser, Marian L. Schenk, Jeannette M. Thompson, Ian M. Meyskens, Frank L., Jr. Goodman, Gary E. Minasian, Lori M. Parnes, Howard L. Klein, Eric A. TI Plasma Vitamin D and Prostate Cancer Risk: Results from the Selenium and Vitamin E Cancer Prevention Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID 25-HYDROXYVITAMIN D; ASSOCIATION; CALCIUM; MEN AB Background: In vitro, animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent. Methods: Data for this case (n = 1,731) and cohort (n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2-6, 7-10, and 8-10 prostate cancer. Results: There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66-1.03; P = 0.092], 0.74 (95% CI, 0.59-0.92; P = 0.008), 0.86 (95% CI, 0.69-1.07; P = 0.181), and 0.98 (95% CI, 0.78-1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7-10 cancer, corresponding HRs were 0.63 (95% CI, 0.45-0.90; P = 0.010), 0.66 (95% CI, 0.47-0.92; P = 0.016), 0.79 (95% CI, 0.56-1.10; P = 0.165), and 0.88 (95% CI, 0.63-1.22; P = 0.436). Among African American men (n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7-10 cancer only: in the a posteriori contrast of quintiles 1-2 versus 3-5, the HR was 0.55 (95% CI, 0.31-0.97; P = 0.037), with no evidence of dose-response or a U-shaped association. Conclusions: Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease. Impact: The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. (C) 2014 AACR. C1 [Kristal, Alan R.; Song, Xiaoling; Tangen, Catherine M.; Neuhauser, Marian L.; Schenk, Jeannette M.] Univ Washington, Canc Prevent Program, Seattle, WA 98195 USA. [Till, Cathee; Tangen, Catherine M.; Goodman, Phyllis J.] Univ Washington, SWOG Stat Ctr, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Kristal, Alan R.; Goodman, Gary E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Goodman, Gary E.] Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Chao Family Comprehens Canc, Irvine, CA USA. [Minasian, Lori M.; Parnes, Howard L.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. RP Kristal, AR (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M4-B402,POB 19024, Seattle, WA 98109 USA. EM Akristal@fhcrc.org FU Public Health Service Cooperative Agreements [CA37429]; NCI; National Center for Complementary and Alternative Medicine [CA182883] FX This work was supported by Public Health Service Cooperative Agreements grant CA37429 (C. Blanke, principal investigator) by the NCI and the National Center for Complementary and Alternative Medicine, and by grant CA182883 (C. Tangen, principal investigator) by the NCI. Study agents and packaging were provided by Perrigo Company, Sabinsa Corporation, Tishcon Corporation, and DSM Nutritional Products Inc. NR 30 TC 33 Z9 33 U1 1 U2 12 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 AUG PY 2014 VL 23 IS 8 BP 1494 EP 1504 DI 10.1158/1055-9965.EPI-14-0115 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200006 PM 24732629 ER PT J AU Steinmaus, C Ferreccio, C Acevedo, J Yuan, Y Liaw, J Duran, V Cuevas, S Garcia, J Meza, R Valdes, R Valdes, G Benitez, H VanderLinde, V Villagra, V Cantor, KP Moore, LE Perez, SG Steinmaus, S Smith, AH AF Steinmaus, Craig Ferreccio, Catterina Acevedo, Johanna Yuan, Yan Liaw, Jane Duran, Viviana Cuevas, Susana Garcia, Jose Meza, Rodrigo Valdes, Rodrigo Valdes, Gustavo Benitez, Hugo VanderLinde, Vania Villagra, Vania Cantor, Kenneth P. Moore, Lee E. Perez, Saida G. Steinmaus, Scott Smith, Allan H. TI Increased Lung and Bladder Cancer Incidence in Adults after In Utero and Early-Life Arsenic Exposure SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DRINKING-WATER; NORTHERN CHILE; RISK-ASSESSMENT; CHILDHOOD EXPOSURE; TOBACCO-SMOKE; CHILDREN; MORTALITY; HEALTH; CARCINOGENESIS; DISEASE AB Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer. Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls. Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of <= 110, 110 to 800, and >800 mu g/L were 1.00, 1.88 [95% confidence interval (CI), 0.96-3.71], and 5.24 (3.05-9.00; P-trend < 0.001) for lung cancer, and 1.00, 2.94 (1.29-6.70), and 8.11 (4.31-15.25; P-trend < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 mu g/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed. Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure. Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease. (C) 2014 AACR. C1 [Steinmaus, Craig; Yuan, Yan; Liaw, Jane; Smith, Allan H.] Univ Calif Berkeley, Arsen Hlth Effects Res Program, Berkeley, CA 94720 USA. [Steinmaus, Craig] Calif Environm Protect, Off Environm Hlth Hazard Assessment, Oakland, CA USA. [Perez, Saida G.] Univ Calif San Francisco, Global Hlth Sci Program, San Francisco, CA 94143 USA. [Steinmaus, Scott] Calif Polytech State Univ San Luis Obispo, Dept Biol Sci, San Luis Obispo, CA 93407 USA. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. [Moore, Lee E.] NCI, Bethesda, MD 20892 USA. [Villagra, Vania] Pontificia Univ Catolica Chile, Fac Med, Santiago, Chile. [Duran, Viviana] Hosp Reg Arica Dr Juan Noe, Arica, Chile. [Cuevas, Susana] Ctr Salud Familiar Iris Veliz Hume, Arica, Chile. [Garcia, Jose] Hosp Reg Iquique Dr Ernesto Torres Galdames, Iquique, Chile. [Meza, Rodrigo] Hosp Reg Calama, Calama, Chile. [Valdes, Rodrigo; Valdes, Gustavo] Lab Histonor, Antofagasta, Chile. [Benitez, Hugo; VanderLinde, Vania] Hosp Reg Antofagasta Dr Leonardo Guzman, Antofagasta, Chile. [Ferreccio, Catterina] Pontificia Univ Catolica Chile, Fac Med, CTR FONDAP ACCDIS, Santiago, Chile. RP Steinmaus, C (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 50 Univ Hall,MC7360, Berkeley, CA 94720 USA. EM craigs@berkeley.edu FU NIEHS NIH HHS [R01ES014032, P42 ES004705, P42 ES04705, R01 ES014032, R01 ES017463] NR 40 TC 28 Z9 29 U1 1 U2 12 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 AUG PY 2014 VL 23 IS 8 BP 1529 EP 1538 DI 10.1158/1055-9965.EPI-14-0059 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200010 PM 24859871 ER PT J AU McDonald, E Freedman, DM Alexander, BH Doody, MM Tucker, MA Linet, MS Cahoon, EK AF McDonald, Emily Freedman, D. Michal Alexander, Bruce H. Doody, Michele M. Tucker, Margaret A. Linet, Martha S. Cahoon, Elizabeth K. TI Prescription Diuretic Use and Risk of Basal Cell Carcinoma in the Nationwide US Radiologic Technologists Cohort SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NONMELANOMA SKIN-CANCER; UNITED-STATES; PHOTOSENSITIZING AGENTS; FOLLOW-UP; MANAGEMENT; DRUGS; HYPERTENSION; ULTRAVIOLET; PREVENTION; THERAPY AB Background: UV radiation (UVR) exposure is the primary risk factor for basal cell carcinoma (BCC). Although prescription diuretics have photosensitizing properties, the relationship between diuretic use and BCC remains unclear. Methods: Using data from the United States Radiologic Technologists Study, a large, nationwide prospective cohort, we assessed the relationship between diuretic use and first primary BCC while accounting for sun exposure history, constitutional characteristics, lifestyle factors, and anthropometric measurements for geographically dispersed individuals exposed to a wide range of ambient UVR. Results: After adjustment for potential confounders, we found a significantly increased risk of BCC associated with diuretic use [HR, 1.22; 95% confidence interval (CI), 1.07-1.38]. This relationship was modified by body mass index (P = 0.019), such that BCC risk was increased with diuretic use in overweight (HR, 1.43; 95% CI, 1.16-1.76) and obese individuals (HR, 1.43; 95% CI, 1.09-1.88), but not in normal weight individuals (HR, 0.99; 95% CI, 0.81-1.21). Conclusions: Increased risk of BCC associated with diuretic use in overweight and obese participants may be related to higher dosages, longer duration of medication use, reduced drug metabolism, or drug interactions. Impact: Future cohort studies should obtain more detailed information on medication use, consider factors that affect drug metabolism, and measure intermediate endpoints such as photosensitivity reactions. (C) 2014 AACR. C1 [McDonald, Emily] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. [McDonald, Emily; Freedman, D. Michal; Doody, Michele M.; Tucker, Margaret A.; Linet, Martha S.; Cahoon, Elizabeth K.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP McDonald, E (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM ecmcdona@indiana.edu RI Tucker, Margaret/B-4297-2015 FU Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. NR 27 TC 4 Z9 4 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2014 VL 23 IS 8 BP 1539 EP 1545 DI 10.1158/1055-9965.EPI-14-0251 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200011 PM 24812037 ER PT J AU Yu, MD Feuer, EJ Cronin, KA Caporaso, NE AF Yu, Mandi Feuer, Eric J. Cronin, Kathleen A. Caporaso, Neil E. TI Use of Multiple Imputation to Correct for Bias in Lung Cancer Incidence Trends by Histologic Subtype SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; MISSING-DATA; THERAPY; ADENOCARCINOMA; CLASSIFICATION; POPULATION; REGRESSION; MUTATIONS; GEFITINIB; CARCINOMA AB Background: Over the past several decades, advances in lung cancer research and practice have led to refinements of histologic diagnosis of lung cancer. The differential use and subsequent alterations of nonspecific morphology codes, however, may have caused artifactual fluctuations in the incidence rates for histologic subtypes, thus biasing temporal trends. Methods: We developed a multiple imputation (MI) method to correct lung cancer incidence for nonspecific histology using data from the Surveillance, Epidemiology, and End Results Program during 1975 to 2010. Results: For adenocarcinoma in men and squamous in both genders, the change to an increasing trend around 2005, after more than 10 years of decreasing incidence, is apparently an artifact of the changes in histopathology practice and coding system. After imputation, the rates remained decreasing for adenocarcinoma and squamous in men, and became constant for squamous in women. Conclusions: As molecular features of distinct histologies are increasingly identified by new technologies, accurate histologic distinctions are becoming increasingly relevant to more effective "targeted" therapies, and therefore, are important to track in patients. However, without incorporating the coding changes, the incidence trends estimated for histologic subtypes could be misleading. Impact: The MI approach provides a valuable tool for bridging the different histology definitions, thus permitting meaningful inferences about the long-term trends of lung cancer by histologic subtype. (C) 2014 AACR. C1 [Yu, Mandi; Feuer, Eric J.; Cronin, Kathleen A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Yu, MD (reprint author), NCI, Div Canc Control & Populat Sci, 9606 Med Ctr Dr,Room 4E560, Rockville, MD 20850 USA. EM yum3@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 4 Z9 4 U1 0 U2 3 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 AUG PY 2014 VL 23 IS 8 BP 1546 EP 1558 DI 10.1158/1055-9965.EPI-14-0130 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200012 PM 24855099 ER PT J AU Li, WQ Hu, N Burton, VH Yang, HH Su, H Conway, CM Wang, LM Wang, CY Ding, T Xu, Y Giffen, C Abnet, CC Goldstein, AM Hewitt, SM Taylor, PR AF Li, Wen-Qing Hu, Nan Burton, Victoria H. Yang, Howard H. Su, Hua Conway, Catherine M. Wang, Lemin Wang, Chaoyu Ding, Ti Xu, Yi Giffen, Carol Abnet, Christian C. Goldstein, Alisa M. Hewitt, Stephen M. Taylor, Philip R. TI PLCE1 mRNA and Protein Expression and Survival of Patients with Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PHOSPHOLIPASE-C-EPSILON; GENOME-WIDE ASSOCIATION; IDENTIFIES SUSCEPTIBILITY LOCI; CRUCIAL ROLE; CANCER; RISK; VARIANTS; CHINA; OVEREXPRESSION; INFLAMMATION AB Background: Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival. Methods: PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n = 132), gastric cardia adenocarcinoma (GCA, n = 62), and gastric noncardia adenocarcinoma (GNCA, n = 72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n = 303), and tumors of GCA (n = 298) and GNCA (n = 124). Results: Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P = 0.03, probe_205112_at), as well as in GCA and GNCA tumors (P < 0.0001, each probe). Protein expression was nonsignificantly reduced in ESCC tumors (P = 0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs. lowest quartile; P-trend = 0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; P-trend = 0.04), but not for GNCA cases (P = 0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; P-trend = 0.04). Conclusions: Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression seems to be associated with cancer prognosis. Impact: Apotential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation. (C) 2014 AACR. C1 [Li, Wen-Qing; Hu, Nan; Burton, Victoria H.; Su, Hua; Wang, Lemin; Wang, Chaoyu; Abnet, Christian C.; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Conway, Catherine M.; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Yang, Howard H.] NCI, Off Director, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. [Ding, Ti; Xu, Yi] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. RP Taylor, PR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E444, Rockville, MD 20890 USA. EM ptaylor@mail.nih.gov RI Li, Wenqing/N-2293-2014; Abnet, Christian/C-4111-2015; OI Li, Wenqing/0000-0002-1283-4091; Abnet, Christian/0000-0002-3008-7843; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the NIH, National Cancer Institute, the Division of Cancer Epidemiology and Genetics; Center for Cancer Research FX This analysis was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, the Division of Cancer Epidemiology and Genetics (to W.-Q. Li, N. Hu, V.H. Burton, H. Su, L. Wang, C. Wang, C. C. Abnet, A. M. Goldstein, and P.R. Taylor), and the Center for Cancer Research (to H.H. Yang, C.M. Conway, and S.M. Hewitt). NR 36 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2014 VL 23 IS 8 BP 1579 EP 1588 DI 10.1158/1055-9965.EPI-13-1329 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200015 PM 24867265 ER PT J AU Black, A Gibson, TM Shiels, MS Park, Y Robien, K Albanes, D Weinstein, SJ Freeman, LEB Andreotti, G Purdue, MP Fraumeni, JF Hartge, P Tucker, MA Hoover, RN Cerhan, JR Zeleniuch-Jacquotte, A Curtis, RE Elena, J Sampson, JN de Gonzalez, AB Morton, LM AF Black, Amanda Gibson, Todd M. Shiels, Meredith S. Park, Yikyung Robien, Kim Albanes, Demetrius Weinstein, Stephanie J. Freeman, Laura E. Beane Andreotti, Gabriella Purdue, Mark P. Fraumeni, Joseph F. Hartge, Patricia Tucker, Margaret A. Hoover, Robert N. Cerhan, James R. Zeleniuch-Jacquotte, Anne Curtis, Rochelle E. Elena, Joanne Sampson, Joshua N. de Gonzalez, Amy Berrington Morton, Lindsay M. TI Pooling Prospective Studies to Investigate the Etiology of Second Cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NON-HODGKINS-LYMPHOMA; PHASE-III TRIAL; BREAST-CANCER; SCREENING TRIAL; PRIMARY TUMORS; LUNG-CANCER; STAGE-I; RADIOTHERAPY; RISK; CHEMOTHERAPY AB Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology. Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements. Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (>= 80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers. Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues-some of which are barriers to specific research questions-that require special attention. Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. (C) 2014 AACR. C1 [Black, Amanda; Gibson, Todd M.; Shiels, Meredith S.; Park, Yikyung; Albanes, Demetrius; Weinstein, Stephanie J.; Freeman, Laura E. Beane; Andreotti, Gabriella; Purdue, Mark P.; Fraumeni, Joseph F.; Hartge, Patricia; Tucker, Margaret A.; Hoover, Robert N.; Curtis, Rochelle E.; Sampson, Joshua N.; de Gonzalez, Amy Berrington; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Elena, Joanne] NCI, Div Canc Control & Populat Sci, NIH, US Dept HHS, Rockville, MD USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. [Cerhan, James R.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. RP Morton, LM (reprint author), NCI, 9609 Med Ctr Dr,Room 7E-454,MSC 9778, Bethesda, MD 20892 USA. EM mortonli@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Morton, Lindsay/B-5234-2015; Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016; OI Morton, Lindsay/0000-0001-9767-2310; Purdue, Mark/0000-0003-1177-3108; Cerhan, James/0000-0002-7482-178X; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Park, Yikyung/0000-0002-6281-489X FU Intramural Program of the NCI, NIH; U.S. Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; NCI, Department of Health and Human Services; National Institute of Environmental Health Sciences [Z01-ES049030]; National Cancer Institute [Z01-CP010119]; NCI [RO1-CA39742] FX This research was supported by the Intramural Program of the NCI, NIH. In addition, the ATBC study was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C and from the NCI, Department of Health and Human Services, the AHS study also was supported (in part) by the National Institute of Environmental Health Sciences (Z01-ES049030) and National Cancer Institute (Z01-CP010119), and the IWHS was supported by a grant RO1-CA39742 from the NCI (D. Lazovich, principal investigator). NR 33 TC 2 Z9 2 U1 0 U2 3 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 AUG PY 2014 VL 23 IS 8 BP 1598 EP 1608 DI 10.1158/1055-9965.EPI-14-0191 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200017 PM 24832874 ER PT J AU Jung, S Qian, ZR Yamauchi, M Bertrand, KA Fitzgerald, KC Inamura, K Kim, SA Mima, K Sukawa, Y Zhang, XH Wang, ML Smith-Warner, SA Wu, KN Fuchs, CS Chan, AT Giovannucci, EL Ng, K Cho, E Ogino, S Nishihara, R AF Jung, Seungyoun Qian, Zhi Rong Yamauchi, Mai Bertrand, Kimberly A. Fitzgerald, Kathryn C. Inamura, Kentaro Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Zhang, Xuehong Wang, Molin Smith-Warner, Stephanie A. Wu, Kana Fuchs, Charles S. Chan, Andrew T. Giovannucci, Edward L. Ng, Kimmie Cho, Eunyoung Ogino, Shuji Nishihara, Reiko TI Predicted 25(OH)D Score and Colorectal Cancer Risk According to Vitamin D Receptor Expression SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; FOOD FREQUENCY QUESTIONNAIRE; MEDIATED ACTIVATION; SIGNALING PATHWAYS; PIK3CA MUTATION; KRAS MUTATIONS; COLON-CANCER; ASSOCIATIONS; DISEASE; MODELS AB Background: Despite accumulating evidence for the preventive effect of vitamin D on colorectal carcinogenesis, its precise mechanisms remain unclear. We hypothesized that vitamin D was associated with a lower risk of colorectal cancer with high-level vitamin D receptor (VDR) expression, but not with risk of tumor with low-level VDR expression. Methods: Among 140,418 participants followed from 1986 through 2008 in the Nurses' Health Study and the Health Professionals' Follow-up Study, we identified 1,059 incident colorectal cancer cases with tumor molecular data. The predicted 25-hydroxyvitamin D [25(OH)D] score was developed using the known determinants of plasma 25(OH)D. We estimated the HR for cancer subtypes using the duplication method Cox proportional hazards model. Results: Ahigher predicted 25(OH)D score was associated with a lower risk of colorectal cancer irrespective of VDR expression level (P-heterogeneity for subtypes = 0.75). Multivariate HRs (95% confidence intervals) comparing the highest with the lowest quintile of predicted 25(OH)D scores were 0.48 (0.30-0.78) for VDR-negative tumor and 0.56 (0.42-0.75) for VDR-positive tumor. Similarly, the significant inverse associations of the predicted 25(OH)D score with colorectal cancer risk did not significantly differ by KRAS, BRAF, or PIK3CA status (P-heterogeneity for subtypes >= 0.22). Conclusions: Ahigher predicted vitamin Dscore was significantly associated with a lower colorectal cancer risk, regardless of VDR status and other molecular features examined. Impact: The preventive effect of vitamin D on colorectal carcinogenesis may not totally depend on tumor factors. Host factors (such as local and systemic immunity) may need to be considered. (C) 2014 AACR. C1 [Jung, Seungyoun; Bertrand, Kimberly A.; Zhang, Xuehong; Fuchs, Charles S.; Chan, Andrew T.; Giovannucci, Edward L.; Cho, Eunyoung] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Qian, Zhi Rong; Yamauchi, Mai; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Fuchs, Charles S.; Ng, Kimmie; Ogino, Shuji; Nishihara, Reiko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fitzgerald, Kathryn C.; Wang, Molin; Smith-Warner, Stephanie A.; Giovannucci, Edward L.; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wang, Molin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Smith-Warner, Stephanie A.; Wu, Kana; Giovannucci, Edward L.; Nishihara, Reiko] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Inamura, Kentaro] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. RP Nishihara, R (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,Room 304, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu; rnishiha@hsph.harvard.edu FU NIH [P01 CA87969, P01 CA55075, UM1 CA167552, P50 CA127003, R01 CA137178, R01 CA151993, R01 CA136950, R25 CA098566, K07 CA148894]; American Society of Clinical Oncology (ASCO) Conquer Cancer Foundation; Bennett Family Fund; Asan Medical Center; Japan Society for Promotion of Sciences; Takashi Tsuruo Memorial Fund; Uehara Memorial Foundation; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance FX This work was supported by NIH grants (P01 CA87969 to S.E. Hankinson; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S. Fuchs; R01 CA137178 to A.T. Chan; R01 CA151993 to S. Ogino; R01 CA136950 to E. Cho; R25 CA098566 to M.J. Stampfer, and K07 CA148894 to K. Ng), by grants from the American Society of Clinical Oncology (ASCO) Conquer Cancer Foundation (Career Development Award to K. Ng), Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and by postdoctoral fellowships from Asan Medical Center (to S.A. Kim), Japan Society for Promotion of Sciences (to K. Inamura), Takashi Tsuruo Memorial Fund (to K. Inamura), and the Uehara Memorial Foundation (to K. Mima). NR 58 TC 7 Z9 7 U1 0 U2 3 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 AUG PY 2014 VL 23 IS 8 BP 1628 EP 1637 DI 10.1158/1055-9965.EPI-14-0229 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200020 PM 24920642 ER PT J AU Gritz, ER Arnold, KB Moinpour, CM Burton-Chase, AM Tangen, CM Probstfield, JF See, WA Lieber, MM Caggiano, V Moody-Thomas, S Szczepanek, C Ryan, A Carlin, S Hill, S Goodman, PJ Padberg, RM Minasian, LM Meyskens, FL Thompson, IM AF Gritz, Ellen R. Arnold, Kathryn B. Moinpour, Carol M. Burton-Chase, Allison M. Tangen, Catherine M. Probstfield, Jeffrey F. See, William A. Lieber, Michael M. Caggiano, Vincent Moody-Thomas, Sarah Szczepanek, Connie Ryan, Anne Carlin, Susie Hill, Shannon Goodman, Phyllis J. Padberg, Rose Mary Minasian, Lori M. Meyskens, Frank L. Thompson, Ian M., Jr. TI Factors Associated with Adherence to an End-of-Study Biopsy: Lessons from the Prostate Cancer Prevention Trial (SWOG-Coordinated Intergroup Study S9217) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEALTH SURVEY SF-36; SCREENING TRIAL; QUALITY; PROGRAM; TESTS; RISK; LIFE; LUNG AB Background: The Prostate Cancer Prevention Trial (PCPT) was a 7-year randomized, double-blind, placebo-controlled trial of the efficacy of finasteride for the prevention of prostate cancer with a primary outcome of histologically determined prevalence of prostate cancer at the end of 7 years. Methods: A systematic modeling process using logistic regression identified factors available at year 6 that are associated with end-of-study (EOS) biopsy adherence at year 7, stratified by whether participants were ever prompted for a prostate biopsy by year 6. Final models were evaluated for discrimination. At year 6, 13,590-men were available for analysis. Results: Participants were more likely to have the EOS biopsy if they were adherent to study visit schedules and procedures and/or were in good health (P < 0.01). Participants at larger sites and/or sites that received retention and adherence grants were also more likely to have the EOS biopsy (P < 0.05). Conclusions: Our results show good adherence to study requirements 1 year before the EOS biopsy was associated with greater odds that a participant would comply with the invasive EOS requirement. Impact: Monitoring adherence behaviors may identify participants at risk of nonadherence to more demanding study end points. Such information could help frame adherence intervention strategies in future trials. (C) 2014 AACR. C1 [Gritz, Ellen R.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Arnold, Kathryn B.; Tangen, Catherine M.; Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Carlin, Susie] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Probstfield, Jeffrey F.] C3 Res Associates, Seattle, WA USA. [Hill, Shannon] Univ Washington, Dept Med, Kirkland, WA USA. [Burton-Chase, Allison M.] Albany Coll Pharm & Hlth Sci, Dept Basic & Social Sci, Albany, NY 12208 USA. [See, William A.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Div Urol, Milwaukee, WI 53226 USA. [Lieber, Michael M.] Mayo Clin, Dept Urol, Rochester, MN USA. [Caggiano, Vincent] Sutter Inst Med Res, Sacramento, CA USA. [Meyskens, Frank L.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA. [Moody-Thomas, Sarah] Louisiana State Univ, Sch Publ Hlth, Hlth Sci Ctr, New Orleans, LA USA. [Szczepanek, Connie] Grand Rapids Clin Oncol Program, Grand Rapids, MI USA. [Ryan, Anne; Minasian, Lori M.] NCI, Canc Prevent Div, Rockville, MD USA. [Padberg, Rose Mary] Arlington Free Clin, Arlington, VA USA. RP Burton-Chase, AM (reprint author), Albany Coll Pharm & Hlth Sci, Dept Basic & Social Sci, 106 New Scotland Ave, Albany, NY 12208 USA. EM allison.burton-chase@acphs.edu RI Burton-Chase, Allison/A-6878-2017 OI Burton-Chase, Allison/0000-0002-5141-6095 FU Public Health Service from the Department of Cancer Prevention, National Cancer Institute, NIH, Department of Health and Human Services (Bethesda, MD) [CA37429]; National Cancer Institute (NCI), Division of Cancer Prevention (DCP); National Cancer Institute [P30CA16672] FX This research was supported by Public Health Service grant number CA37429 (C.D. Blanke; C.A. Coltman) from the Department of Cancer Prevention, National Cancer Institute, NIH, Department of Health and Human Services (Bethesda, MD). The study agents (finasteride and placebo) were provided by Merck, Inc. Merck, Inc. and the National Cancer Institute (NCI), Division of Cancer Prevention (DCP), also provided funding to produce videos and to support projects to enhance trial recruitment and adherence. E. Gritz was supported in part by funding from the National Cancer Institute and P30CA16672 (to R.A. DePinho). NR 25 TC 3 Z9 3 U1 0 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 AUG PY 2014 VL 23 IS 8 BP 1638 EP 1648 DI 10.1158/1055-9965.EPI-14-0202 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200021 PM 25028457 ER PT J AU Galassi, AL Grady, MA O'Mara, AM Ness, EA Parreco, LK Belcher, AE Hastings, CE AF Galassi, Annette L. Grady, Meredith A. O'Mara, Ann M. Ness, Elizabeth A. Parreco, Linda K. Belcher, Anne E. Hastings, Clare E. TI Clinical Research Education: Perspectives of Nurses, Employers, and Educators SO JOURNAL OF NURSING EDUCATION LA English DT Article ID UNDERGRADUATE RESEARCH; STUDENTS; INSTITUTE; SCIENCE AB The aim of this study was to understand the current environment around clinical research relating to nursing education and practice. This descriptive study analyzed data from 33 in-depth interviews with faculty members, nurse executives, staff development directors, and practicing nurses, as well as an online interactive brainstorming session with 28 deans of schools of nursing (or their designee). Patterns and themes that emerged within each group were identified and analyzed in relation to study objectives. Central themes emerged around participants' knowledge and attitudes about clinical research education for baccalaureate nursing students, factors enhancing or inhibiting inclusion of clinical research content in baccalaureate nursing programs, and professional roles nursing students could expect to assume after graduation. Although the participants agreed that mastery of clinical research knowledge and related skills is important, there was no agreement whether nurses should receive this education and training in baccalaureate programs or in staff development. C1 [Galassi, Annette L.; Grady, Meredith A.; O'Mara, Ann M.; Ness, Elizabeth A.; Parreco, Linda K.] NCI, Rockville, MD 20850 USA. [Hastings, Clare E.] NIH, Dept Nursing, Ctr Clin, Bethesda, MD 20892 USA. [Belcher, Anne E.] Johns Hopkins Univ, Sch Nursing, Off Teaching Excellence, Baltimore, MD USA. RP Galassi, AL (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 3W250, Rockville, MD 20850 USA. EM agalassi@mail.nih.gov NR 28 TC 1 Z9 1 U1 1 U2 4 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0148-4834 EI 1938-2421 J9 J NURS EDUC JI J. Nurs. Educ. PD AUG PY 2014 VL 53 IS 8 BP 466 EP 472 DI 10.3928/01484834-20140724-04 PG 7 WC Nursing SC Nursing GA AT9RD UT WOS:000345263000007 PM 25050563 ER PT J AU Kalyani, RR Tra, Y Egan, JM Ferrucci, L Brancati, F AF Kalyani, Rita R. Tra, Y. Egan, J. M. Ferrucci, L. Brancati, F. TI HYPERGLYCEMIA IS ASSOCIATED WITH RELATIVELY LOWER LEAN BODY MASS IN OLDER ADULTS SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Hyperglycemia; muscle function; elderly; diabetes ID NUTRITION EXAMINATION SURVEY; SKELETAL-MUSCLE MASS; NATIONAL-HEALTH; INSULIN-RESISTANCE; DIABETES-MELLITUS; STRENGTH; MEN; NEUROPATHY; DISABILITY; MORTALITY AB Background/Objectives: Older adults with known diabetes are vulnerable to accelerated loss of lean body mass. However, the relationship of hyperglycemia per se with lean body mass is not fully understood. We sought to examine the independent relationship of hyperglycemia with relative lean body mass in older persons without a reported history of diabetes. Design: cross-sectional nationally representative survey. Setting: united States. Participants: We studied U.S. adults >50 years without known diabetes (n=5434) in the national Health and nutrition Examination Survey (1999-2004). Measurements: in linear regression models, we studied the relationship of measured HbA1c (<5.0%, 5.0-5.4%, 5.5-5.9%, 6.0-6.4%, >= 6.5%) with percent lean body mass, measured by dual-energy x-ray absorptiometry, after accounting for potential confounders. Results: among older U.S. men and women, progressively higher HbA1c was associated with relatively lower total, appendicular, and trunk percent lean mass, independent of demographics and height (all p<0.05). accounting for physical activity, c-reactive protein, and diabetes-related comorbidities (heart disease, peripheral arterial disease, arthritis, neuropathy, hip fracture, amputation, cancer, pulmonary disease), undiagnosed diabetes (i.e. HbA1c >= 6.5%) versus reference (<5.0%) in both men and women was associated with lower total (-3.5 +/- 0.8% and -2.9 +/- 0.8%), appendicular (-1.8 +/- 0.5% and -1.2 +/- 0.4%), and trunk percent lean mass (-1.2 +/- 0.4% and -1.3 +/- 0.5%), respectively (all p<0.05). Persons at increased risk for diabetes (i.e. HbA1c 6.0-6.4%) also had significant decrements at these sites versus reference. Conclusions: Hyperglycemia is associated with relatively lower lean mass in a nationally representative population of older adults without history of diabetes. Future longitudinal studies are needed to investigate the relationship of hyperglycemia with the accelerated decline of skeletal muscle mass in older persons. C1 [Kalyani, Rita R.; Brancati, F.] Johns Hopkins Univ, Dept Med, Div Endocrinol Diabet & Metab, Baltimore, MD 21287 USA. [Tra, Y.] Univ Maryland, Sch Pharm, Maryland Poison Ctr, Baltimore, MD 21201 USA. [Egan, J. M.; Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Brancati, F.] Johns Hopkins Univ, Dept Med, Div Gen Internal Med, Baltimore, MD 21287 USA. RP Kalyani, RR (reprint author), Johns Hopkins Univ, Sch Med, Div Endocrinol Diabet & Metab, Dept Med, 1830 East Monument St,Suite 333, Baltimore, MD 21287 USA. EM rrastogi@jhmi.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK093583, K24-DK062222, P60-DK079637]; Johns Hopkins Older Americans Independence Center [P30-AG021334]; National Institute on Aging FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23-DK093583, K24-DK062222, P60-DK079637), the Johns Hopkins Older Americans Independence Center (P30-AG021334), and the intramural research program of the National Institute on Aging. NR 27 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 EI 1760-4788 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD AUG PY 2014 VL 18 IS 8 BP 737 EP 743 PG 7 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA AU0AL UT WOS:000345285400003 PM 25286453 ER PT J AU Boyce, RD Ryan, PB Noren, GN Schuemie, MJ Reich, C Duke, J Tatonetti, NP Trifiro, G Harpaz, R Overhage, JM Hartzema, AG Khayter, M Voss, EA Lambert, CG Huser, V Dumontier, M AF Boyce, Richard D. Ryan, Patrick B. Noren, G. Niklas Schuemie, Martijn J. Reich, Christian Duke, Jon Tatonetti, Nicholas P. Trifiro, Gianluca Harpaz, Rave Overhage, J. Marc Hartzema, Abraham G. Khayter, Mark Voss, Erica A. Lambert, Christophe G. Huser, Vojtech Dumontier, Michel TI Bridging Islands of Information to Establish an Integrated Knowledge Base of Drugs and Health Outcomes of Interest SO DRUG SAFETY LA English DT Article ID ALGORITHM; DATABASE; EVENTS; IDENTIFICATION; PROBABILITY; VALIDATION; CAUSALITY; ONTOLOGY; DISEASE AB The entire drug safety enterprise has a need to search, retrieve, evaluate, and synthesize scientific evidence more efficiently. This discovery and synthesis process would be greatly accelerated through access to a common framework that brings all relevant information sources together within a standardized structure. This presents an opportunity to establish an open-source community effort to develop a global knowledge base, one that brings together and standardizes all available information for all drugs and all health outcomes of interest (HOIs) from all electronic sources pertinent to drug safety. To make this vision a reality, we have established a workgroup within the Observational Health Data Sciences and Informatics (OHDSI, http://ohdsi.org) collaborative. The workgroup's mission is to develop an open-source standardized knowledge base for the effects of medical products and an efficient procedure for maintaining and expanding it. The knowledge base will make it simpler for practitioners to access, retrieve, and synthesize evidence so that they can reach a rigorous and accurate assessment of causal relationships between a given drug and HOI. Development of the knowledge base will proceed with the measureable goal of supporting an efficient and thorough evidence-based assessment of the effects of 1,000 active ingredients across 100 HOIs. This non-trivial task will result in a high-quality and generally applicable drug safety knowledge base. It will also yield a reference standard of drug-HOI pairs that will enable more advanced methodological research that empirically evaluates the performance of drug safety analysis methods. C1 [Boyce, Richard D.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Ryan, Patrick B.; Schuemie, Martijn J.; Voss, Erica A.] Janssen Res & Dev, Titusville, NJ USA. [Noren, G. Niklas] Uppsala Monitoring Ctr, Uppsala, Sweden. [Reich, Christian] AstraZeneca, Waltham, MA USA. [Duke, Jon] Regenstrief Inst Hlth Care, Indianapolis, IN USA. [Tatonetti, Nicholas P.] Columbia Univ, New York, NY USA. [Trifiro, Gianluca] Univ Messina, Messina, Italy. [Trifiro, Gianluca] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Harpaz, Rave] Stanford Univ, Palo Alto, CA 94304 USA. [Overhage, J. Marc] Siemens Healthcare, Malvern, PA USA. [Hartzema, Abraham G.] Univ Florida, Gainesville, FL USA. [Khayter, Mark] Ephir, Boston, MA USA. [Lambert, Christophe G.] Montana State Univ, Bozeman, MT 59717 USA. [Huser, Vojtech] NIH, Bethesda, MD 20892 USA. [Dumontier, Michel] Stanford Univ, Stanford, CA 94305 USA. RP Boyce, RD (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM rdb20@pitt.edu RI Trifiro, Gianluca/K-9744-2016; OI Trifiro, Gianluca/0000-0003-1147-7296; Overhage, Joseph/0000-0003-0223-0195; Tatonetti, Nicholas/0000-0002-2700-2597 FU National Institute on Aging [K01AG044433]; National Library of Medicine [1R01LM011838-01]; National Institutes of Health Clinical Center; Pfizer; Merck; Janssen; Lilly FX First author (Richard Boyce) is funded by National Institute on Aging grant K01AG044433 and National Library of Medicine grant 1R01LM011838-01. Vojtech Huser is supported by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Library of Medicine.; Patrick Ryan, Martijn Schuemie, and Erica Voss are employees of Janssen Research and Development. Christian Reich is an employee of AstraZeneca. Abraham Hartzema received funding from Pfizer, although not for this project; he is also a paid senior consultant to the FDA CDRH; the content in this manuscript reflects his own opinion and not that of the FDA. Rave Harpaz is an employee of Oracle. Jon Duke has received research funding from pharmaceutical industry sources, including Merck, Janssen and Lilly. NR 46 TC 15 Z9 16 U1 1 U2 8 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD AUG PY 2014 VL 37 IS 8 BP 557 EP 567 DI 10.1007/s40264-014-0189-0 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA AT0GI UT WOS:000344614700001 PM 24985530 ER PT J AU Boufraqech, M Zhang, L Jain, M Patel, D Ellis, R Xiong, Y He, M Nilubol, N Merino, MJ Kebebew, E AF Boufraqech, Myriem Zhang, Lisa Jain, Meenu Patel, Dhaval Ellis, Ryan Xiong, Yin He, Mei Nilubol, Naris Merino, Maria J. Kebebew, Electron TI miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3 SO ENDOCRINE-RELATED CANCER LA English DT Article DE miR-145; thyroid cancer; AKT3; metastasis; biomarker ID EPITHELIAL-MESENCHYMAL TRANSITION; COLORECTAL-CANCER; C-MYC; MICRORNAS; CELLS; EXPRESSION; CARCINOMA; SURVIVAL; PATHWAY; TUMORS AB The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis. C1 [Boufraqech, Myriem; Zhang, Lisa; Jain, Meenu; Patel, Dhaval; Ellis, Ryan; Xiong, Yin; He, Mei; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016; OI Patel, Dhaval/0000-0002-5744-568X FU intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 47 TC 23 Z9 24 U1 2 U2 8 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD AUG PY 2014 VL 21 IS 4 BP 517 EP 531 DI 10.1530/ERC-14-0077 PG 15 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA AT2TE UT WOS:000344788200020 PM 24781864 ER PT J AU Haller, F Moskalev, EA Faucz, FR Barthelmess, S Wiemann, S Bieg, M Assie, G Bertherat, J Schaefer, IM Otto, C Rattenberry, E Maher, ER Stroebel, P Werner, M Carney, JA Hartmann, A Stratakis, CA Agaimy, A AF Haller, Florian Moskalev, Evgeny A. Faucz, Fabio R. Barthelmess, Sarah Wiemann, Stefan Bieg, Matthias Assie, Guillaume Bertherat, Jerome Schaefer, Inga-Marie Otto, Claudia Rattenberry, Eleanor Maher, Eamonn R. Stroebel, Philipp Werner, Martin Carney, J. Aidan Hartmann, Arndt Stratakis, Constantine A. Agaimy, Abbas TI Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad SO ENDOCRINE-RELATED CANCER LA English DT Article DE Carney triad; SDH complex; SDHC; GIST; paraganglioma ID GASTROINTESTINAL STROMAL TUMORS; GERMLINE MUTATIONS; FAMILIAL PARAGANGLIOMA; MOLECULAR-GENETICS; STRATAKIS-SYNDROME; PHEOCHROMOCYTOMAS; GENES; METHYLATION AB Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism tumorigenesis in CT. C1 [Haller, Florian; Moskalev, Evgeny A.; Barthelmess, Sarah; Hartmann, Arndt; Agaimy, Abbas] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Pathol, D-91054 Erlangen, Germany. [Faucz, Fabio R.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Wiemann, Stefan] German Canc Res Ctr, Div Mol Genome Anal, Heidelberg, Germany. [Bieg, Matthias] German Canc Res Ctr, Div Theoret Bioinformat, Heidelberg, Germany. [Assie, Guillaume; Bertherat, Jerome] Univ Paris 05, Sorbonne Paris Cite, CNRS UMR 8104, Inst Cochin,INSERM U1016, Paris, France. [Assie, Guillaume; Bertherat, Jerome] Hop Cochin, AP HP, Referal Ctr Rare Adrenal Dis, Dept Endocrinol, Paris, France. [Schaefer, Inga-Marie; Stroebel, Philipp] Univ Gottingen, Univ Med Ctr, Inst Pathol, D-37073 Gottingen, Germany. [Otto, Claudia; Werner, Martin] Univ Freiburg, Univ Hosp, Inst Pathol, D-79106 Freiburg, Germany. [Maher, Eamonn R.] Birmingham Womens Hosp, Univ Birmingham, Ctr Rare Dis & Personalised Med, Sch Clin & Expt Med,Coll Med & Dent Sci, Birmingham, W Midlands, England. [Maher, Eamonn R.] Birmingham Womens Hosp, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Maher, Eamonn R.] Univ Cambridge, Dept Med Genet, Cambridge CB2 0QQ, England. [Carney, J. Aidan] Mayo Clin, Emeritus Staff, Lab Med & Pathol, Rochester, MN USA. RP Haller, F (reprint author), Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Pathol, Krankenhausstr 8-10, D-91054 Erlangen, Germany. EM florian.haller@uk-erlangen.de; stratakc@cc1.nichd.nih.gov RI MAHER, EAMONN/A-9507-2008; Wiemann, Stefan/E-4424-2013 OI MAHER, EAMONN/0000-0002-6226-6918; Wiemann, Stefan/0000-0003-4683-3174 FU Interdisciplinary Centre for Clinical Research (IZKF) at the University of Erlangen-Nuremberg; Mildred Scheel Stiftung fur Krebsforschung [110822] FX E A Moskalev is supported by a research grant from the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Erlangen-Nuremberg. I-M Schaefer is supported by a research grant from the Dr Mildred Scheel Stiftung fur Krebsforschung (no. 110822). NR 31 TC 41 Z9 42 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD AUG PY 2014 VL 21 IS 4 BP 567 EP 577 DI 10.1530/ERC-14-0254 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA AT2TE UT WOS:000344788200024 PM 24859990 ER PT J AU Creamer, M Bowles, HR von Hofe, B Gabriel, KP Kohl, HW Bauman, A AF Creamer, MeLisa Bowles, Heather R. von Hofe, Belinda Gabriel, Kelley Pettee Kohl, Harold W., III Bauman, Adrian TI Utility of Computer-Assisted Approaches for Population Surveillance of Physical Activity SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE motor activity; physical activity assessment; questionnaires; validity ID PUBLIC-HEALTH SURVEILLANCE; RETEST RELIABILITY; UNITED-STATES; VALIDITY; WOMEN; ACCELEROMETER; INTERVENTIONS; AGREEMENT; EDUCATION; INTERNET AB Background: Computer-assisted techniques may be a useful way to enhance physical activity surveillance and increase accuracy of reported behaviors. Purpose: Evaluate the reliability and validity of a physical activity (PA) self-report instrument administered by telephone and internet. Methods: The telephone-administered Active Australia Survey was adapted into 2 forms for internet self-administration: survey questions only (internet-text) and with videos demonstrating intensity (internet-video). Data were collected from 158 adults (20-69 years, 61% female) assigned to telephone (telephone-interview) (n = 56), internet-text (n = 51), or internet-video (n = 51). Participants wore an accelerometer and completed a logbook for 7 days. Test-retest reliability was assessed using intraclass correlation coefficients (ICC). Convergent validity was assessed using Spearman correlations. Results: Strong test-retest reliability was observed for PA variables in the internet-text (ICC = 0.69 to 0.88), internet-video (ICC = 0.66 to 0.79), and telephone-interview (ICC = 0.69 to 0.92) groups (P-values < 0.001). For total PA, correlations (rho) between the survey and Actigraph+logbook were rho = 0.47 for the internet-text group, rho = 0.57 for the internet-video group, and rho = 0.65 for the telephone-interview group. For vigorous-intensity activity, the correlations between the survey and Actigraph+logbook were 0.52 for internet-text, 0.57 for internet-video, and 0.65 for telephone-interview (P < .05). Conclusions: Internet-video of the survey had similar test-retest reliability and convergent validity when compared with the telephone-interview, and should continue to be developed. C1 [Creamer, MeLisa; Gabriel, Kelley Pettee; Kohl, Harold W., III] Univ Texas Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Austin, TX 78713 USA. [Bowles, Heather R.] NCI, Risk Factor Monitoring & Methods Branch, Washington, DC USA. [von Hofe, Belinda; Bauman, Adrian] Univ Sydney, Sch Publ Hlth, Camperdown, NSW, Australia. RP Creamer, M (reprint author), Univ Texas Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Austin, TX 78713 USA. EM melisa.r.creamer@uth.tmc.edu OI Creamer, MeLisa/0000-0002-5606-7445 NR 32 TC 0 Z9 0 U1 2 U2 3 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 EI 1543-5474 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD AUG PY 2014 VL 11 IS 6 BP 1111 EP 1119 DI 10.1123/jpah.2012-0266 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT3LL UT WOS:000344836300007 PM 23963721 ER PT J AU Brooks-Russell, A Simons-Morton, B Haynie, D Farhat, T Wang, J AF Brooks-Russell, Ashley Simons-Morton, Bruce Haynie, Denise Farhat, Tilda Wang, Jing TI Longitudinal Relationship Between Drinking with Peers, Descriptive Norms, and Adolescent Alcohol Use SO PREVENTION SCIENCE LA English DT Article DE Adolescent alcohol use; Peer influence; Mediation ID PERSONALIZED NORMATIVE FEEDBACK; SOCIAL-INFLUENCE PROCESSES; PERCEIVED NORMS; COLLEGE-STUDENTS; GENDER-DIFFERENCES; HIGH-SCHOOL; HEAVY DRINKING; SUBSTANCE USE; YOUNG-PEOPLE; FIT INDEXES AB Descriptive norms are consistently found to predict adolescent alcohol use but less is known about the factors that predict descriptive norms. The objective of this study is to test if drinking with peers predicts later alcohol consumption and if this relationship is mediated by a change in the descriptive norms of peer alcohol use. Data are from a nationally representative cohort of high school students surveyed in the 10th and 11th grade (N= 2,162). Structural equation modeling was used to test a mediation model of the relationship between drinking with peers (T1) on later alcohol use (T2) and mediation of the relationship by descriptive norms (T2). Descriptive norms significantly mediated the relationship between drinking with peers and alcohol use for both males and females with a somewhat larger effect for males compared to females. These results support a continued focus on the development and evaluation of interventions to alter descriptive norms of alcohol use. C1 [Brooks-Russell, Ashley; Simons-Morton, Bruce; Haynie, Denise; Farhat, Tilda; Wang, Jing] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Brooks-Russell, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd Room 7B13, Bethesda, MD 20892 USA. EM Ashley.Russell@nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU Intramural NIH HHS [ZIA HD002525-19]; NICHD NIH HHS [HHSN267200800009C] NR 51 TC 10 Z9 11 U1 1 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD AUG PY 2014 VL 15 IS 4 BP 497 EP 505 DI 10.1007/s11121-013-0391-9 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT3AF UT WOS:000344805500006 PM 23564529 ER PT J AU Nieratschker, V Massart, R Gilles, M Luoni, A Suderman, MJ Krumm, B Meier, S Witt, SH Nothen, MM Suomi, SJ Peus, V Scharnholz, B Dukal, H Hohmeyer, C Wolf, IAC Cirulli, F Gass, P Sutterlin, MW Filsinger, B Laucht, M Riva, MA Rietschel, M Deuschle, M Szyf, M AF Nieratschker, V. Massart, R. Gilles, M. Luoni, A. Suderman, M. J. Krumm, B. Meier, S. Witt, S. H. Noethen, M. M. Suomi, S. J. Peus, V. Scharnholz, B. Dukal, H. Hohmeyer, C. Wolf, I. A-C Cirulli, F. Gass, P. Suetterlin, M. W. Filsinger, B. Laucht, M. Riva, M. A. Rietschel, M. Deuschle, M. Szyf, M. TI MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID ADVERSE CHILDHOOD EXPERIENCES; MAJOR DEPRESSIVE DISORDER; DNA METHYLATION; EPIGENETIC REGULATION; GLUCOCORTICOID-RECEPTOR; PSYCHIATRIC-DISORDERS; MATERNAL-BEHAVIOR; BIPOLAR DISORDER; ALCOHOL EXPOSURE; GENE-EXPRESSION AB Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD. C1 [Nieratschker, V.; Meier, S.; Witt, S. H.; Dukal, H.; Hohmeyer, C.; Rietschel, M.] Heidelberg Univ, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany. [Nieratschker, V.] Univ Tubingen, Dept Psychiat & Psychotherapy, D-72076 Tubingen, Germany. [Massart, R.; Suderman, M. J.; Szyf, M.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada. [Gilles, M.; Peus, V.; Scharnholz, B.; Wolf, I. A-C; Deuschle, M.] Heidelberg Univ, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Med Fac Mannheim, Mannheim, Germany. [Luoni, A.] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Suderman, M. J.] McGill Univ, Sackler Program Epigenet & Dev Psychobiol, Montreal, PQ, Canada. [Suderman, M. J.] McGill Univ, McGill Ctr Bioinformat, Montreal, PQ, Canada. [Krumm, B.] Heidelberg Univ, Cent Inst Mental Hlth, Dept Biostat, Med Fac Mannheim, Mannheim, Germany. [Noethen, M. M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Noethen, M. M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Bethesda, MD USA. [Cirulli, F.] Ist Super Sanita, Dept Neurosci & Cell Biol, I-00161 Rome, Italy. [Gass, P.] Heidelberg Univ, Cent Inst Mental Hlth, Res Grp Anim Models Psychiat, Med Fac Mannheim,Dept Psychiat & Psychotherapy, Mannheim, Germany. [Suetterlin, M. W.] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Obstet & Gynecol, Mannheim, Germany. [Filsinger, B.] St Marien & St Annastiftskrankenhaus, Dept Obstet, Ludwigshafen, Germany. [Laucht, M.] Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Dept Child & Adolescent Psychiat & Psychotherapy, Mannheim, Germany. RP Nieratschker, V (reprint author), Univ Tubingen, Dept Psychiat & Psychotherapy, Calwerstr 14, D-72076 Tubingen, Germany. EM vanessa.nieratschker@med.uni-tuebingen.de; michael.deuschle@zi-mannheim.de RI Cirulli, Francesca/B-1581-2013; OI Luoni, Alessia/0000-0001-5174-0787; cirulli, francesca/0000-0001-9440-1873; Dukal, Helene/0000-0002-6188-807X; Riva, Marco Andrea/0000-0002-1699-5060; Nothen, Markus/0000-0002-8770-2464 FU Era-Net Neuron grant; fonds de recherche Sante Quebec (FRSQ) [24419]; National Genome Research Network (NGFNplus) of the German Federal Ministry of Education and Research (BMBF) [01GS08144, 01GS08147]; Fondazione CARIPLO [2012-0503]; Dietmar-Hopp Foundation; Olympia-Morata-Programme of the University of Heidelberg; Boehringer-Ingelheim Fonds; Division of Intramural Research, NICHD, HIH FX This work was supported by an Era-Net Neuron grant to MD, MR, MAR, ML, FC, PG and MS, fonds de recherche Sante Quebec (FRSQ) 24419 to MS, by grants 01GS08144 (MMN) and 01GS08147 (MR) from the National Genome Research Network (NGFNplus) of the German Federal Ministry of Education and Research (BMBF) and from Fondazione CARIPLO-grant no. 2012-0503 to MAR and FC. MD, MR and ML received support from the Dietmar-Hopp Foundation. VN received support from the Olympia-Morata-Programme of the University of Heidelberg and the Boehringer-Ingelheim Fonds. SJS was supported by funds from the Division of Intramural Research, NICHD, HIH. We thank Christine Schmel for critical reading of the manuscript and gratefully acknowledge Alessandra Berry, Veronica Bellisario and Sara Capoccia for their precious help with the rat prenatal stress model. We are very grateful for the essential contributions of the midwives, and would like to thank all families for their participation. NR 65 TC 19 Z9 19 U1 1 U2 13 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 PY 2014 VL 4 AR e429 DI 10.1038/tp.2014.75 PG 8 WC Psychiatry SC Psychiatry GA AT3HR UT WOS:000344826900010 PM 25158004 ER PT J AU Lin, FC Young, HA AF Lin, Fan-ching Young, Howard A. TI Interferons: Success in anti-viral immunotherapy SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Antiviral therapy; IFN-alpha/beta; IFN-gamma; IFN-lambda ID CHRONIC HEPATITIS-C; RENAL-CELL CARCINOMA; CHRONIC MYELOID-LEUKEMIA; RANDOMIZED CONTROLLED-TRIAL; PHASE-II TRIAL; PEGYLATED INTERFERON; VIRUS-INFECTION; IFN-ALPHA; FUSION PROTEIN; GENOTYPE 1 AB The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered as "standard of care" in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lin, Fan-ching; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc, Frederick, MD 21702 USA. RP Lin, FC (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc, Frederick, MD 21702 USA. EM fanching.lin@nih.gov; younghow@mail.nih.gov NR 69 TC 25 Z9 29 U1 4 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG PY 2014 VL 25 IS 4 BP 369 EP 376 DI 10.1016/j.cytogfr.2014.07.015 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AR8RL UT WOS:000343842100003 PM 25156421 ER PT J AU Tu, E Chia, PZC Chen, WJ AF Tu, Eric Chia, Pei Zhi Cheryl Chen, Wanjun TI TGF beta in T cell biology and tumor immunity: Angel or devil? SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review ID GROWTH-FACTOR-BETA; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; IMMUNOLOGICAL SELF-TOLERANCE; NATURAL-KILLER-CELLS; DENDRITIC CELLS; SUPPRESSOR-CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; REGULATORY-CELLS; RETINOIC-ACID; IN-VIVO AB The evolutionally conserved transforming growth factor beta (TGF beta) affects multiple cell types in the immune system by either stimulating or inhibiting their differentiation and function. Studies using transgenic mice with ablation of TGF beta or its receptor have revealed the biological significance of TGF beta signaling in the control of T cells. However, it is now clear that TGF beta is more than an immunosuppressive cytokine. Disruption of TGF beta signaling pathway also leads to impaired generation of certain T cell populations. Therefore, in the normal physiological state, TGF beta actively maintains T cell homeostasis and regulates T cell function. However, in the tumor microenvironment, TGF beta creates an immunosuppressive milieu that inhibits antitumor immunity. Here, we review recent advances in our understanding of the roles of TGF beta in the regulation of T cells and tumor immunity. Published by Elsevier Ltd. C1 [Tu, Eric; Chia, Pei Zhi Cheryl; Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, OPCB, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, OPCB, NIH, Bethesda, MD 20892 USA. EM wchen@mail.nih.gov FU NIH, NIDCR FX This work was supported by the Intramural Research Program of the NIH, NIDCR. NR 216 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG PY 2014 VL 25 IS 4 BP 423 EP 435 DI 10.1016/j.cytogfr.2014.07.014 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AR8RL UT WOS:000343842100008 PM 25156420 ER PT J AU Poirier, MC Schwartz, JL Aardema, MJ AF Poirier, Miriam C. Schwartz, Jeffrey L. Aardema, Marilyn J. TI Achieving Professional Success in US Government, Academia, and Industry: An EMGS Commentary SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Editorial Material DE career development; Government; academia; industry AB One of the goals of the EMGS is to help members achieve professional success in the fields they have trained in. Today, there is greater competition for jobs in genetic toxicology, genomics, and basic research than ever before. In addition, job security and the ability to advance in one's career is challenging, regardless of whether one works in a regulatory, academic, or industry environment. At the EMGS Annual Meeting in Monterey, CA (September, 2013), the Women in EMGS Special Interest Group held a workshop to discuss strategies for achieving professional success. Presentations were given by three speakers, each representing a different employment environment: Government (Miriam C. Poirier), Academia (Jeffrey L. Schwartz), and Industry (Marilyn J. Aardema). Although some differences in factors or traits affecting success in the three employment sectors were noted by each of the speakers, common factors considered important for advancement included networking, seeking out mentors, and developing exceptional communication skills. (C) 2014 Wiley Periodicals, Inc. C1 [Poirier, Miriam C.] NCI, NIH, Bethesda, MD 20892 USA. [Schwartz, Jeffrey L.] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Aardema, Marilyn J.] Marilyn Aardema Consulting LLC, Fairfield, OH USA. RP Schwartz, JL (reprint author), Univ Washington, Med Ctr, Dept Radiat Oncol, 1959 NE Pacific,NW134, Seattle, WA 98195 USA. EM jschwart@uw.edu NR 4 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2014 VL 55 IS 7 BP 525 EP 529 DI 10.1002/em.21871 PG 5 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AR8KI UT WOS:000343823600001 PM 24788591 ER PT J AU Olivero, OA Ongele, MO Braun, HM Marrogi, A Divi, K Mitchell, JB Poirier, MC AF Olivero, Ofelia A. Ongele, Michael O. Braun, Hannan M. Marrogi, Ariadna Divi, Kathyiani Mitchell, James B. Poirier, Miriam C. TI Selective Protection of Zidovudine-Induced DNA-Damage by the Antioxidants WR-1065 and Tempol SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE cytome assay; micronuclei; chromatin neoplasmic bridges; nuclear buds; apoptosis; necrosis; CBMN assay; MOLT-3 cells ID REVERSE-TRANSCRIPTASE INHIBITORS; 3-AZIDO-2,3-DIDEOXYTHYMIDINE AZT; INDUCED MUTAGENESIS; DIRECT GAVAGE; CELLS; GENOTOXICITY; RADIATION; MICRONUCLEI; MICE; ANEUPLOIDY AB The cytokinesis-block micronucleus cytome (CBMN) assay, introduced by Fenech, was used to demonstrate different types of DNA damage in MOLT-3 human lymphoblastoid cells exposed to 10 mu M zidovudine (AZT). In addition, we explored the cytoprotective potential of two antioxidants, WR-1065 and Tempol, to decrease AZT-induced genotoxicity. Binucleated cells, arrested by Cytochalasin B (Cyt B), were evaluated for micronuclei (MN), caused by DNA damage or chromosomal loss, and chromatin nucleoplasmic bridges (NPBs), caused by telomere attrition. Additionally, nuclear buds (NBUDs), caused by amplified DNA, and apoptotic and necrotic (A/N) cells were scored. We hypothesized that AZT exposure would increase the frequency of genotoxic end points, and that the antioxidants Tempol and WR-1065 would protect against AZT-induced genotoxicity. MOLT-3 cells were exposed to 0 or 10 mu M AZT for a total of 76 hr. After the first 24 hr, 0 or 5 mu M WR-1065 and/or 0 or 200 mu M Tempol were added for the remainder of the experiment. For the last 28 hr (of 76 hr), Cyt B was added to arrest replication after one cell division, leaving a predominance of binucleated cells. The nuclear division index (NDI) was similar for all treatment groups, indicating that the exposures did not alter cell viability. MOLT-3 cells exposed to AZT alone had significant (P < 0.05) increases in MN and NBs, compared to unexposed cells. Both Tempol and WR-1065 protected against AZT-induced MN formation (P < 0.003 for both), and WR-1065, but not Tempol, reduced the levels of A/N (P = 0.041). In cells exposed to AZT/Tempol there were significantly reduced levels of NBUDs, compared to cells exposed to AZT alone (P = 0.015). Cells exposed to AZT/WR-1065 showed reduced levels of NPBs, compared to cells exposed to AZT alone (P = 0.037). Thus WR-1065 and Tempol protected MOLT-3 cells against specific types of AZT-induced DNA damage. (C) 2014 Wiley Periodicals, Inc. C1 [Olivero, Ofelia A.; Ongele, Michael O.; Braun, Hannan M.; Marrogi, Ariadna; Divi, Kathyiani; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mitchell, James B.] NCI, Tumor Biol Sect, Radiat Biol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Olivero, OA (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, NIH, 37 Convent Dr MSC 4255,Bldg 37 Rm 4032, Bethesda, MD 20892 USA. EM oliveroo@exchange.nih.gov FU Intramural NIH HHS NR 46 TC 2 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2014 VL 55 IS 7 BP 566 EP 572 DI 10.1002/em.21872 PG 7 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AR8KI UT WOS:000343823600005 PM 24833597 ER PT J AU Dasgeb, B Smirnov, AV Ardeshirpour, Y Sackett, DL Knutson, JR Mehregan, D Gandjbakhche, A Halpern, AC AF Dasgeb, Bahar Smirnov, Aleksandr V. Ardeshirpour, Yasaman Sackett, Dan L. Knutson, Jay R. Mehregan, Darius Gandjbakhche, Amir Halpern, Allan C. TI Multiscale BerEp4 Molecular Imaging of Microtumor Phantoms: Toward Theranostics for Basal Cell Carcinoma SO MOLECULAR IMAGING LA English DT Article ID IN-VIVO; EP-CAM; FLUORESCENCE MICROSCOPY; MULTIPHOTON MICROSCOPY; CONFOCAL MICROSCOPY; MONOCLONAL-ANTIBODY; EXPRESSION; ANTIGEN; SKIN; DIAGNOSTICS AB Basal cell carcinoma (BCC), the most common cancer in humans, appears macroscopically and microscopically similar to many other skin lesions, which makes differential diagnosis difficult. We are developing an approach for quantitative molecular imaging of BerEP4, a transmembrane biomarker for BCC, with the goal of increasing the precision and accuracy of diagnosis. This pilot study was conducted to assess the affinity and selectivity of BerEp4 antibody and assess its possible use in designing theranostic probes for BCC. We provide evidence that our photon-counting fluorescence macrodetection system can recover specific signal increases from a film/pellet phantom. Additionally, we show that a two-photon excited fluorescence /backscatter confocal microscopy system can image BerEP4 antibody/antigen complex on the surface of BerEP4-expressing cancer cells in three dimensions. Based on the initial results, BerEP4 seems to be a promising biomarker for molecular imaging of BCC. To prepare BerEP4 for eventual theranostic use, we examined the feasibility of a combined macro-/micro-optical approach to imaging BCC with various histologies. These optical methods, endowed with the ability to monitor treatment in real time, may open an opportunity for noninvasive diagnosis, treatments, and follow-up. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NHLBI, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dermatol Serv, Dept Med, New York, NY 10022 USA. Wayne State Univ, Dept Dermatol, Dearborn, MI USA. Pinkus Dermatopathol Labs, Monroe, MI USA. RP Halpern, AC (reprint author), Mem Sloan Kettering Canc Ctr, Dermatol Serv, 160 E 63rd St, New York, NY 10022 USA. EM dasgebb@mskcc.org; halperna@mskcc.org FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NHLBI FX Financial disclosure of authors: Support in funding and facilities was provided by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NHLBI. NR 30 TC 1 Z9 1 U1 0 U2 2 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 EI 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD AUG PY 2014 VL 13 DI 10.2310/7290.2014.00016 PG 9 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA AS4AJ UT WOS:000344215700001 ER PT J AU Bhatt, N Fox, A Chan, CC Roschewski, M Sen, HN AF Bhatt, Nirali Fox, Austin Chan, Chi-Chao Roschewski, Mark Sen, H. Nida TI Intraocular (vitreoretinal) lymphoma with renal, pelvic, and central nervous system lesions SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Letter C1 [Bhatt, Nirali; Fox, Austin; Chan, Chi-Chao; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. [Roschewski, Mark] NCI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 EI 1715-3360 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD AUG PY 2014 VL 49 IS 4 BP E104 EP E106 DI 10.1016/j.jcjo.2014.05.009 PG 4 WC Ophthalmology SC Ophthalmology GA AR2GI UT WOS:000343401400010 PM 25103663 ER PT J AU Cooks, T Harris, CC Oren, M AF Cooks, Tomer Harris, Curtis C. Oren, Moshe TI Caught in the cross fire: p53 in inflammation SO CARCINOGENESIS LA English DT Review ID NF-KAPPA-B; TUMOR-SUPPRESSOR P53; WILD-TYPE P53; DNA-DAMAGE; STROMAL FIBROBLASTS; NITRIC-OXIDE; CELL-CYCLE; MICROSATELLITE INSTABILITY; HELICOBACTER-PYLORI; GENE-EXPRESSION AB The p53 transcription factor is a major tumor suppressor, whose diverse activities serve to ensure genome stability and inhibit neoplastic processes. In recent years, it is becoming increasingly clear that p53 also plays a broader role in maintaining cellular homeostasis, as well as contributing to tissue homeostasis in a non-cell-autonomous fashion. Chronic inflammation is a potential cancer-promoting condition, and as such is also within the radar of p53, which mounts a multifaceted attempt to prevent the escalation of chronic tissue imbalance into neoplasia. Recent understanding of the p53 pathway and other family members reveals a broad interaction with inflammatory elements such as reactive oxygen and nitrogen species, cytokines, infectious agents and major immune-regulatory pathways like nuclear factor-kappaB. This complex cross talk is highly dependent on p53 status, as different p53 isoforms and p53 mutants can mediate different responses and even promote chronic inflammation and associated cancer, acting in the tumor cells as well as in the stromal and immune compartments. C1 [Cooks, Tomer; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Oren, Moshe] Weizmann Inst Sci, IL-76100 Rehovot, Israel. RP Cooks, T (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM tomer.cooks@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Center of Excellence grant from the Israel Science Foundation [1779/11]; Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI); National Cancer Institute [R37 CA40099]; Robert Bosch Foundation FX Intramural Research Program of the National Institutes of Health, National Cancer Institute; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; a Center of Excellence grant (1779/11) from the Israel Science Foundation; a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI); National Cancer Institute (R37 CA40099); Robert Bosch Foundation. NR 161 TC 23 Z9 23 U1 3 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2014 VL 35 IS 8 BP 1680 EP 1690 DI 10.1093/carcin/bgu134 PG 11 WC Oncology SC Oncology GA AR2NA UT WOS:000343423000002 PM 24942866 ER PT J AU Figueroa, JD Han, SS Garcia-Closas, M Baris, D Jacobs, EJ Kogevinas, M Schwenn, M Malats, N Johnson, A Purdue, MP Caporaso, N Landi, MT Prokunina-Olsson, L Wang, ZM Hutchinson, A Burdette, L Wheeler, W Vineis, P Siddiq, A Cortessis, VK Kooperberg, C Cussenot, O Benhamou, S Prescott, J Porru, S Bueno-De-Mesquita, HB Trichopoulos, D Ljungberg, B Clavel-Chapelon, F Weiderpass, E Krogh, V Dorronsoro, M Travis, R Tjonneland, A Brenan, P Chang-Claude, J Riboli, E Conti, D Gago-Dominguez, M Stern, MC Pike, MC Van den Berg, D Yuan, JM Hohensee, C Rodabough, R Cancel-Tassin, G Roupret, M Comperat, E Chen, C De Vivo, I Giovannucci, E Hunter, DJ Kraft, P Lindstrom, S Carta, A Pavanello, S Arici, C Mastrangelo, G Karagas, MR Schned, A Armenti, KR Hosain, GMM Haiman, CA Fraumeni, JF Chanock, SJ Chatterjee, N Rothman, N Silverman, DT AF Figueroa, Jonine D. Han, Summer S. Garcia-Closas, Montserrat Baris, Dalsu Jacobs, Eric J. Kogevinas, Manolis Schwenn, Molly Malats, Nuria Johnson, Alison Purdue, Mark P. Caporaso, Neil Landi, Maria Teresa Prokunina-Olsson, Ludmila Wang, Zhaoming Hutchinson, Amy Burdette, Laurie Wheeler, William Vineis, Paolo Siddiq, Afshan Cortessis, Victoria K. Kooperberg, Charles Cussenot, Olivier Benhamou, Simone Prescott, Jennifer Porru, Stefano Bueno-de-Mesquita, H. Bas Trichopoulos, Dimitrios Ljungberg, Boerje Clavel-Chapelon, Franoise Weiderpass, Elisabete Krogh, Vittorio Dorronsoro, Miren Travis, Ruth Tjonneland, Anne Brenan, Paul Chang-Claude, Jenny Riboli, Elio Conti, David Gago-Dominguez, Manuela Stern, Mariana C. Pike, Malcolm C. Van den Berg, David Yuan, Jian-Min Hohensee, Chancellor Rodabough, Rebecca Cancel-Tassin, Geraldine Roupret, Morgan Comperat, Eva Chen, Constance De Vivo, Immaculata Giovannucci, Edward Hunter, David J. Kraft, Peter Lindstrom, Sara Carta, Angela Pavanello, Sofia Arici, Cecilia Mastrangelo, Giuseppe Karagas, Margaret R. Schned, Alan Armenti, Karla R. Hosain, G. M. Monawar Haiman, Chris A. Fraumeni, Joseph F., Jr. Chanock, Stephen J. Chatterjee, Nilanjan Rothman, Nathaniel Silverman, Debra T. TI Genome-wide interaction study of smoking and bladder cancer risk SO CARCINOGENESIS LA English DT Article ID NAT2 SLOW ACETYLATION; NADH CYTOCHROME B(5); CONFERS SUSCEPTIBILITY; DNA-REPAIR; GSTM1 NULL; GENE; ASSOCIATION; POLYMORPHISMS; INDEPENDENCE; PHENOTYPE AB Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 x 10(-5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 x 10(-7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 x 10-7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer. C1 [Figueroa, Jonine D.; Han, Summer S.; Baris, Dalsu; Purdue, Mark P.; Caporaso, Neil; Landi, Maria Teresa; Prokunina-Olsson, Ludmila; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, London SW3 6JB, England. [Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, Manolis; Dorronsoro, Miren] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Wang, Zhaoming; Hutchinson, Amy; Burdette, Laurie] NCI, Ctr Genom Res, SAIC Frederick Inc, Frederick, MD 21701 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Vineis, Paolo; Siddiq, Afshan; Bueno-de-Mesquita, H. Bas; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, London, England. [Cortessis, Victoria K.; Conti, David; Stern, Mariana C.; Van den Berg, David] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Cortessis, Victoria K.; Conti, David; Stern, Mariana C.; Van den Berg, David] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Kooperberg, Charles; Hohensee, Chancellor; Rodabough, Rebecca] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Tenon Hosp, AP HP, Dept Urol, Paris, France. [Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Ctr Rech Pathol Prostat, Paris, France. [Benhamou, Simone] Fdn Jean Dausset Ctr Etud Polymorphisme Humain CE, INSERM, U946, Paris, France. [Benhamou, Simone] Inst Gustave Roussy, CNRS, UMR8200, Villejuif, France. [Prescott, Jennifer; De Vivo, Immaculata; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Prescott, Jennifer; De Vivo, Immaculata; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Porru, Stefano; Carta, Angela; Arici, Cecilia] Univ Brescia, Dept Med & Surg Specialties, I-20124 Brescia, Italy. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulos, Dimitrios] Acad Athens, Bureau Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Ljungberg, Boerje] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Clavel-Chapelon, Franoise] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, U1018, Nutr Hormones & Womens Hlth Team, F-94805 Villejuif, France. [Clavel-Chapelon, Franoise] Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France. [Clavel-Chapelon, Franoise] IGR, F-94805 Villejuif, France. [Weiderpass, Elisabete] Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Dorronsoro, Miren] BioDonostia Res Inst, Hlth Dept Basque Reg, Publ Hlth Div Gipuzkoa, San Sebastian, Spain. [Travis, Ruth] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Brenan, Paul] Int Agcy Res Canc, Lyon, France. [Chang-Claude, Jenny] DKFZ, Heidelberg, Germany. [Gago-Dominguez, Manuela] Inst Invest Sanitaria Santiago IDIS, Galician Fdn Genom Med, Genom Med Grp, Complejo Hosp Univ Santiago,Serv Galego Saude SER, Santiago De Compostela, Spain. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Yuan, Jian-Min; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Univ Paris 06, ONCOTYPE URO, GRC 5, Paris, France. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA. [Hunter, David J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Pavanello, Sofia] Univ Padua, Dept Cardiac Thorac & Vasc Sci, Padua, Italy. [Mastrangelo, Giuseppe] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Karagas, Margaret R.; Schned, Alan; Armenti, Karla R.; Hosain, G. M. Monawar] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Haiman, Chris A.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. RP Figueroa, JD (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM figueroaj@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Purdue, Mark/C-9228-2016; Benhamou, Simone/K-6554-2015; Krogh, Vittorio/K-2628-2016; Weiderpass, Elisabete/M-4029-2016; Kogevinas, Manolis/C-3918-2017; OI Cancel-Tassin, Geraldine/0000-0002-9583-6382; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Purdue, Mark/0000-0003-1177-3108; Krogh, Vittorio/0000-0003-0122-8624; Weiderpass, Elisabete/0000-0003-2237-0128; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Yuan, Jian-Min/0000-0002-4620-3108 FU EPIC - ICL - Europe Against Cancer Program of the European Commission (SANCO); IARC - International Agency for Research on Cancer; France - Ligue contre le Cancer Societe 3M, Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (INSERM); Italy - Italian Association for Research on Cancer National Research Council; Spain - Health Research Fund (FIS) of the Spanish Ministry of Health; CIBER en Epidemiologia y Salud Publica (CIBERESP), Spain; ISCIII RETIC [RD06/0020]; Spanish Regional Government of Andalusia; Spanish Regional Government of Asturias; Spanish Regional Government of Basque Country; Spanish Regional Government of Murcia [N 6236]; Spanish Regional Government of Navarra; Catalan Institute of Oncology; UK - Cancer Research UK Medical Research Council; Association; British Heart Foundation; Department of Health; Food Standards Agency; Wellcome Trust; Netherlands - Dutch Ministry of Public Health; Dutch Prevention Funds LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Greece - Hellenic Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Germany - German Cancer Aid, German Cancer Research Center Federal Ministry of Education and Research [01-EA-9401]; Sweden - Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Denmark - Danish Cancer Society; Ligue Contre le Cancer du Val-de-Marne; Fondation de France; Groupement d'Entreprises Francaises dans la Lutte contre le Cancer; Association pour la Recherche sur le Cancer, France; National Institutes of Health [R01CA65726, R01CA114665, 1P01CA86871]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics [NCI N02-CP-01037]; NHS HPFS [CA055075, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262, UM1 CA167552]; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [NCI N02-CP-11015]; FIS/Spain [98/1274, 00/0745, PI061614, G03/174]; Fundacio Marato TV3; Red Tematica Investigacion Cooperativa en Cancer (RTICC); Consolider ONCOBIO [EU-FP7-201663]; National Heart, Lung, and Blood Institute; National Institutes of Health; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; [RO1-CA089715]; [CA34627]; Associazione Italiana per la Ricerca sul Cancro FX EPIC (P.V.) - ICL - Europe Against Cancer Program of the European Commission (SANCO); IARC - International Agency for Research on Cancer; France - Ligue contre le Cancer Societe 3M, Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (INSERM); Italy - Italian Association for Research on Cancer National Research Council; Spain - Health Research Fund (FIS) of the Spanish Ministry of Health; the CIBER en Epidemiologia y Salud Publica (CIBERESP), Spain; ISCIII RETIC (RD06/0020); Spanish Regional Governments of Andalusia, Asturias, Basque Country, Murcia (N 6236) and Navarra and the Catalan Institute of Oncology; UK - Cancer Research UK Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust; The Netherlands - Dutch Ministry of Public Health, Dutch Prevention Funds LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); Greece - Hellenic Ministry of Health, the Stavros Niarchos Foundation and the Hellenic Health Foundation; Germany - German Cancer Aid, German Cancer Research Center Federal Ministry of Education and Research (Grant 01-EA-9401); Sweden - Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane, Sweden; Denmark - Danish Cancer Society. FBCS (S. B.) - Ligue Contre le Cancer du Val-de-Marne; Fondation de France; Groupement d'Entreprises Francaises dans la Lutte contre le Cancer; Association pour la Recherche sur le Cancer, France. LABCS (M. P.) - National Institutes of Health grants (R01CA65726, R01CA114665, R01CA114665, 1P01CA86871). NEBCS (D. T. S.) - Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics and intramural contract number (NCI N02-CP-01037). NHS & HPFS (I. D. V.) - CA055075, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262, UM1 CA167552. PLCO (M. P. P.) - The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01, RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438, NIH HHSN268200782096C) and study coordination at the GENEVA (N. C.). Coordination Center (U01HG004446) for the genotyping of the lung studies with controls from EAGLE study and part of the PLCO. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. SBCS (D. T. S.) - Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number (NCI N02-CP-11015). FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614, G03/174; Fundacio Marato TV3; Red Tematica Investigacion Cooperativa en Cancer (RTICC); Consolider ONCOBIO, EU-FP7-201663; RO1-CA089715 and CA34627. WHI (C. K.) - The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; U.S.; Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C. NR 40 TC 11 Z9 13 U1 2 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2014 VL 35 IS 8 BP 1737 EP 1744 DI 10.1093/carcin/bgu064 PG 8 WC Oncology SC Oncology GA AR2NA UT WOS:000343423000008 PM 24662972 ER PT J AU Noinaj, N Buchanan, SK AF Noinaj, Nicholas Buchanan, Susan K. TI Structural insights into the transport of small molecules across membranes SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID BILE-ACID TRANSPORTERS; CRYSTAL-STRUCTURE; PATHOGENIC NEISSERIA; CELLULOSE SYNTHESIS; ECF TRANSPORTER; YERSINIA-PESTIS; X-RAY; RECEPTORS; MECHANISM; FAMILY AB While hydrophobic small molecules often can freely permeate a lipid bilayer, ions and other polar molecules cannot and require transporters to mediate their transport. Recently, a number of important structures have been reported which have advanced our understanding of how membrane protein transporters function to transport small molecules. Structures of TbpA/B and HmuUV provided new insight into iron uptake by pathogenic bacteria while the structures of Nark, ASBT, and VclNDY revealed molecular details about the transport of nitrate, bile acids and dicarboxylates, respectively. The structure of the folate ECF transporter indicated that the S component likely undergoes a large conformational shift to mediate folate transport, while the cellulose synthase/transporter contains an elongated translocation pore for passage through the inner membrane. C1 [Noinaj, Nicholas; Buchanan, Susan K.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Buchanan, SK (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX NN and SKB are supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 45 TC 5 Z9 5 U1 1 U2 21 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD AUG PY 2014 VL 27 BP 8 EP 15 DI 10.1016/j.sbi.2014.02.007 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AR6JG UT WOS:000343689300004 PM 24681594 ER PT J AU Molina-Cruz, A Barillas-Mury, C AF Molina-Cruz, Alvaro Barillas-Mury, Carolina TI The remarkable journey of adaptation of the Plasmodium falciparum malaria parasite to New World anopheline mosquitoes SO MEMORIAS DO INSTITUTO OSWALDO CRUZ LA English DT Article DE malaria; Plasmodium falciparum; Anopheles; adaptation; mosquito; Americas ID GENETIC DIVERSITY; DISTRIBUTION MAPS; BIONOMIC PRECIS; SURFACE PROTEIN; GAMBIAE; ORIGIN; COMPLEMENT; VECTORS; IMMUNITY; AMERICA AB Plasmodium falciparum originated in Africa, dispersed around the world as a result of human migration and had to adapt to several different indigenous anopheline mosquitoes. Anophelines from the New World are evolutionary distant form African ones and this probably resulted in a more stringent selection of Plasmodium as it adapted to these vectors. It is thought that Plasmodium has been genetically selected by some anopheline species through unknown mechanisms. The mosquito immune system can greatly limit infection and P. falciparum evolved a strategy to evade these responses, at least in part mediated by Pfs47, a highly polymorphic gene. We propose that adaptation of P. falciparum to new vectors may require evasion of their immune system. Parasites with a Pfs47 haplotype compatible with the indigenous mosquito vector would be able to survive and be transmitted. The mosquito antiplasmodial response could be an important determinant of P. falciparum population structure and could affect malaria transmission in the Americas. C1 [Molina-Cruz, Alvaro; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Molina-Cruz, A (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM amolina-cruz@niaid.nih.gov FU Intramural Research Program/DIR/NIAID/NIH FX Intramural Research Program/DIR/NIAID/NIH NR 51 TC 12 Z9 12 U1 3 U2 18 PU FUNDACO OSWALDO CRUZ PI RIO DE JANEIRO, RJ PA AV BRASIL 4365, 21045-900 RIO DE JANEIRO, RJ, BRAZIL SN 0074-0276 EI 1678-8060 J9 MEM I OSWALDO CRUZ JI Mem. Inst. Oswaldo Cruz PD AUG PY 2014 VL 109 IS 5 BP 662 EP 667 DI 10.1590/0074-0276130553 PG 6 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA AR5CW UT WOS:000343603800018 PM 25185006 ER PT J AU Enoch, MA AF Enoch, Mary-Anne TI Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE OPRM1; 5-HTTLPR; GABRA2; ALDH2; ADH1B; Level of response to alcohol ID MU-OPIOID-RECEPTOR; SEROTONIN TRANSPORTER GENE; SINGLE-NUCLEOTIDE POLYMORPHISM; NATIONAL EPIDEMIOLOGIC SURVEY; COGNITIVE-BEHAVIORAL THERAPY; FUNCTIONAL POLYMORPHISM; METABOLIZING GENES; DEPENDENT PATIENTS; DOPAMINE RELEASE; UNITED-STATES AB Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5' and 3' functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs/ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. Published by Elsevier Inc. C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov FU Intramural NIH HHS [ZIA AA000306-08] NR 119 TC 7 Z9 9 U1 10 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 2014 VL 123 SI SI BP 17 EP 24 DI 10.1016/j.pbb.2013.11.001 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA AR6HO UT WOS:000343685100003 PM 24220019 ER PT J AU Stukas, S Freeman, L Lee, M Wilkinson, A Ossoli, A Vaisman, B Demosky, S Chan, J Hirsch-Reinshagen, V Remaley, AT Wellington, CL AF Stukas, Sophie Freeman, Lita Lee, Michael Wilkinson, Anna Ossoli, Alice Vaisman, Boris Demosky, Stephen Chan, Jeniffer Hirsch-Reinshagen, Veronica Remaley, Alan T. Wellington, Cheryl L. TI LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lecithin:cholesterol acyltransferase; high density lipoprotein metabolism; apolipoproteins; Alzheimer's disease ID LECITHIN-CHOLESTEROL ACYLTRANSFERASE; CENTRAL-NERVOUS-SYSTEM; TRANSGENIC MOUSE MODEL; HUMAN CEREBROSPINAL-FLUID; BETA-PEPTIDE DEPOSITION; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; PLAQUE-FORMATION; TYPE-4 ALLELE; APOE LEVELS AB A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating beta-amyloid (A beta) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for A beta clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase A beta or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient A beta clearance. C1 [Stukas, Sophie; Lee, Michael; Wilkinson, Anna; Chan, Jeniffer; Hirsch-Reinshagen, Veronica; Wellington, Cheryl L.] Univ British Columbia, Dept Pathol & Lab Med, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada. [Freeman, Lita; Ossoli, Alice; Vaisman, Boris; Demosky, Stephen; Remaley, Alan T.] NIH, Bethesda, MD 20892 USA. RP Wellington, CL (reprint author), Univ British Columbia, Dept Pathol & Lab Med, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada. EM Cheryl@cmmt.ubc.ca RI Ossoli, Alice/K-5917-2016 OI Ossoli, Alice/0000-0002-9902-252X FU Heart and Stroke Foundation of Canada; Canadian Institutes of Health Research (CIHR); CIHR Vanier Scholarship; CIHR postdoctoral fellowship; intramural National Heart, Lung, and Blood Institute research funds FX This work was supported by operating grants from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research (CIHR) to C.L.W., a CIHR Vanier Scholarship to S.S., and a CIHR postdoctoral fellowship to V.H-R. A.T.R., L.F., A.O., and B.V. were supported by intramural National Heart, Lung, and Blood Institute research funds. NR 58 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD AUG PY 2014 VL 55 IS 8 BP 1721 EP 1729 DI 10.1194/jlr.M049940 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ7VN UT WOS:000343027400014 PM 24950691 ER PT J AU Collins, MA Tajuddin, N Moon, KH Kim, HY Nixon, K Neafsey, EJ AF Collins, Michael A. Tajuddin, Nuzhath Moon, Kwan-Hoon Kim, Hee-Yong Nixon, Kimberly Neafsey, Edward J. TI Alcohol, Phospholipase A(2)-associated Neuroinflammation, and omega 3 Docosahexaenoic Acid Protection SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Ethanol; PLA(2); PARP-1; Neurodegeneration; Neuroprotection; DHA; Organotypic ID ADULT-RAT BRAIN; INDUCED COGNITIVE DEFICITS; ETHANOL EXPOSURE; OXIDATIVE STRESS; SLICE CULTURES; INDUCED NEURODEGENERATION; NEURONAL DEGENERATION; LIPID-PEROXIDATION; CEREBRAL EDEMA; IN-VIVO AB Chronic alcohol (ethanol) abuse causes neuroinflammation and brain damage that can give rise to alcoholic dementia. Insightfully, Dr. Albert Sun was an early proponent of oxidative stress as a key factor in alcoholism-related brain deterioration. In fact, oxidative stress has proven to be critical to the hippocampal and temporal cortical neurodamage resulting from repetitive "binge" alcohol exposure in adult rat models. Although the underlying mechanisms are uncertain, our immunoelectrophoretic and related assays in binge alcohol experiments in vivo (adult male rats) and in vitro (rat organotypic hippocampal-entorhinal cortical slice cultures) have implicated phospholipase A(2) (PLA(2))-activated neuroinflammatory pathways, release of pro-oxidative arachidonic acid (20:4 omega 6), and elevated oxidative stress adducts (i.e., 4-hydroxynonenal-protein adducts). Also, significantly increased by the binge alcohol treatments was aquaporin-4 (AQP4), a water channel enriched in astrocytes that, when augmented, may trigger brain (esp. cellular) edema and neuroinflammation; of relevance, glial swelling is known to provoke increased PLA(2) activities or levels. Concomitant with PLA(2) activation, the results have further implicated binge alcohol-elevated poly (ADP-ribose) polymerase-1 (PARP-1), an oxidative stress-responsive DNA repair enzyme linked to parthanatos, a necrotic-like neuronal death process. Importantly, supplementation of the brain slice cultures with docosahexaenoic acid (22:6 omega 3) exerted potent suppression of the induced changes in PLA(2) isoforms, AQP4, PARP-1 and oxidative stress footprints, and prevention of the binge alcohol neurotoxicity, by as yet unknown mechanisms. These neuroinflammatory findings from our binge alcohol studies and supportive rat binge studies in the literature are reviewed. C1 [Collins, Michael A.; Tajuddin, Nuzhath; Moon, Kwan-Hoon; Neafsey, Edward J.] Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, Maywood, IL 60153 USA. [Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD 20892 USA. [Nixon, Kimberly] Univ Kentucky, Dept Pharmaceut Sci, Lexington, KY 40536 USA. RP Collins, MA (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, Maywood, IL 60153 USA. EM mcollin@lumc.edu RI Nixon, Kimberly/A-1217-2015 FU National Institutes of Health [U01AA018279, R01AA0016959, T32DA016176]; Loyola University Chicago Research Funding Committee; Alcohol Research Program FX The research was supported by the National Institutes of Health U01AA018279, R01AA0016959, and T32DA016176 and Loyola University Chicago Research Funding Committee and the Alcohol Research Program. The technical support of Dr. S. Alex Marshall is acknowledged. Dr. Toni Pak and Dr. Magdalena Szymanska, Department of Physiology at Loyola University Medical Center, are recognized for providing brain regions from alcohol-binged young adult rats that generated in their neuroendocrine studies [51]. NR 51 TC 5 Z9 5 U1 1 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD AUG PY 2014 VL 50 IS 1 BP 239 EP 245 DI 10.1007/s12035-014-8690-0 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AQ8DX UT WOS:000343055000022 PM 24705861 ER PT J AU Subash, S Essa, MM Al-Adawi, S Memon, MA Manivasagam, T Akbar, M AF Subash, Selvaraju Essa, Musthafa Mohamed Al-Adawi, Samir Memon, Mushtaq A. Manivasagam, Thamilarasan Akbar, Mohammed TI Neuroprotective effects of berry fruits on neurodegenerative diseases SO NEURAL REGENERATION RESEARCH LA English DT Article DE nerve regeneration; berry fruit; neurodegenerative disease; neuroprotection; Alzheimer's disease; Parkinson's disease; review; neural regeneration ID SUPPLEMENTATION IMPROVES MEMORY; NEURONAL SIGNAL-TRANSDUCTION; HEAVY-PARTICLE IRRADIATION; AMYLOID-BETA-PEPTIDE; ANTIOXIDANT CAPACITY; ALZHEIMERS-DISEASE; BLUEBERRY SUPPLEMENTATION; OXIDATIVE STRESS; DIETARY SUPPLEMENTATION; BEHAVIORAL DEFICITS AB Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegenerative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation, cell survival, neurotransmission and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents. C1 [Subash, Selvaraju; Essa, Musthafa Mohamed] Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman. [Subash, Selvaraju; Essa, Musthafa Mohamed; Al-Adawi, Samir] Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. [Al-Adawi, Samir] Sultan Qaboos Univ, Coll Med & Hlth Sci, Muscat, Oman. [Memon, Mushtaq A.] Washington State Univ, Coll Vet Med, Pullman, WA 99164 USA. [Manivasagam, Thamilarasan] Annamalai Univ, Dept Biochem & Biotechnol, Annamalainagar 608002, Tamil Nadu, India. [Akbar, Mohammed] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Essa, MM (reprint author), Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, PO 34,PC 123, Muscat, Oman. EM drmdessa@squ.edu.om OI Al-Adawi, Samir/0000-0002-9858-5582 FU Research Councial of Sultanate of Oman [RC/AGR/FOOD/11/01] FX This study was supported by a grant from the Research Councial of Sultanate of Oman, No. RC/AGR/FOOD/11/01. NR 108 TC 15 Z9 16 U1 4 U2 43 PU SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES PI SHENYANG PA PO BOX 1234, SHENYANG, LIAONING 110004, PEOPLES R CHINA SN 1673-5374 J9 NEURAL REGEN RES JI Neural Regen. Res. PD AUG PY 2014 VL 9 IS 16 BP 1557 EP 1566 DI 10.4103/1673-5374.139483 PG 10 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA AR1GJ UT WOS:000343333400013 PM 25317174 ER PT J AU Remaley, AT Norata, GD Catapano, AL AF Remaley, Alan T. Norata, Giuseppe D. Catapano, Alberico L. TI Novel concepts in HDL pharmacology SO CARDIOVASCULAR RESEARCH LA English DT Review DE HDL; Cholesterol; Atherosclerosis; Cardiovascular disease; Drugs ID HIGH-DENSITY-LIPOPROTEIN; RANDOMIZED CONTROLLED-TRIAL; SCAVENGER RECEPTOR-BI; ABCA1-DEPENDENT CHOLESTEROL EFFLUX; APOLIPOPROTEIN MIMETIC PEPTIDES; ACUTE CORONARY SYNDROME; HIGH-RISK; A-I; LYSOPHOSPHATIDIC ACID; SMALL-INTESTINE AB High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these new HDL based therapies will also be discussed. C1 [Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20824 USA. [Norata, Giuseppe D.; Catapano, Alberico L.] Univ Milan, Dept Pharmacol Sci, Milan, Italy. [Norata, Giuseppe D.] Osped Bassini, Ctr Study Atherosclerosis, Soc Italiana Studio Aterosclerosi, Cinisello Balsamo, Italy. [Norata, Giuseppe D.] Queen Mary Univ, Barts & London Sch Med & Dent, Blizard Inst, Ctr Diabet, London, England. [Catapano, Alberico L.] IRCCS Multimed, Milan, Italy. RP Remaley, AT (reprint author), NHLBI, NIH, 10 Ctr Dr,Bldg 10,Rm 2C-433, Bethesda, MD 20824 USA. EM aremaley1@cc.nih.gov OI Norata, Giuseppe Danilo/0000-0002-6081-1257; Catapano, Alberico Luigi/0000-0002-7593-2094 FU National Heart, Lung and Blood Institute, NIH; UNIMI Piano Sviluppo B FX A.T.R. research is supported by intramural research funds from the National Heart, Lung and Blood Institute, NIH. G.D.N. is supported by UNIMI Piano Sviluppo B 2014. NR 75 TC 11 Z9 11 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG 1 PY 2014 VL 103 IS 3 BP 423 EP 428 DI 10.1093/cvr/cvu141 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AQ6JG UT WOS:000342916900010 PM 24951539 ER PT J AU Zhao, C Shi, GP Vistica, BP Hinshaw, SJH Wandu, WS Tan, CY Zhang, MF Gery, I AF Zhao, Chan Shi, Guangpu Vistica, Barbara P. Hinshaw, Samuel J. H. Wandu, Wambui S. Tan, Cuiyan Zhang, Meifen Gery, Igal TI Induced regulatory T-cells (iTregs) generated by activation with anti-CD3/CD28 antibodies differ from those generated by the physiological-like activation with antigen/APC SO CELLULAR IMMUNOLOGY LA English DT Article DE T regulatory (Treg) cells; Proliferation assay; Cell adhesion molecules; TCR transgenic; T cell activation ID TRANSCRIPTION FACTOR FOXP3; TGF-BETA; IMMUNE TOLERANCE; CUTTING EDGE; CD4 CELLS; IN-VIVO; INDUCTION; IL-2; TH17; AUTOIMMUNE AB Regulatory T-cells (Tregs) are responsible for homeostasis of the immune system, as well as for inhibition of pathogenic autoimmune processes. Induced-(i)-Tregs, can be generated in vitro by activation of CD4 cells in the presence of TGF-beta. A commonly used activation mechanism is by antibodies against CD3 and CD28. The physiological-like activation of T-cells, however, is with the specific target antigen presented by antigen-presenting cells (APC). The two modes of activation have been considered to yield the same populations of iTregs. Here, we compared between iTreg populations generated by either one of the two methods and found differences between their capacities to inhibit T-lymphocyte proliferative response, their expression of cell surface antigens and particularly, in their transcript expression profiles of certain chemokines and chemokine receptors. Our data thus indicate that iTregs generated by activation with anti-CD3/CD28 antibodies cannot be considered identical to iTregs generated by antigen/APC. Published by Elsevier Inc. C1 [Zhao, Chan; Shi, Guangpu; Vistica, Barbara P.; Hinshaw, Samuel J. H.; Wandu, Wambui S.; Tan, Cuiyan; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Chan; Zhang, Meifen] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Ophthalmol, Beijing 100730, Peoples R China. [Zhao, Chan; Zhang, Meifen] Peking Union Med Coll, Beijing 100021, Peoples R China. RP Zhang, MF (reprint author), Beijing Union Med Coll Hosp, Dept Ophthalmol, 1 Shuai Fu Yuan, Beijing 100730, Peoples R China. EM meifen_zhang@hotmail.com; geryi@nei.nih.gov FU National Natural Science Foundation of China [30973273]; National Eye Institute, NIH FX This study was partially supported by the National Natural Science Foundation of China (No. 30973273) and the intramural Research Program of the National Eye Institute, NIH. NR 24 TC 3 Z9 5 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG PY 2014 VL 290 IS 2 BP 179 EP 184 DI 10.1016/j.cellimm.2014.06.004 PG 6 WC Cell Biology; Immunology SC Cell Biology; Immunology GA AQ6WQ UT WOS:000342955000001 PM 25038545 ER PT J AU Dubey, SK Hejtmancik, JF Krishnadas, SR Sharmila, R Haripriya, A Sundaresan, P AF Dubey, Sushil Kumar Hejtmancik, J. Fielding Krishnadas, Subbaiah Ramasamy Sharmila, Rajendrababu Haripriya, Aravind Sundaresan, Periasamy TI Lysyl Oxidase-Like 1 Gene in the Reversal of Promoter Risk Allele in Lysyl OPseudoexfoliation Syndrome SO JAMA OPHTHALMOLOGY LA English DT Article ID PRIMARY OPEN-ANGLE; SINGLE NUCLEOTIDE POLYMORPHISMS; COMMON SEQUENCE VARIANTS; LOXL1 GENE; EXFOLIATION GLAUCOMA; PSEUDOEXFOLIATION SYNDROME; JAPANESE PATIENTS; UNITED-STATES; POPULATION; ASSOCIATION AB IMPORTANCE This study was necessary to establish the association between common genetic variants in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation (PEX) syndrome and emphasize the reversal of promoter risk allele in a South Indian population. OBJECTIVE To investigate the potential association of genetic variants across the LOXL1gene in South Indian patients with PEX syndrome and glaucoma. DESIGN, SETTING, AND PARTICIPANTS A case-control study of individuals from Madurai, India, with PLX s'y Zirici glaucoma as well as healthy people serving as controls. Three hundred unrelated people with PEX syndrome and 225 age- and ethnically matched controls were recruited for genetic analysis. MAIN OUTCOMES AND MEASURES Four single-nucleotide polymorphisms in LOXL1 (rs16958477, rs1048661, rs3825942, and rs2165241) were genotyped by direct sequencing in all participants. Regulatory regions and 7 coding exons of LOXL1were directly sequenced in 50 patients and 50 controls. A case-control association analysis was performed using the Golden Helix SVS suite. RESULTS An association between 4 LOXL1single-nucleotide polymorphisms with PEX syndrome and glaucoma was observed (rs16958477, P = 4.77 x 10(-6) [odds ratio, 0.50]; rs1048661, P = 4.28 x 10(-5) [1.79]; rs3825942, P = 4.68 x 10(-3) [9.19]; and rs2165241, P = 1.98 x 10(-15) [2.88]). Sequencing of 7 exons and regulatory regions of LOXL1identified 11 additional sequence variants; only rs41435250 showed an association (P = 3.80 x 10(-5) [0.49]) with PEX syndrome and glaucoma. CONCLUSIONS AND RELEVANCE Genetic variants in LOXL1are associated with PEX syndrome and glaucoma in the South Indian population. To our knowledge, this is the first study to demonstrate the association of rs41435250 with PEX as well as reversal of the promoter risk allele. Understanding the role of the LOXL1gene in PEX pathogenesis will facilitate early detection in individuals at risk for this condition. C1 [Dubey, Sushil Kumar; Sundaresan, Periasamy] Dr G Venkataswamy Eye Res Inst, Aravind Med Res Fdn, Dept Genet, Madurai, Tamil Nadu, India. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Rockville, MD USA. [Krishnadas, Subbaiah Ramasamy; Sharmila, Rajendrababu] Aravind Eye Hosp, Glaucoma Clin, Madurai 625020, Tamil Nadu, India. [Haripriya, Aravind] Aravind Eye Hosp, Intraocular Lens & Cataract Clin, Madurai 625020, Tamil Nadu, India. RP Sundaresan, P (reprint author), Aravind Eye Hosp, Dr G Venkataswamy Eye Res Inst, Dept Genet, Aravind Med Res Fdn, 1 Anna Nagar, Madurai 625020, Tamil Nadu, India. EM sundar@aravind.org FU Alcon-Aravind Eye Care System, India FX This study was supported by a research grant from Alcon-Aravind Eye Care System, India. NR 42 TC 10 Z9 11 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD AUG PY 2014 VL 132 IS 8 BP 949 EP 955 DI 10.1001/jamaophthalmol.2014.845 PG 7 WC Ophthalmology SC Ophthalmology GA AQ8EX UT WOS:000343058000006 PM 24809751 ER PT J AU Chew, EY Clemons, TE AF Chew, Emily Y. Clemons, Traci E. TI Making Sense of the Evidence From the Age-Related Eye Disease Study 2 Randomized Clinical Trial Reply SO JAMA OPHTHALMOLOGY LA English DT Letter ID MACULAR DEGENERATION C1 [Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,MSC 1204,Bldg 10,CRC Room 3-2531, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 4 TC 0 Z9 0 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD AUG PY 2014 VL 132 IS 8 BP 1031 EP 1032 PG 3 WC Ophthalmology SC Ophthalmology GA AQ8EX UT WOS:000343058000030 PM 25124958 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO PAIN MEDICINE LA English DT Article DE Low Back Pain; Chronic Low Back Pain; Research Standards; Minimum Dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Objective. Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific, and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Design. Expert panel and preliminary evaluation of key recommendations. Methods. The NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting. Results. The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. Conclusion. The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will be come a dynamic document, and undergo continual improvement. Perspective. A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Cook, Karon; Weiner, Debra K.] Northwestern Univ, Evanston, IL USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [DeLitto, Anthony] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. NR 126 TC 11 Z9 11 U1 8 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD AUG PY 2014 VL 15 IS 8 BP 1249 EP 1267 DI 10.1111/pme.12538 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA AQ2PW UT WOS:000342630800004 PM 25132307 ER PT J AU Aranko, AS Wlodawer, A Iwai, H AF Aranko, A. Sesilja Wlodawer, Alexander Iwai, Hideo TI Nature's recipe for splitting inteins SO PROTEIN ENGINEERING DESIGN & SELECTION LA English DT Review DE protein ligation; protein splicing; protein transsplicing; split intein ID TUBERCULOSIS RECA INTEIN; FUNCTIONAL MINI-INTEINS; DNAE INTEIN; CRYSTAL-STRUCTURE; HOMING ENDONUCLEASE; NOSTOC-PUNCTIFORME; PROTEIN LIGATION; HIGHLY EFFICIENT; IN-VIVO; ADENOSINE-TRIPHOSPHATASE AB Protein splicing in trans by split inteins has increasingly become a powerful protein-engineering tool for protein ligation, both in vivo and in vitro. Over 100 naturally occurring and artificially engineered split inteins have been reported for protein ligation using protein trans-splicing. Here, we review the current status of the reported split inteins in order to delineate an empirical or rational strategy for constructing new split inteins suitable for various applications in biotechnology and chemical biology. C1 [Aranko, A. Sesilja; Iwai, Hideo] Univ Helsinki, Inst Biotechnol, Res Program Struct Biol & Biophys, FIN-00014 Helsinki, Finland. [Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Iwai, H (reprint author), Univ Helsinki, Inst Biotechnol, Res Program Struct Biol & Biophys, POB 65, FIN-00014 Helsinki, Finland. EM hideo.iwai@helsinki.fi RI Iwai, Hideo/A-6416-2009; Aranko, Aino Sesilja/N-1224-2016 OI Iwai, Hideo/0000-0001-7376-5264; Aranko, Aino Sesilja/0000-0001-9425-3524 FU Viikki Doctoral Programme in Molecular Biosciences; Academy of Finland [137995]; Sigrid Juselius Foundation; Biocenter Finland; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX A.S.A. acknowledges Viikki Doctoral Programme in Molecular Biosciences for financial support. This work was supported by the Academy of Finland (137995), Sigrid Juselius Foundation, Biocenter Finland, and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 69 TC 10 Z9 10 U1 4 U2 45 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-0126 EI 1741-0134 J9 PROTEIN ENG DES SEL JI Protein Eng. Des. Sel. PD AUG PY 2014 VL 27 IS 8 BP 263 EP 271 DI 10.1093/protein/gzu028 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AQ8AK UT WOS:000343042400003 PM 25096198 ER PT J AU Lissek, S Bradford, DE Alvarez, RP Burton, P Espensen-Sturges, T Reynolds, RC Grillon, C AF Lissek, Shmuel Bradford, Daniel E. Alvarez, Ruben P. Burton, Philip Espensen-Sturges, Tori Reynolds, Richard C. Grillon, Christian TI Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE anxiety; conditioned generalization; fear-conditioning; fMRI; neurobiology ID VENTROMEDIAL PREFRONTAL CORTEX; STIMULUS-GENERALIZATION; ANXIETY DISORDER; AUDITORY-CORTEX; NMDA RECEPTORS; HIPPOCAMPAL; EXTINCTION; MEMORY; RATS; MECHANISMS AB Recent research on classical fear-conditioning in the anxiety disorders has identified overgeneralization of conditioned fear as an important conditioning correlate of anxiety pathology. Unfortunately, only one human neuroimaging study of classically conditioned fear generalization has been conducted, and the neural substrates of this clinically germane process remain largely unknown. The current generalization study employs a clinically validated generalization gradient paradigm, modified for the fMRI environment, to identify neural substrates of classically conditioned generalization that may function aberrantly in clinical anxiety. Stimuli include five rings of gradually increasing size with extreme sizes serving as cues of conditioned danger (CS+) and safety (CS-). The three intermediately sized rings serve as generalization stimuli (GSs) and create a continuum-of-size from CS+ to CS-. Results demonstrate 'positive' generalization gradients, reflected by declines in responding as the presented stimulus differentiates from CS+, in bilateral anterior insula, dorsomedial prefrontal cortex, and bilateral inferior parietal lobule. Conversely, 'negative' gradients, reflected by inclines in responding as the presented stimulus differentiates from CS+ were instantiated in bilateral ventral hippocampus, ventromedial prefrontal cortex and precuneus cortex. These results as well as those from connectivity analyses are discussed in relation to a working neurobiology of conditioned generalization centered on the hippocampus. C1 [Lissek, Shmuel; Reynolds, Richard C.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,DHHS, Bethesda, MD 20892 USA. [Lissek, Shmuel; Burton, Philip; Espensen-Sturges, Tori] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN USA. [Bradford, Daniel E.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. [Alvarez, Ruben P.] Laureate Inst Brain Res, Tulsa, OK USA. RP Lissek, S (reprint author), Univ Minnesota, Dept Psychol, 75 E River Rd, Minneapolis, MN 55455 USA. EM smlissek@umn.edu FU National Institute of Mental Health [K99 MH080130] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health and by the Extramural Research Program of the National Institute of Mental Health (grant no. K99 MH080130 to S.L.). NR 45 TC 36 Z9 38 U1 8 U2 29 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD AUG PY 2014 VL 9 IS 8 BP 1134 EP 1142 DI 10.1093/scan/nst096 PG 9 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AQ7IA UT WOS:000342984900012 PM 23748500 ER PT J AU Zuliani, G Morieri, ML Volpato, S Maggio, M Cherubini, A Francesconi, D Bandinelli, S Paolisso, G Guralnik, JM Ferrucci, L AF Zuliani, Giovanni Morieri, Mario Luca Volpato, Stefano Maggio, Marcello Cherubini, Antonio Francesconi, Daniela Bandinelli, Stefania Paolisso, Giuseppe Guralnik, Jack M. Ferrucci, Luigi TI Insulin resistance and systemic inflammation, but not metabolic syndrome phenotype, predict 9 years mortality in older adults SO ATHEROSCLEROSIS LA English DT Article DE Insulin resistance; C reactive protein; Mortality; Metabolic syndrome; Elderly ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; POPULATION-BASED COHORT; CARDIOVASCULAR-DISEASE; FOLLOW-UP; ELDERLY INDIVIDUALS; HEALTH; RISK; ATHEROSCLEROSIS; MEN AB Background: Although metabolic syndrome (MS) is a typical condition of middle-aged/older person, the association between MS and mortality risk has not been confirmed in people over 65 years. We hypothesized that while in the elderly MS phenotype might lose its value in predicting mortality risk, the two core factors of MS, i.e. insulin resistance (IR) and low grade systemic inflammation (LGSI) would not. Methods: 1011 community-dwelling older individuals (InCHIANTI study) were included. MS phenotype was defined by NCEP-ATP-III criteria. IR was calculated by HOMA; high-sensitivity C reactive protein was measured by ELISA. Subjects were divided into four groups based on presence/absence of IR (HOMA >= 2.27) and LGSI (hs-CRP >= 3 g/L): Group 1: no IR/LGSI (reference); Group 2: LGSI only; Group 3: IR only; Group 4: IR + LGSI. Hazard Ratios (HR) for 9-years cardiovascular (CVD) and total mortality, according to IR/LGSI groups, were estimated in subjects with (n. 311) and without MS by Cox model. Results: 31.8% of subjects with MS phenotype had no IR, 45.3% had no LGSI; moreover, 51% of subjects with both IR and LGSI didn't display the MS phenotype. MS phenotype was not associated with CVD (HR: 1.29; 95% C. I.: 0.92-1.81) or total (HR: 1.07; 95% C. I.: 0.86-1.34) mortality risk, whereas the presence of IR plus LGSI was associated with increased CVD (no MS: HR 2.07, 95% CI: 1.12-3.72; MS: HR 9.88, 95% CI: 2.18 -4), and overall (no MS: HR 1.72, 95% CI: 1.001-3.17; MS: HR 1.51, 95% CI: 1.02-2.28) mortality risk. The presence of IR (HR: 6.90, 95% CI: 1.45-32) or LGSI (HR 7.56, 95% CI: 1.63-35) was associated with CVD mortality, only among individuals with MS phenotype. Conclusions: Among community-dwelling older individuals, IR and LGSI, but not MS phenotype, was associated with 9-years overall and CVD mortality risk. Since a reduced "overlap" between MS phenotype and its physiopathological core (IR and LGSI) might be present with aging, we suggest that the definition of MS might be more holistic in advanced age, and probably comprise the measurement of IR and LGSI. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Zuliani, Giovanni; Morieri, Mario Luca; Volpato, Stefano; Francesconi, Daniela] Univ Ferrara, Dept Med Sci, Sect Internal & CardioResp Med, I-44100 Ferrara, Italy. [Maggio, Marcello] Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, I-43100 Parma, Italy. [Cherubini, Antonio] INNRCA, Inst Gerontol & Geriatr, Ancona, Italy. [Bandinelli, Stefania] ASF Geriatr Rehabil, Florence, Italy. [Bandinelli, Stefania] IOT, Tuscany Reg Hlth Agcy, Florence, Italy. [Paolisso, Giuseppe] Univ Naples 2, Dept Gerontol Geriatr & Metab Dis, Naples, Italy. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Zuliani, G (reprint author), Univ Ferrara, Dept Med Sci, Sect Internal & CardioResp Med, Via Savonarola 9, I-44100 Ferrara, Italy. EM gzuliani@hotmail.com RI VOLPATO, STEFANO/H-2977-2014; OI VOLPATO, STEFANO/0000-0003-4335-6034; Paolisso, Giuseppe/0000-0002-2137-455X; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health [ICS110.1/RF97.71]; National Institute on Aging [263 MD 9164, 263 MD 821336]; U.S. National Institute on Aging [N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Institute on Aging, National Institutes of Health, Baltimore, Maryland FX The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health, and in part by the National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). The Follow-up 1(2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the Follow-up 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002). Supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. NR 39 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 BP 538 EP 545 DI 10.1016/j.atherosclerosis.2014.05.959 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000943 PM 24956526 ER PT J AU Arakelyan, A Ivanova, O Lebedeva, A Vagida, M Nikitskaya, E Ryazankina, N Grivel, JC Shpektor, A Margolis, L Vasilieva, E AF Arakelyan, A. Ivanova, O. Lebedeva, A. Vagida, M. Nikitskaya, E. Ryazankina, N. Grivel, J. C. Shpektor, A. Margolis, L. Vasilieva, E. TI IMPACT OF ANTIPLATELET THERAPY ON EXTRACELLULAR VESICLES IN PATIENTS WITH ACUTE CORONARY SYNDROMES SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT 82nd Congress of the European-Atherosclerosis-Society (EAS) CY MAY 31-JUN 03, 2014 CL Spanish Soc Atherosclerosis, Madrid, SPAIN SP European Atherosclerosis Soc HO Spanish Soc Atherosclerosis C1 [Arakelyan, A.; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Ivanova, O.; Lebedeva, A.; Vagida, M.; Nikitskaya, E.; Ryazankina, N.; Grivel, J. C.; Shpektor, A.; Vasilieva, E.] Moscow State Univ Med & Dent, Dept Cardiol, Moscow, Russia. RI Shpektor, Alexander/B-1083-2016; Vasilieva, Elena/B-2137-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 MA EAS-1160 BP E296 EP E296 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000884 ER PT J AU Casas-Agustench, P Sloan, S Jacques, P Willinger, C Yin, X Courchesne, P Ramachandran, V Robin, S Larson, M Chen, B Mendelson, M Levy, D Ordovas, JM AF Casas-Agustench, P. Sloan, S. Jacques, P. Willinger, C. Yin, X. Courchesne, P. Ramachandran, V. Robin, S. Larson, M. Chen, B. Mendelson, M. Levy, D. Ordovas, J. M. TI CONNECTIONS BETWEEN DARK FISH INTAKE, LIPIDOMICS AND PLASMA TRIGLYCERIDES IN THE FRAMINGHAM HEART STUDY SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT 82nd Congress of the European-Atherosclerosis-Society (EAS) CY MAY 31-JUN 03, 2014 CL Spanish Soc Atherosclerosis, Madrid, SPAIN SP European Atherosclerosis Soc HO Spanish Soc Atherosclerosis C1 [Casas-Agustench, P.] Inst IMDEA Alimentac, Madrid, Spain. [Sloan, S.; Ordovas, J. M.] Tufts Univ, Nutr & Genom Lab, Boston, MA 02111 USA. [Jacques, P.] Tufts Univ, Nutr Epidemiol Lab, Boston, MA 02111 USA. [Willinger, C.; Yin, X.; Courchesne, P.; Ramachandran, V.; Robin, S.; Larson, M.; Chen, B.; Mendelson, M.; Levy, D.] NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 MA EAS-0278 BP E186 EP E186 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000539 ER PT J AU Fuster, J Zuriaga, MA Ngo, D Farb, MG Aprahamian, T Yamaguchi, TP Gokce, N Walsh, K AF Fuster, J. Zuriaga, M. A. Ngo, D. Farb, M. G. Aprahamian, T. Yamaguchi, T. P. Gokce, N. Walsh, K. TI NON-CANONICAL WNT SIGNALING PROMOTES OBESITY-INDUCED ADIPOSE TISSUE INFLAMMATION AND METABOLIC DYSFUNCTION SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT 82nd Congress of the European-Atherosclerosis-Society (EAS) CY MAY 31-JUN 03, 2014 CL Spanish Soc Atherosclerosis, Madrid, SPAIN SP European Atherosclerosis Soc HO Spanish Soc Atherosclerosis C1 [Fuster, J.; Zuriaga, M. A.; Ngo, D.; Farb, M. G.; Aprahamian, T.; Gokce, N.; Walsh, K.] Boston Univ, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [Yamaguchi, T. P.] NCI, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 MA EAS-0718 BP E25 EP E25 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000041 ER PT J AU Sorokin, AV Vaisman, BL Thacker, S Yu, ZX Fitzgerald, JM Serhan, CN Remaley, AT AF Sorokin, A. V. Vaisman, B. L. Thacker, S. Yu, Z. X. Fitzgerald, J. M. Serhan, C. N. Remaley, A. T. TI DIETARY OMEGA-3 POLYUNSATURATED FATTY ACIDS PLUS ASPIRIN DECREASES PLASMA LIPIDS AND INCREASES PRO-RESOLVING LIPID MEDIATORS IN APOE-DEFICIENT MICE SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT 82nd Congress of the European-Atherosclerosis-Society (EAS) CY MAY 31-JUN 03, 2014 CL Spanish Soc Atherosclerosis, Madrid, SPAIN SP European Atherosclerosis Soc HO Spanish Soc Atherosclerosis C1 [Sorokin, A. V.; Vaisman, B. L.; Thacker, S.; Yu, Z. X.; Remaley, A. T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Fitzgerald, J. M.; Serhan, C. N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 MA EAS-0038 BP E269 EP E269 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000797 ER PT J AU Nilsson, O Weise, M Landman, EBM Meyers, JL Barnes, KM Baron, J AF Nilsson, Ola Weise, Martina Landman, Ellie B. M. Meyers, Jodi L. Barnes, Kevin M. Baron, Jeffrey TI Evidence That Estrogen Hastens Epiphyseal Fusion and Cessation of Longitudinal Bone Growth by Irreversibly Depleting the Number of Resting Zone Progenitor Cells in Female Rabbits SO ENDOCRINOLOGY LA English DT Article ID CATCH-UP GROWTH; PLATE SENESCENCE; INDIAN HEDGEHOG; PRECOCIOUS PUBERTY; GENE-EXPRESSION; RECEPTOR-ALPHA; RAT TIBIA; CARTILAGE; CHONDROGENESIS; PROTEIN AB With age, growth plate cartilage undergoes programmed senescence, eventually causing cessation of bone elongation and epiphyseal fusion. Estrogen accelerates this developmental process. We hypothesized that senescence occurs because progenitor cells in the resting zone are depleted in number and that estrogen acts by accelerating this depletion. To test this hypothesis, juvenile ovariectomized rabbits received injections of estradiol cypionate or vehicle for 5 weeks, and then were left untreated for an additional 5 weeks. Exposure to estrogen accelerated the normal decline in growth plate height and in the number of proliferative and hypertrophic chondrocytes. Five weeks after discontinuation of estrogen treatment, these structural parameters remained advanced, indicating an irreversible advancement in structural senescence. Similarly, transient estrogen exposure hastened epiphyseal fusion. Estrogen also caused a more rapid decline in functional parameters of growth plate senescence, including growth rate, proliferation rate, and hypertrophic cell size. However, in contrast to the structural parameters, once the estrogen treatment was discontinued, the growth rate, chondrocyte proliferation rate, and hypertrophic cell size all normalized, suggesting that estrogen has a reversible, suppressive effect on growth plate function. In addition, estrogen accelerated the normal loss of resting zone chondrocytes with age. This decrease in resting zone cell number did not appear to be due to apoptosis. However, it was maintained after the estrogen treatment stopped, suggesting that it represents irreversible depletion. The findings are consistent with the hypothesis that estrogen causes irreversible depletion of progenitor cells in the resting zone, thus irreversibly accelerating structural senescence and hastening epiphyseal fusion. In addition, estrogen reversibly suppresses growth plate function. C1 [Nilsson, Ola; Weise, Martina; Landman, Ellie B. M.; Meyers, Jodi L.; Barnes, Kevin M.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Nilsson, Ola; Landman, Ellie B. M.] Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Mol Med & Pediat Endocrinol, SE-17176 Stockholm, Sweden. Karolinska Univ Hosp, SE-17176 Stockholm, Sweden. RP Baron, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg CRC,Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM Jeffrey.Baron@nih.gov OI Nilsson, Ola/0000-0002-9986-8138 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; ESPE Research Fellowship grant; Novo Nordisk; Swedish Research Council [K2012-99X-21998-01-3]; Swedish Society of Medicine; Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care; Wera Ekstrom's Foundation for Pediatric Research; Marta och Gunnar V Philipson's Foundation; Sallskapet Barnavard; Stiftelsen Frimurare Barnhuset i Stockholm; Karolinska Institutet; zgsx FX The work of O.N., M.W., E.B.M.L., and J.B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. O.N. was supported by an ESPE Research Fellowship grant, supported by Novo Nordisk, and grants from the Swedish Research Council (K2012-99X-21998-01-3), the Swedish Society of Medicine, Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care, Wera Ekstrom's Foundation for Pediatric Research, zgsx, Marta och Gunnar V Philipson's Foundation, Sallskapet Barnavard, Stiftelsen Frimurare Barnhuset i Stockholm, and Karolinska Institutet. NR 34 TC 8 Z9 9 U1 2 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2014 VL 155 IS 8 BP 2892 EP 2899 DI 10.1210/en.2013-2175 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QL UT WOS:000342343800015 PM 24708243 ER PT J AU Wall, EH Case, LK Hewitt, SC Trang, NV Candelaria, NR Teuscher, C Lin, CY AF Wall, Emma H. Case, Laure K. Hewitt, Sylvia C. Trang Nguyen-Vu Candelaria, Nicholes R. Teuscher, Cory Lin, Chin-Yo TI Genetic Control of Ductal Morphology, Estrogen-Induced Ductal Growth, and Gene Expression in Female Mouse Mammary Gland SO ENDOCRINOLOGY LA English DT Article ID ESTRADIOL-REGULATED RESPONSES; BREAST-CANCER RISK; RECEPTOR-ALPHA; POLYGENIC SUSCEPTIBILITY; STRAIN DIFFERENCES; RUNX FAMILY; BONE LOSS; MECHANISMS; MICE; MORPHOGENESIS AB The uterotropic response of the uterus to 17 beta-estradiol (E-2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high (C57BL6/J; B6) or low (C3H/HeJ; C3H) responders to E-2 led to the identification of quantitative trait loci (QTL) associated with phenotypic variation in uterine growth and leukocyte infiltration. Like the uterus, phenotypic variation in the responsiveness of the mammary gland to E-2 during both normal and pathologic conditions has been reported. In the current experiment, we utilized an E-2-specific model of mammary ductal growth combined with a microarray approach to determine the degree to which genotype influences the responsiveness of the mammary gland to E-2, including the associated transcriptional programs, in B6 and C3H mice. Our results reveal that E-2-induced mammary ductal growth and ductal morphology are genetically controlled. In addition, we observed a paradoxical effect of mammary ductal growth in response to E-2 compared with what has been reported for the uterus; B6 is a high responder for the uterus and was a low responder for mammary ductal growth, whereas the reverse was observed for C3H. In contrast, B6 was a high responder for mammary ductal side branching. The B6 phenotype was associated with increased mammary epithelial cell proliferation and apoptosis, and a distinct E-2-induced transcriptional program. These findings lay the groundwork for future experiments designed to investigate the genes and mechanisms underlying phenotypic variation in tissue-specific sensitivity to systemic and environmental estrogens during various physiological and disease states. C1 [Wall, Emma H.; Case, Laure K.; Teuscher, Cory] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Hewitt, Sylvia C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Trang Nguyen-Vu; Candelaria, Nicholes R.; Teuscher, Cory; Lin, Chin-Yo] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 USA. RP Lin, CY (reprint author), NSM, Ctr Nucl Receptors & Cell Signaling, Dept Biol & Biochem, 3605 Cullen Blvd,SERC Bldg 545,Rm 3023, Houston, TX 77204 USA. EM C.Teuscher@uvm.edu; clin23@Central.UH.EDU FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES70065]; National Institutes of Health Research [R01NS36526, R01NS061014, R01NS060901, R01NS069628, R01AI41747]; State of Texas Emerging Technologies Fund [300-9-1958] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences project number Z01ES70065 to S.C.H and National Institutes of Health Research project numbers R01NS36526, R01NS061014, R01NS060901, R01NS069628, and R01AI41747 to C.T.. C.Y.L. is a member of the Center for Nuclear Receptors and Cell Signaling at the University of Houston supported by the State of Texas Emerging Technologies Fund (grant number 300-9-1958). NR 61 TC 6 Z9 6 U1 0 U2 6 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2014 VL 155 IS 8 BP 3025 EP 3035 DI 10.1210/en.2013-1910 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QL UT WOS:000342343800028 PM 24708240 ER PT J AU Kessler, RC Nock, MK Schoenbaum, M AF Kessler, Ronald C. Nock, Matthew K. Schoenbaum, Michael TI Mental Health and the Army Reply SO JAMA PSYCHIATRY LA English DT Letter ID ASSESS RISK; RESILIENCE; STARRS; SOLDIERS; PREVALENCE; DISORDERS; SUICIDE C1 [Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu NR 7 TC 0 Z9 0 U1 3 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD AUG PY 2014 VL 71 IS 8 BP 967 EP 968 PG 2 WC Psychiatry SC Psychiatry GA AP0SP UT WOS:000341774600019 PM 25102903 ER PT J AU Diker-Cohen, T Abraham, SB Rauschecker, M Papadakis, GZ Munir, KM Brown, E Lyssikatos, C Belyavskaya, E Merino, M Stratakis, CA AF Diker-Cohen, Talia Abraham, Smita Baid Rauschecker, Mitra Papadakis, Georgios Z. Munir, Kashif M. Brown, Eric Lyssikatos, Charalampos Belyavskaya, Elena Merino, Maria Stratakis, Constantine A. TI Reninoma Presenting in Pregnancy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID JUXTAGLOMERULAR CELL TUMOR C1 [Diker-Cohen, Talia] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20814 USA. [Abraham, Smita Baid; Rauschecker, Mitra; Papadakis, Georgios Z.; Lyssikatos, Charalampos; Belyavskaya, Elena; Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol, NIH, Bethesda, MD 20814 USA. NICHHD, Genet & Pediat Endocrinol Interinst Training Pro, Eunice Kennedy Shriver Ctr Mental Retardat Inc, NIH, Bethesda, MD 20814 USA. [Munir, Kashif M.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Brown, Eric] Mid Atlantic Nephrol Associates, Baltimore, MD 21117 USA. [Merino, Maria] NCI, Lab Diagnost Pathol, NIH, Bethesda, MD 20814 USA. RP Diker-Cohen, T (reprint author), NIDDK, NIH, 10 Ctr Dr,Bldg 10,Clin Res Ctr,Room 5-3961, Bethesda, MD 20814 USA. EM talia.diker-cohen@nih.gov OI Munir, Kashif/0000-0002-1075-1284 NR 6 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP 2625 EP 2626 DI 10.1210/jc.2014-1730 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200029 PM 24848711 ER PT J AU Zhang, C Yang, AI Vasconcelos, L Moon, S Yang, CZ Nesvick, CL Saidkhodjaeva, L Abdullaev, Z Pack, SD Ghosh, A Chittiboina, P Heiss, JD Zhuang, ZP Quezado, MM Zaghloul, KA AF Zhang, Chao Yang, Andrew I. Vasconcelos, Lucas Moon, Seog Yang, Chunzhang Nesvick, Cody L. Saidkhodjaeva, Lola Abdullaev, Ziedulla Pack, Svetlana D. Ghosh, Arunima Chittiboina, Prashant Heiss, John D. Zhuang, Zhengping Quezado, Martha M. Zaghloul, Kareem A. TI Von Hippel-Lindau Disease Associated Pulmonary Carcinoid with Cranial Metastasis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COMMON BILE-DUCT; TUMOR; CANCER; COMPLICATION; DOMAIN; BRAIN; GENE; RARE AB Context: Carcinoids have rarely been described in von Hippel-Lindau (VHL) disease. Objective: We describe the first reported case of a patient with VHL who developed a pulmonary carcinoid that subsequently metastasized to a pre-existent cranial hemangioblastoma. Results: Histological and immunohistochemical features of the metastatic lesion were similar to the primary carcinoid. Both lesions demonstrated heterozygous VHL gene deletions with fluorescence in situ hybridization analysis. Conclusions: This case provides direct molecular genetic evidence of an association between VHL and carcinoids. C1 [Zhang, Chao; Yang, Andrew I.; Yang, Chunzhang; Nesvick, Cody L.; Chittiboina, Prashant; Heiss, John D.; Zhuang, Zhengping; Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Vasconcelos, Lucas; Moon, Seog; Saidkhodjaeva, Lola; Abdullaev, Ziedulla; Pack, Svetlana D.; Ghosh, Arunima; Quezado, Martha M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Chao] Third Mil Med Univ, Xinqiao Hosp, Dept Orthoped, Chongqing 400037, Peoples R China. RP Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM quezadom@mail.nih.gov; kareem.zaghloul@nih.gov OI Heiss, John/0000-0002-3890-0165 FU National Institutes of Health (NIH) Medical Research; NIH FX A.I.Y. is supported through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities Inc and Mr and Mrs Joel S. Marcus, and the Howard Hughes Medical Institute. NR 20 TC 2 Z9 2 U1 1 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP 2633 EP 2636 DI 10.1210/jc.2014-1732 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200031 PM 24878057 ER PT J AU Schisterman, EF Mumford, SL Browne, RW Barr, DB Chen, Z Louis, GMB AF Schisterman, Enrique F. Mumford, Sunni L. Browne, Richard W. Barr, Dana Boyd Chen, Zhen Louis, Germaine M. Buck TI Lipid Concentrations and Couple Fecundity: The LIFE Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BODY-MASS INDEX; ASSISTED REPRODUCTIVE TECHNOLOGY; LIVER X RECEPTORS; TIME-TO-PREGNANCY; LIPOPROTEIN CHOLESTEROL; METABOLIC SYNDROME; OVULATORY INFERTILITY; MENSTRUAL-CYCLE; UNITED-STATES; FERTILITY AB Context: A role of lipids in human fecundity is hypothesized as cholesterol is the main substrate for steroid synthesis and has also been shown to affect the hormonal milieu and steroidogenesis in both men and women. Objective: The objective of the study was to evaluate the association between male and female serum lipid concentrations and time to pregnancy (TTP). Design/Setting: A population-based prospective cohort study recruiting couples from 16 counties in Michigan and Texas (2005-2009) using sampling frameworks allowing for identification of couples planning pregnancy in the near future. Participants: Five hundred one couples desiring pregnancy and discontinuing contraception were followed up for 12 months or until a human chorionic gonadotropin pregnancy was detected. Main Outcome and Measures: Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated after adjusting for age, body mass index, race, and education in relationship to female, male, and joint couple lipid concentrations. Results: Serum free cholesterol levels were higher on average among male and female partners of couples who did not became pregnant during the study follow-up (female, P = .04; male, P = .009), and levels in female partners were associated with significantly longer TTP in models based on both individual and couples concentrations (individual models: FOR 0.98, 95% CI 0.97, 0.99; couple models: FOR 0.98,95% CI 0.97, 0.99). Male free cholesterol concentrations were associated with TTP only in the couple-based models (FOR 0.98, 95% CI 0.97, 0.99). Sensitivity analyses suggested that the observed associations are unlikely to be explained by potential unmeasured confounding such as diet. Conclusions: Our results suggest that serum free cholesterol concentrations in both men and women have an effect on TTP, highlighting the importance of cholesterol and lipid homeostasis for male and female fecundity. C1 [Schisterman, Enrique F.; Mumford, Sunni L.; Chen, Zhen; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Browne, Richard W.] SUNY Buffalo, Dept Biotechn & Clin Lab Sci, Buffalo, NY 14214 USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institutes of Health Contracts N01-HD-3-3355, N01-HD-3-3356, and N01-HD-3-3358. NR 62 TC 11 Z9 11 U1 1 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP 2786 EP 2794 DI 10.1210/jc.2013-3936 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200052 PM 24846535 ER PT J AU Christensen, JD Lungu, AO Cochran, E Collins, MT Gafni, RI Reynolds, JC Rother, KI Gorden, P Brown, RJ AF Christensen, John D. Lungu, Andreea O. Cochran, Elaine Collins, Michael T. Gafni, Rachel I. Reynolds, James C. Rother, Kristina I. Gorden, Phillip Brown, Rebecca J. TI Bone Mineral Content in Patients With Congenital Generalized Lipodystrophy Is Unaffected by Metreleptin Replacement Therapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID REVERSES INSULIN-RESISTANCE; DEFICIENT OB/OB MICE; LONG-TERM EFFICACY; GROWTH-FACTOR 23; LEPTIN-REPLACEMENT; BODY-COMPOSITION; RECOMBINANT LEPTIN; PLASMA ADIPONECTIN; OBESE GENE; CHILDREN AB Context: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. Patients with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. Objective: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. Design and Setting: An open-label nonrandomized study at the National Institutes of Health. Patients: Thirty-one patients with CGL (ages 4.3 to 46.7 y). Intervention: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. Outcome Measures: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. Results: At baseline, patients demonstrated significantly increased total body less head BMC(mean SDS, 1.8 +/- 0.7), height (mean SDS, 1.3 +/- 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 +/- 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D. Conclusions: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature. C1 [Christensen, John D.; Cochran, Elaine; Rother, Kristina I.; Gorden, Phillip; Brown, Rebecca J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. [Lungu, Andreea O.] Joslin Diabet Ctr, Brookline, MA 02215 USA. RP Brown, RJ (reprint author), 10 Ctr Dr,MSC 1612,Room CRC 6-5942, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov FU Intramural Research Programs of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Dental and Craniofacial Research FX This work was supported by Intramural Research Programs of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Dental and Craniofacial Research. NR 39 TC 11 Z9 12 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP E1493 EP E1500 DI 10.1210/jc.2014-1353 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200014 PM 25070319 ER PT J AU Crocker, MK Stern, EA Sedaka, NM Shomaker, LB Brady, SM Ali, AH Shawker, TH Hubbard, VS Yanovski, JA AF Crocker, Melissa K. Stern, Elizabeth A. Sedaka, Nicole M. Shomaker, Lauren B. Brady, Sheila M. Ali, Asem H. Shawker, Thomas H. Hubbard, Van S. Yanovski, Jack A. TI Sexual Dimorphisms in the Associations of BMI and Body Fat with Indices of Pubertal Development in Girls and Boys SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; STIMULATES ANDROGEN ACCUMULATION; HORMONE-BINDING-GLOBULIN; INSULIN-RESISTANCE; MASS INDEX; BIRTH-WEIGHT; PELVIC ULTRASONOGRAPHY; PREMATURE ADRENARCHE; PRECOCIOUS PUBARCHE; SKELETAL MATURATION AB Context: The effect of obesity and concomitant insulin resistance on pubertal development is incompletely elucidated. Objective: To determine how measures of adiposity and insulin resistance are associated with pubertal maturation in boys and girls. Setting and Design: Breast and pubic hair Tanner stage and testicular volume by orchidometry were determined by physical examination in 1066 children. Ovarian volume was estimated by trans-abdominal ultrasound. Fat mass, skeletal age, and fasting serum for insulin and glucose, total T, estradiol, estrone, dehydroepiandrosterone-sulfate, and androstenedione were measured at the National Institutes of Health Clinical Research Center. Convenience sample; 52% obese, 59% female. Results: Logistic regression identified a significant interaction between sex and obesity for prediction of pubertal development (P <= .01). There was a negative association between boys' testicular volume and body mass index (BMI)/fat mass but a positive association between girls' breast stage and BMI/fat mass. Ovarian volume in girls was positively associated with insulin resistance but not with BMI/fat mass. There was a positive association between obesity and measures of estrogen exposure (breast development and skeletal age) in both sexes. Positive correlations were seen for girls between BMI and pubic hair development and between insulin resistance and T production, whereas adiposity was negatively associated with pubic hair in boys. Conclusions: Significant sexual dimorphisms in the manifestations of pubertal development are seen in obese girls and boys. Two known effects of obesity, increased peripheral conversion of low-potency androgens to estrogens by adipose tissue-aromatase and increased insulin resistance, may be in large part responsible for these differences. C1 [Crocker, Melissa K.; Stern, Elizabeth A.; Sedaka, Nicole M.; Shomaker, Lauren B.; Brady, Sheila M.; Ali, Asem H.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Crocker, Melissa K.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Shomaker, Lauren B.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Shawker, Thomas H.] Ctr Clin, NIH, Bethesda, MD 20892 USA. [Hubbard, Van S.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. Natl Inst Diabet Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHD, Hatfield Clin Res Ctr, Sect Growth & Obes, NIH, 9000 Rockville Pike,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural Research Program, NIH from NICHD [1ZIAHD000641]; National Institute for Minority Health and Health Disparities; Division of Nutrition Research Coordination, NIH; Division of Nutrition Research Coordination; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by Intramural Research Program, NIH, grant 1ZIAHD000641 (to J.A.Y.) from NICHD with supplemental funding from the National Institute for Minority Health and Health Disparities and the Division of Nutrition Research Coordination, NIH. N.M.S. was supported by the Division of Nutrition Research Coordination and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Yanovski is a Commissioned Officer in the U.S. Public Health Service, DHHS. The first draft of the manuscript was written by Drs Crocker and Yanovski. NR 96 TC 12 Z9 13 U1 5 U2 12 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP E1519 EP E1529 DI 10.1210/jc.2014-1384 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200017 PM 24780051 ER PT J AU Nilsson, O Guo, MH Dunbar, N Popovic, J Flynn, D Jacobsen, C Lui, JC Hirschhorn, JN Baron, J Dauber, A AF Nilsson, Ola Guo, Michael H. Dunbar, Nancy Popovic, Jadranka Flynn, Daniel Jacobsen, Christina Lui, Julian C. Hirschhorn, Joel N. Baron, Jeffrey Dauber, Andrew TI Short Stature, Accelerated Bone Maturation, and Early Growth Cessation Due to Heterozygous Aggrecan Mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IDIOPATHIC SHORT STATURE; DNA-SEQUENCING DATA; RECEPTOR-B NPR2; SPONDYLOEPIPHYSEAL DYSPLASIA; PLATE; GENE; PROTEIN; GENOME; CHONDROCYTES; DISORDERS AB Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common. Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age. Setting and Design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation. Results: Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c. 2026 + 1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function. Conclusions: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation. C1 [Nilsson, Ola; Lui, Julian C.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Nilsson, Ola] Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden. [Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, SE-17176 Stockholm, Sweden. Karolinska Univ Hosp, SE-17176 Stockholm, Sweden. [Guo, Michael H.] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA. [Dunbar, Nancy] Connecticut Childrens Med Ctr, Hartford, CT 06106 USA. [Popovic, Jadranka; Flynn, Daniel] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15224 USA. [Guo, Michael H.; Jacobsen, Christina; Hirschhorn, Joel N.; Dauber, Andrew] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Guo, Michael H.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Dauber, Andrew] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. RP Dauber, A (reprint author), Boston Childrens Hosp, Div Endocrinol, 300 Longwood Ave, Boston, MA 02115 USA. EM andrew.dauber@childrens.harvard.edu RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Harvard Catalyst The Harvard Clinical and Translational Science Center (National Institutes of Health Award from Harvard University) [UL1 TR001102]; Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [1K23HD073351]; Pediatric Endocrine Society Clinical Scholar Award; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; ESPE Research Fellowship Grant; Swedish Research Council [K2012-99X-21998-01-3]; Swedish Society of Medicine; Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care; Wera Ekstrom's Foundation for Pediatric Research; Marta och Gunnar V Philipson's Foundation; Sallskapet Barnavard; Stiftelsen Frimurare Barnhuset i Stockholm; Karolinska Institutet FX This work was supported by Harvard Catalyst The Harvard Clinical and Translational Science Center (National Institutes of Health Award No. UL1 TR001102 and financial contributions from Harvard University and its affiliated academic health care centers). This work was also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [1K23HD073351 to A.D.] and the Pediatric Endocrine Society Clinical Scholar Award to A.D. Genomic sequencing for family 2 was performed by Boston Children's Hospital Genomic Diagnostic Laboratory, now called Claritas Genomics through the Research Connection of Boston Children's Hospital.; The work of O.N., J.C.L., and J.B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. O.N. was supported by an ESPE Research Fellowship Grant and a grant from the Swedish Research Council (K2012-99X-21998-01-3), the Swedish Society of Medicine, Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care, Wera Ekstrom's Foundation for Pediatric Research, Marta och Gunnar V Philipson's Foundation, Sallskapet Barnavard, Stiftelsen Frimurare Barnhuset i Stockholm, and Karolinska Institutet. NR 33 TC 15 Z9 16 U1 0 U2 6 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP E1510 EP E1518 DI 10.1210/jc.2014-1332 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200016 PM 24762113 ER PT J AU Burns, KA Li, Y Liu, LW Korach, KS AF Burns, Katherine A. Li, Yin Liu, Liwen Korach, Kenneth S. TI Research Resource: Comparison of Gene Profiles From Wild-Type ER alpha and ER alpha Hinge Region Mutants SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; BINDING DOMAIN; TRANSCRIPTIONAL ACTIVATION; IN-VIVO; NUCLEAR; TRANSACTIVATION; NONNUCLEAR; PATHWAY; GROWTH; BETA AB We showed previously that the hinge region of estrogen receptor (ER) alpha is involved in mediating its actions. The hinge 1 (H1) ER alpha mutant has disrupted nuclear localization and has lost interaction with c-JUN, but retains estrogen response element (ERE)-mediated functions. The hinge 2 + nuclear export sequence (H2NES) ER alpha mutant does not maintain nuclear translocation with hormone and no longer activates ERE target genes but does retain a nongenomic, nonnuclear, rapid-action response. Herein, we used the human endometrial cancer Ishikawa stable cell lines (Ishikawa/vector, Ishikawa/wild-type [WT] ER alpha, Ishikawa/H1 ER alpha, or Ishikawa/H2NES ER alpha) to characterize the biological activities of these 2 ER alpha hinge region mutants. We confirmed by confocal microscopy increased cytoplasmic ER alpha in the H1 ER alpha cell line and full cytoplasmic ER alpha localization in the H2NES ER alpha cell line. Luciferase assays using the 3xERE reporter showed activation of H1 ER alpha and H2NES ER alpha by estradiol (E-2) treatment, but using the endogenous pS2 reporter, luciferase activity was only seen with the H1 ER alpha cell line. Examining cell proliferation revealed that only the WTER alpha and H1 ER alpha cell lines increased proliferation after treatment. Using microarrays, we found that WT ER alpha and H1 ER alpha cluster together, whereas vector and H2NES ER alpha are most similar and cluster independently of E-2 treatment. These studies revealed that the nongenomic activities of ER alpha are unable to mediate proliferative changes or the transcriptional profile after treatment and demonstrate the importance of genomic action for ER alpha/E-2-mediated responses with the nongenomic actions of ER alpha being complementary to elicit the full biological actions of ER alpha. C1 [Burns, Katherine A.; Li, Yin; Korach, Kenneth S.] NIEHS, NIH, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27790 USA. [Liu, Liwen] NIEHS, NIH, Mol Genom Core Facil, Res Triangle Pk, NC 27790 USA. RP Korach, KS (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27790 USA. EM korach@niehs.nih.gov FU National Institutes of Health [Z01ES70065] FX This work was supported by the National Institutes of Health (Grant Z01ES70065 to K.S.K.). NR 44 TC 1 Z9 1 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2014 VL 28 IS 8 BP 1352 EP 1361 DI 10.1210/me.2014-1122 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8RF UT WOS:000342345800013 PM 24947674 ER PT J AU Katz, LS Geras-Raaka, E Gershengorn, MC AF Katz, Liora S. Geras-Raaka, Elizabeth Gershengorn, Marvin C. TI Heritability of fat accumulation in white adipocytes SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE white adipose tissue; differentiation; fluorescence-activated cell sorter; epigenetics; Ppar gamma; fat ID ADIPOSE CELL LINE; PPAR-GAMMA; GENE-EXPRESSION; TRANSCRIPTION FACTORS; HISTONE METHYLATION; MATURE ADIPOCYTES; DIFFERENTIATION; ADIPOGENESIS; TISSUE; RECEPTOR AB Since individual cells from freshly isolated white adipose tissue (WAT) exhibit variable levels of fat accumulation, we attempted to determine which factor(s) cause this variation. We used primary WAT cells from adult mice and the mouse 3T3-L1 cell-line of preadipocytes for these studies. Cells were labeled with BODIPY (boron-dipyrromethene) lipid probe, a marker for fat accumulation in live cells, and sorted on a fluorescence-activated cell sorter into two populations exhibiting low or high BODIPY fluorescence intensity. After more than 12 doublings as dedifferentiated cells in growth medium, the sorted populations were exposed to adipogenic medium for 7 days and analyzed for BODIPY accumulation and mRNA expression of adipogenic markers. WAT-derived cells initially sorted to have low or high BODIPY fluorescence intensity maintained a similar low or high lipid phenotype after redifferentiation. Cell surface TSH receptor expression, which is known to increase when preadipocytes are differentiated, correlated with BODIPY staining in all states. mRNA levels of Ppar gamma, Srebp1c, aP2, and Pref1, key regulators of adipogenesis, and leptin, Glut4, Fasn, and Tshr, markers of adipocyte differentiation, correlated with the levels of fat accumulation. Overexpression of Ppar gamma in 3T3-L1 cells, as expected, caused cells from low- and high-BODIPY populations to accumulate more fat. More importantly, prior to differentiation, the endogenous Ppar gamma promoter exhibited higher levels of acetylated histone H3, an activatory modification, in high-BODIPY-compared with low-BODIPY-derived populations. We conclude that fat accumulation is a heritable trait in WAT and that epigenetic modification on the Ppar gamma promoter contributes to this heritability. C1 [Katz, Liora S.; Geras-Raaka, Elizabeth; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov NR 39 TC 4 Z9 5 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG 1 PY 2014 VL 307 IS 3 BP E335 EP E344 DI 10.1152/ajpendo.00075.2014 PG 10 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA AO9WB UT WOS:000341709200009 PM 24939735 ER PT J AU Grady, PA Gough, LL AF Grady, Patricia A. Gough, Lisa Lucio TI Self-Management: A Comprehensive Approach to Management of Chronic Conditions SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; SKILLS TRAINING-PROGRAM; CHRONIC DISEASE; SOCIAL SUPPORT; OLDER-ADULTS; CHRONIC PAIN; HEALTH-STATUS; OUTCOMES; INTERVENTION AB For both clinical and economic reasons, the increasing number of persons living with chronic conditions represents a public health issue of growing importance. Emphasizing patient responsibility, and acting in concert with the provider community, self-management represents a promising strategy for treating chronic conditions-moving beyond education to teaching individuals to actively identify challenges and solve problems associated with their illness. Self-management also shows potential as an effective paradigm across the prevention spectrum (primary, secondary, and tertiary) by establishing a pattern for health early in life and providing strategies for mitigating illness and managing it in later life. We suggest ways to advance research methods and practical applications of self-management as steps in its future development and implementation. C1 [Grady, Patricia A.; Gough, Lisa Lucio] NINR, NIH, Bethesda, MD 20892 USA. RP Gough, LL (reprint author), 6701 Democracy Blvd,Suite 710, Bethesda, MD 20817 USA. EM goughll@mail.nih.gov NR 69 TC 8 Z9 8 U1 1 U2 17 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2014 VL 104 IS 8 BP E25 EP E31 DI 10.2105/AJPH.2014.302041 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EY UT WOS:000341811000010 PM 24922170 ER PT J AU Huang, GC Soto, D Fujimoto, K Valente, TW AF Huang, Grace C. Soto, Daniel Fujimoto, Kayo Valente, Thomas W. TI The Interplay of Friendship Networks and Social Networking Sites: Longitudinal Analysis of Selection and Influence Effects on Adolescent Smoking and Alcohol Use SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PEER INFLUENCE; CIGARETTE-SMOKING; SUBSTANCE USE; TOBACCO USE; BEHAVIOR; SOCIALIZATION; RISK; ATTRIBUTES; MARIJUANA; DYNAMICS AB Objectives. We examined the coevolution of adolescent friendships and peer influences with respect to their risk behaviors and social networking site use. Methods. Investigators of the Social Network Study collected longitudinal data during fall 2010 and spring 2011 from 10th-grade students in 5 Southern California high schools (n = 1434). We used meta-analyses of stochastic actor-based models to estimate changes in friendship ties and risk behaviors and the effects of Facebook and MySpace use. Results. Significant shifts in adolescent smoking and drinking occurred despite little change in overall prevalence rates. Students with higher levels of alcohol use were more likely to send and receive friendship nominations and become friends with other drinkers. They were also more likely to increase alcohol use if their friends drank more. Adolescents selected friends with similar Facebook and MySpace use habits. Exposure to friends' risky online pictures increased smoking behaviors but had no significant effects on alcohol use. Conclusions. Our findings support a greater focus on friendship selection mechanisms in school-based alcohol use interventions. Social media platforms may help identify at-risk adolescent groups and foster positive norms about risk behaviors. C1 [Huang, Grace C.; Soto, Daniel; Valente, Thomas W.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Inst Prevent Res, Los Angeles, CA 90033 USA. [Fujimoto, Kayo] Univ Texas Houston, Sch Publ Hlth, Div Hlth Promot & Behav Sci, Houston, TX USA. RP Huang, GC (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E624, Rockville, MD 20850 USA. EM grace.huang@nih.gov FU National Institute on Alcohol Abuse and Alcoholism [1RC1AA019239-01]; National Cancer Institute Ruth L. Kirschstein NRSA award [T32 CA- 009492-28] FX This study was supported by the National Institute on Alcohol Abuse and Alcoholism (grant 1RC1AA019239-01 to T. W. V.) and the National Cancer Institute Ruth L. Kirschstein NRSA award (T32 CA- 009492-28). NR 55 TC 13 Z9 13 U1 9 U2 53 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2014 VL 104 IS 8 BP E51 EP E59 DI 10.2105/AJPH.2014.302038 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EY UT WOS:000341811000013 PM 24922126 ER PT J AU Ziegelbauer, JM AF Ziegelbauer, Joseph M. TI Viral microRNA genomics and target validation SO CURRENT OPINION IN VIROLOGY LA English DT Article ID PRIMARY EFFUSION LYMPHOMA; VIRUS-ENCODED MICRORNAS; SYSTEMATIC ANALYSIS; MESSENGER-RNAS; MOUSE MODEL; HUMAN GENES; CELLS; EXPRESSION; IDENTIFICATION; INFECTION AB A subset of viruses express their own microRNAs (miRNAs) and one way to understand the functions of these microRNAs is to identify the targets of these miRNAs. Sequence analysis and mRNA expression profiling were some of the first techniques to identify targets of viral miRNAs. More recently, proteomics and sequencing of RNA by crosslinking and immunoprecipitation (CLIP) methods have-been insightful and discovered many miRNA targets that may be missed using other methods. We are now at a point where numerous validated miRNA targets have been described and integration of these genomic datasets will provide a richer understanding of miRNA targeting and viral infection, persistence, and pathogenesis. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ziegelbauer, JM (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Comments were provided by Christine Happel and Anna Serquina. It is regrettable that certain citations could not be included due to various restrictions. NR 60 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD AUG PY 2014 VL 7 BP 33 EP 39 DI 10.1016/j.coviro.2014.03.014 PG 7 WC Virology SC Virology GA AP2KV UT WOS:000341902000007 PM 24763063 ER PT J AU Kuzembayeva, M Hayes, M Sugden, B AF Kuzembayeva, Malika Hayes, Mitchell Sugden, Bill TI Multiple functions are mediated by the miRNAs of Epstein-Barr virus SO CURRENT OPINION IN VIROLOGY LA English DT Article ID ENCODED MICRORNAS; CELL LYMPHOMA; TARGET; EBV; RECOGNITION; INFECTION; CARCINOMA; CANCERS; CLUSTER; LATENCY AB Epstein-Barr virus is a gammaherpes virus that is causally associated with several malignancies and expresses multiple miRNAs in both normal and tumor cells. Since the identification of virally encoded miRNAs, various mRNAs have been identified as targets for regulation by EBV's miRNAs in host cells. We shall summarize these targets, the robustness of their identification, and examine how the regulation of these targets by EBV contributes to the successful infection of its host. C1 [Kuzembayeva, Malika] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Hayes, Mitchell; Sugden, Bill] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. RP Sugden, B (reprint author), Univ Wisconsin, McArdle Lab Canc Res, 1400 Univ Ave, Madison, WI 53706 USA. EM sugden@oncology.wisc.edu OI Hayes, Mitchell/0000-0002-2736-6542 FU NCI NIH HHS [R01 CA133027, P01 CA022443, R01 CA070723] NR 41 TC 10 Z9 11 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD AUG PY 2014 VL 7 BP 61 EP 65 DI 10.1016/j.coviro.2014.04.003 PG 5 WC Virology SC Virology GA AP2KV UT WOS:000341902000011 PM 24814666 ER PT J AU Rogalsky, DK Mendola, P Metts, TA Martin, WJ AF Rogalsky, Derek K. Mendola, Pauline Metts, Tricia A. Martin, William J., II TI Estimating the Number of Low-Income Americans Exposed to Household Air Pollution from Burning Solid Fuels SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID RESIDENTIAL INDOOR PM2.5; WOOD SMOKE; DEVELOPING-COUNTRIES; BIRTH-WEIGHT; RISK-FACTORS; CHILDREN; DISEASE; INTERVENTION; INFECTIONS; PREVALENCE AB BACKGROUND: Exposure to household air pollution (HAP) from inefficient biomass and coal stoves kills nearly 4 million people every year worldwide. HAP is an environmental risk associated with poverty that affects an estimated 3 billion people mostly in low- and middle-income countries. OBJECTIVES: Our goal was to estimate the number of low-income Americans exposed to potentially health-damaging concentrations of HAP. METHODS: We mapped county-level data for the percentage of households using wood, coal, and/or coke as their primary heating fuel along with percent of the population below the federal poverty level. Using U.S. Census data and the likelihood of fugitive emissions as reported in the literature, we estimated the number of low-income Americans potentially exposed to HAP. RESULTS: Solid fuel is the primary heating source for > 2.5 million U. S. households, or 6.5 million people. The mapping exercise showed several rural areas, primarily in the northern and western regions, that have high levels of solid-fuel use and poverty. We then identified 117 counties with high co-incident poverty and solid-fuel use as high-priority counties for research into potential health risks from HAP. We estimate that between 500,000 and 600,000 low-income people in the United States are likely exposed to HAP from burning solid fuels within their homes. CONCLUSION: HAP occurs within the United States and should be further investigated for adverse health risks, especially among those living in areas with rural poverty. C1 [Rogalsky, Derek K.] Georgetown Univ, Sch Med, Washington, DC USA. [Mendola, Pauline; Martin, William J., II] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Metts, Tricia A.] E Tennessee State Univ, Dept Environm Hlth, Johnson City, TN 37614 USA. RP Martin, WJ (reprint author), Ohio State Univ, Coll Publ Hlth, 250 Cunz Hall,1841 Neil Ave, Columbus, OH 43210 USA. EM wjmartin@cph.osu.edu OI Mendola, Pauline/0000-0001-5330-2844 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research has been supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 46 TC 12 Z9 12 U1 5 U2 20 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 AUG PY 2014 VL 122 IS 8 BP 806 EP 810 DI 10.1289/ehp.1306709 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AO9XL UT WOS:000341713800014 PM 24833615 ER PT J AU Birnbaum, LS Woychik, R AF Birnbaum, Linda S. Woychik, Rick TI Retirement of Hugh A. Tilson SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.; Woychik, Rick] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov; rick.woychik@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 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 AUG PY 2014 VL 122 IS 8 BP A202 EP A202 DI 10.1289/ehp.1408939 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AO9XL UT WOS:000341713800001 ER PT J AU Street, JM Yuen, PST Star, RA AF Street, Jonathan M. Yuen, Peter S. T. Star, Robert A. TI Bioactive Exosomes: Possibilities for Diagnosis and Management of Bladder Cancer SO JOURNAL OF UROLOGY LA English DT Editorial Material ID HUMAN URINE C1 [Street, Jonathan M.; Yuen, Peter S. T.; Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. RP Street, JM (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural NIH HHS NR 11 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2014 VL 192 IS 2 BP 297 EP 298 DI 10.1016/j.juro.2014.05.050 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AP5BT UT WOS:000342095400001 PM 24837807 ER PT J AU Platz, EA Tangen, CM Goodman, PJ Till, C Parnes, HL Figg, WD Albanes, D Neuhouser, ML Klein, EA Lucia, MS Thompson, IM Kristal, AR AF Platz, Elizabeth A. Tangen, Catherine M. Goodman, Phyllis J. Till, Cathee Parnes, Howard L. Figg, William D. Albanes, Demetrius Neuhouser, Marian L. Klein, Eric A. Lucia, M. Scott Thompson, Ian M., Jr. Kristal, Alan R. TI Statin Drug Use is Not Associated with Prostate Cancer Risk in Men Who are Regularly Screened SO JOURNAL OF UROLOGY LA English DT Article DE prostate; hydroxymethylglutaryl-coA reductase inhibitors; prostatic neoplasms; risk; mass screening ID SERUM-CHOLESTEROL; PREVENTION TRIAL; ANTIGEN LEVELS; POPULATION; HEALTH; GRADE AB Purpose: Prospective cohort studies support the hypothesis that statin drug users have a lower risk of aggressive prostate cancer. Whether statin drug use influences the risk of screen detected disease is less clear, possibly because of complex detection biases. Thus, we investigated this association in a setting in which men had low baseline serum prostate specific antigen concentration and were screened annually. Materials and Methods: We performed a cohort study of 9,457 men 55 years old or older at randomization to the placebo arm of PCPT (Prostate Cancer Prevention Trial). The men reported new use of medications quarterly. We estimated the multivariable adjusted HR of prostate cancer (574 cases in 62,192 person-years) for statin drug use and duration of use during the trial using Cox proportional hazards regression. Results: During 7 years of followup statin drug use during the trial was not associated with the risk of total prostate cancer (HR 1.03, 95% CI 0.82-1.30), or lower grade (HR 0.96, 95% CI 0.71-1.29) or higher grade (HR 1.27, 95% CI 0.85-1.90) prostate cancer. Duration of use during followup was also not associated with the risk of total, or lower or higher grade disease (p trend = 0.7, 0.5 and 0.2, respectively). Conclusions: These prospective results do not support the hypothesis that statin drugs protect against prostate cancer in the setting of regular prostate cancer screening. C1 [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, James Buchanan Brady Urol Inst, Dept Epidemiol, Baltimore, MD 21205 USA. [Platz, Elizabeth A.] Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Parnes, Howard L.] NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Med Oncol Branch, Ctr Canc Res, NIH,Hlth & Human Serv, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, Hlth & Human Serv, Bethesda, MD 20892 USA. [Tangen, Catherine M.; Goodman, Phyllis J.; Till, Cathee] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Neuhouser, Marian L.; Kristal, Alan R.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Canc Prevent Program, Seattle, WA 98104 USA. [Klein, Eric A.] Cleveland Clin, Coll Med, Ctr Clin & Translat Res, Cleveland, OH 44106 USA. [Lucia, M. Scott] Univ Colorado Denver, Sch Med, Aurora, CO USA. [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Room E6132,615 North Wolfe St, Baltimore, MD 21205 USA. EM eplatz@jhu.edu RI Albanes, Demetrius/B-9749-2015; Figg Sr, William/M-2411-2016 FU National Cancer Institute, National Institutes of Health [P01 CA108964, U10 CA37429, P50 CA58236] FX Supported by National Cancer Institute, National Institutes of Health P01 CA108964, U10 CA37429 and P50 CA58236. NR 20 TC 15 Z9 15 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2014 VL 192 IS 2 BP 379 EP 384 DI 10.1016/j.juro.2014.01.095 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AP5BT UT WOS:000342095400023 PM 24518774 ER PT J AU Khoury, P Grayson, PC Klion, AD AF Khoury, Paneez Grayson, Peter C. Klion, Amy D. TI Eosinophils in vasculitis: characteristics and roles in pathogenesis SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID CHURG-STRAUSS-SYNDROME; MAJOR BASIC-PROTEIN; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES; ANTIBODY-ASSOCIATED VASCULITIS; PERIPHERAL-BLOOD EOSINOPHILIA; MUSCARINIC RECEPTOR FUNCTION; ANCA-ASSOCIATED VASCULITIS; REGULATORY T-CELLS; WEGENERS-GRANULOMATOSIS; GRANULE PROTEINS AB Eosinophils are multifunctional granular leukocytes that are implicated in the pathogenesis of a wide variety of disorders, including asthma, helminth infection, and rare hypereosinophilic syndromes. Although peripheral and tissue eosinophilia can be a feature of many types of small-vessel and medium-vessel vasculitis, the role of eosinophils has been best studied in eosinophilic granulomatosis with polyangiitis (EGPA), where eosinophils are a characteristic finding in all three clinical stages of the disorder. Whereas numerous studies have demonstrated an association between the presence of eosinophils and markers of eosinophil activation in the blood and tissues of patients with EGPA, the precise role of eosinophils in disease pathogenesis has been difficult to ascertain owing to the complexity of the disease process. In this regard, results of clinical trials using novel agents that specifically target eosinophils are providing the first direct evidence of a central role of eosinophils in EGPA. This Review focuses on the aspects of eosinophil biology most relevant to the pathogenesis of vasculitis and provides an update of current knowledge regarding the role of eosinophils in EGPA and other vasculitides. C1 [Khoury, Paneez; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Grayson, Peter C.] NIAMSD, Vasc Translat Res Program, NIH, Bethesda, MD 20892 USA. RP Khoury, P (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM khouryp@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported in whole or in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. The authors thank C. R. Lee for assistance with the preparation of Figure 3. NR 120 TC 15 Z9 17 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD AUG PY 2014 VL 10 IS 8 BP 474 EP 483 DI 10.1038/nrrheum.2014.98 PG 10 WC Rheumatology SC Rheumatology GA AP1LL UT WOS:000341831300008 PM 25003763 ER PT J AU Tedder, TF Leonard, WJ AF Tedder, Thomas F. Leonard, Warren J. TI AUTOIMMUNITY Regulatory B cells-IL-35 and IL-21 regulate the regulators SO NATURE REVIEWS RHEUMATOLOGY LA English DT Editorial Material ID CELLS; IL-35; CYTOKINES C1 [Tedder, Thomas F.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. RP Tedder, TF (reprint author), Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. EM thomas.tedder@duke.edu FU Intramural NIH HHS NR 10 TC 22 Z9 26 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD AUG PY 2014 VL 10 IS 8 DI 10.1038/nrrheum.2014.95 PG 3 WC Rheumatology SC Rheumatology GA AP1LL UT WOS:000341831300004 PM 24934192 ER PT J AU Li, WT Sun, XL Wang, Y Niu, G Chen, XY Qian, ZY Nie, LM AF Li, Weitao Sun, Xiaolian Wang, Yu Niu, Gang Chen, Xiaoyuan Qian, Zhiyu Nie, Liming TI In vivo quantitative photoacoustic microscopy of gold nanostar kinetics in mouse organs SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID BIODISTRIBUTION; NANOPARTICLES; TOMOGRAPHY AB We developed a high-resolution photoacoustic microscopy (PAM) system with a near-infrared (NIR) laser to noninvasively monitor the distribution of gold nanostar (GNS) in blood vessels, liver and spleen in mice. Photoacoustic images of organs at deep depths were continuously acquired in vivo every 30 minutes after a single dose of GNS by tail vein injection. The experimental results showed that GNS accumulated significantly in both liver and spleen from blood circulation after administration, which was qualitatively validated by fluorescence imaging. Our studies demonstrate that PAM might be potentially used for noninvasive tracing the kinetics of exogenous nanoparticles in biological system. (C) 2014 Optical Society of America C1 [Li, Weitao; Qian, Zhiyu] Nanjing Univ Aeronaut & Astronaut, Coll Automat Engn, Dept Biomed Engn, Nanjing 210016, Jiangsu, Peoples R China. [Li, Weitao; Sun, Xiaolian; Wang, Yu; Niu, Gang; Chen, Xiaoyuan; Nie, Liming] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Nie, Liming] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Li, WT (reprint author), Nanjing Univ Aeronaut & Astronaut, Coll Automat Engn, Dept Biomed Engn, 29 Yudao St, Nanjing 210016, Jiangsu, Peoples R China. EM zhiyu@nuaa.edu.cn; liming.nie@nih.gov RI Nie, Liming/F-7718-2016 FU National Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH; National Natural Science Foundation of China [61275199, 81301257, 61378092]; National Key Basic Research Program (973 project) [2014CB744503]; NUAA Fundamental Research Funds [NS2013035] FX This work was supported by National Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH, and National Natural Science Foundation of China (61275199, 81301257, and 61378092), National Key Basic Research Program (973 project) (2014CB744503), as well as the NUAA Fundamental Research Funds (NS2013035). The authors acknowledge instrumental and technical support from nanoPAM, United Well Inc. We also thank Mr. Darius Zamani for close reading of the manuscript. NR 21 TC 12 Z9 12 U1 3 U2 49 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD AUG 1 PY 2014 VL 5 IS 8 BP 2679 EP 2685 DI 10.1364/BOE.5.002679 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA AO9BA UT WOS:000341649300018 PM 25136493 ER PT J AU Bluemke, DA AF Bluemke, David A. TI Coronary Computed Tomographic Angiography and Incidental Pulmonary Nodules SO CIRCULATION LA English DT Editorial Material DE Editorials; angiography; coronary artery disease; tomography; x-ray computed ID FLEISCHNER-SOCIETY; LUNG-CANCER; TASK-FORCE; MANAGEMENT; STATEMENT; GUIDELINES; CT C1 [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 NR 12 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG PY 2014 VL 130 IS 8 BP 634 EP 637 DI 10.1161/CIRCULATIONAHA.114.011634 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AO4IG UT WOS:000341300100010 PM 25015341 ER PT J AU Dodd, LE Johnson, RF Blaney, JE Follmann, D AF Dodd, Lori E. Johnson, Reed F. Blaney, Joseph E. Follmann, Dean TI Matched Longitudinal Analysis of Biomarkers Associated with Survival SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID MODEL AB The identification of host or pathogen factors linked to clinical outcome is a common goal in many animal studies of infectious diseases. When the disease is fatal, statistical analysis of such factors may be biased from missing observations due to deaths. For example, when observations of a subject are censored before completing the intended study period, the complete trajectory will not be observed. Even if the factor is not associated with outcome, comparisons of data from survivors with those from nonsurvivors may lead to the wrong conclusions regarding associations with survival. Comparisons between subjects must account for differing observation lengths for those who survive relative to those who do not. Analyzing data over an interval common to all subjects provides one solution but requires eliminating data, some of which may be informative about the differences between groups. Here, we present a novel approach, matched longitudinal analysis (MLA), for analyzing such data based on matching biomarker intervals for survivors and nonsurvivors. We describe the results from simulation studies and from a study of monkeypox virus infection in nonhuman primates. In our application, MLA identified low monocyte chemoattractant protein-1 (MCP-1) levels as having a statistically significant association with survival, whereas the alternative methods did not identify an association. The method has general application to longitudinal studies that seek to find associations of biomarker changes with survival. C1 [Dodd, Lori E.; Follmann, Dean] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Reed F.; Blaney, Joseph E.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. RP Dodd, LE (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov FU NIAID Division of Intramural Research FX This study was supported, in part, by the NIAID Division of Intramural Research. NR 7 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 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD AUG PY 2014 VL 21 IS 8 BP 1145 EP 1152 DI 10.1128/CVI.00252-14 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AO8SH UT WOS:000341624000015 PM 24943381 ER PT J AU Ji, XN Huang, Q Yu, L Nussinov, R Ma, BY AF Ji, Xiaona Huang, Qiang Yu, Long Nussinov, Ruth Ma, Buyong TI Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE phosphorylation; p53 protein; p63; p73; protein binding site; cancer; intrinsically disordered proteins ID TUMOR-SUPPRESSOR P53; IARC TP53 DATABASE; DNA-DAMAGE; POSTTRANSLATIONAL MODIFICATIONS; TRANSACTIVATION DOMAIN; MUTANT P53; C-ABL; UNSTRUCTURED PROTEINS; SERINE-15 PHOSPHORYLATION; MEDIATED PHOSPHORYLATION AB p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site and its nearby flanking residues, focusing on the consensus phosphorylation motif pattern, amino-acid correlations within the phosphorylation motifs, the propensity of structural disorder of the phosphorylation motifs, and cancer mutations observed within the phosphorylation motifs. Many p53 phosphorylation sites are targets for several kinases. The phosphorylation sites match 17 consensus sequence motifs out of the 29 classified. In addition to proline, which is common in kinase specificity-determining sites, we found high propensity of acidic residues to be adjacent to phosphorylation sites. Analysis of human cancer mutations in the phosphorylation motifs revealed that motifs with adjacent acidic residues generally have fewer mutations, in contrast to phosphorylation sites near proline residues. p53 phosphorylation motifs are mostly disordered. However, human cancer mutations within phosphorylation motifs tend to decrease the disorder propensity. Our results suggest that combination of acidic residues Asp and Glu with phosphorylation sites provide charge redundancy which may safe guard against loss-of-function mutations, and that the natively disordered nature of p53 phosphorylation motifs may help reduce mutational damage. Our results further suggest that engineering acidic amino acids adjacent to potential phosphorylation sites could be a p53 gene therapy strategy. C1 [Ji, Xiaona; Huang, Qiang; Yu, Long] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Ft Detrick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Yu, L (reprint author), Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. EM xiaonaji@163.com; huangqiang@fudan.edu.cn; longyu@fudan.edu.cn; nussinor@helix.nih.gov; mabuyong@mail.nih.gov FU NCI, NIH [HHSN261200800001E]; NIH, NCI, Center for Cancer Research; National Natural Science Foundation of China [30570406, 30024001]; HI-tech Research and Development Program of China [2008AA02Z311]; National Key Sci-Tech Special Projects of China [2008ZX10002-020] FX This project has been funded in whole or in part with Federal funds from the NCI, NIH, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This study was supported (in part) by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. Huang and Yu were supported by grants from the National Natural Science Foundation of China (30570406, 30024001), the HI-tech Research and Development Program of China (2008AA02Z311), and the National Key Sci-Tech Special Projects of China (2008ZX10002-020). NR 105 TC 2 Z9 2 U1 2 U2 17 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD AUG PY 2014 VL 15 IS 8 BP 13275 EP 13298 DI 10.3390/ijms150813275 PG 24 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA AO7GD UT WOS:000341519600011 PM 25075982 ER PT J AU Parks, CG Miller, FW Pollard, KM Selmi, C Germolec, D Joyce, K Rose, NR Humble, MC AF Parks, Christine G. Miller, Frederick W. Pollard, Kenneth Michael Selmi, Carlo Germolec, Dori Joyce, Kelly Rose, Noel R. Humble, Michael C. TI Expert Panel Workshop Consensus Statement on the Role of the Environment in the Development of Autoimmune Disease SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE National Institute of Environmental Health Sciences (US); consensus; autoimmune diseases; mechanisms; environmental exposures; epidemiology; exposure assessment ID ARYL-HYDROCARBON RECEPTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; REGULATORY T-CELLS; SOUTHEASTERN UNITED-STATES; PRIMARY BILIARY-CIRRHOSIS; RHEUMATOID-ARTHRITIS; SILICA EXPOSURE; TH17 CELLS; OCCUPATIONAL-EXPOSURE; CRYSTALLINE SILICA AB Autoimmune diseases include 80 or more complex disorders characterized by self-reactive, pathologic immune responses in which genetic susceptibility is largely insufficient to determine disease onset. In September 2010, the National Institute of Environmental Health Sciences (NIEHS) organized an expert panel workshop to evaluate the role of environmental factors in autoimmune diseases, and the state of the science regarding relevant mechanisms, animal models, and human studies. The objective of the workshop was to analyze the existing data to identify conclusions that could be drawn regarding environmental exposures and autoimmunity and to identify critical knowledge gaps and areas of uncertainty for future study. This consensus document summarizes key findings from published workshop monographs on areas in which "confident" and "likely" assessments were made, with recommendations for further research. Transcribed notes and slides were reviewed to synthesize an overview on exposure assessment and questions addressed by interdisciplinary panels. Critical advances in the field of autoimmune disease research have been made in the past decade. Collaborative translational and interdisciplinary research is needed to elucidate the role of environmental factors in autoimmune diseases. A focus on exposure assessment methodology is needed to improve the effectiveness of human studies, and more experimental studies are needed to focus on causal mechanisms underlying observed associations of environmental factors with autoimmune disease in humans. C1 [Parks, Christine G.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD 20892 USA. [Pollard, Kenneth Michael] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Selmi, Carlo] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Selmi, Carlo] Humanitas Clin & Res Ctr, I-20089 Milan, Italy. [Germolec, Dori] NIEHS, Natl Toxicol Program, NIH, Morrisville, NC 27560 USA. [Joyce, Kelly] Drexel Univ, Dept Hist & Polit, Philadelphia, PA 19104 USA. [Rose, Noel R.] Bloomberg Sch Publ Hlth, John Hopkins Ctr Autoimmune Dis Res, Baltimore, MD 21205 USA. [Humble, Michael C.] NIEHS, Div Extramural Res & Training, NIH, Res Triangle Pk, NC 27709 USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM parks1@niehs.nih.gov; millerf@mail.nih.gov; mpollard@scripps.edu; carlo.selmi@unimi.it; germolec@niehs.nih.gov; kaj68@drexel.edu; nrose2@jhu.edu; humble@niehs.nih.gov OI Miller, Frederick/0000-0003-2831-9593; Parks, Christine/0000-0002-5734-3456 FU Intramural Research Program of the NIH, National Institute of Environmental Health Science [Z01 ES049028] FX Meeting support was provided by NIEHS, NIH and AARDA. We also extend our great appreciation to all of the workshop participants who contributed to these discussions. We are grateful for the assistance of Linh Pham in summarizing recorded workshop materials, and for the helpful comments of David Sherr, Eric Gershwin, Pat Mastin and Sheetal Thakur. Manuscript preparation was supported, in part, through the Intramural Research Program of the NIH, National Institute of Environmental Health Science (Z01 ES049028). NR 101 TC 12 Z9 13 U1 0 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD AUG PY 2014 VL 15 IS 8 BP 14269 EP 14297 DI 10.3390/ijms150814269 PG 29 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA AO7GD UT WOS:000341519600067 PM 25196523 ER PT J AU Kiykim, A Aydiner, EK Ozen, AO Baris, S Guran, T Hsu, PA Barlan, I AF Kiykim, Ayca Aydiner, Elif Karakoc Ozen, Ahmet Oguzhan Baris, Safa Guran, Tulay Hsu, P. A. Barlan, Isil TI CHRONIC MUCOCUTANEOUS CANDIDIASIS, AUTOIMMUNE THYROIDITIS AND CEREBRAL MYCOTIC ANEURISM; STAT1 MUTATION SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 100th J Project Meeting CY MAR 12-14, 2014 CL Antalya, TURKEY C1 [Kiykim, Ayca; Aydiner, Elif Karakoc; Ozen, Ahmet Oguzhan; Baris, Safa; Barlan, Isil] Marmara Univ Pediat Allergy & Immunol, Istanbul, Turkey. [Guran, Tulay] Marmara Univ Pediat Endocrinol, Istanbul, Turkey. [Hsu, P. A.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD AUG PY 2014 VL 34 IS 6 BP 745 EP 745 PG 1 WC Immunology SC Immunology GA AP1OI UT WOS:000341839800162 ER PT J AU Tenorio, SL O'Donnell, CI Hernandez, J Rozjabek, HM Lynch, D Marcus, PM AF Tenorio, Sally L. O'Donnell, Colin I. Hernandez, Jhenny Rozjabek, Heather M. Lynch, David Marcus, Pamela M. TI Culturally Sensitive Approaches to Recruitment and Retention of Hispanics in the National Lung Screening Trial SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Mass screening; Lung cancer; Patient recruitment; Clinical trials as subject; Hispanic recruitment; Denver, Colorado; USA ID CANCER CLINICAL-TRIALS; DESIGN; RACE AB Hispanics are underrepresented in medical research. At the National Lung Screening Trial's University of Colorado Denver screening center, traditional recruitment methods resulted in enrollment of few Hispanics. In response, the center adopted culturally sensitive recruitment techniques, including use of carefully-crafted bilingual materials. Bilingual interviewers were hired, and persons familiar with culture and language of groups of different Hispanic origin were consulted. Representation of Hispanics among participants enrolled at the Colorado center increased nearly threefold, from 3.3 to 9.4 %, after adoption of these methods. In this manuscript, we report on the specialized recruitment methods that were developed and how they were used to address known barriers to Hispanic recruitment. C1 [Tenorio, Sally L.] Swedish Med Ctr, Englewood, CO 80113 USA. [O'Donnell, Colin I.; Hernandez, Jhenny] Univ Colorado Denver, Aurora, CO 80045 USA. [Rozjabek, Heather M.; Marcus, Pamela M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Lynch, David] Natl Jewish Hosp, Div Radiol, Denver, CO 80206 USA. RP Marcus, PM (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E-440, Bethesda, MD 20892 USA. EM marcusp@mail.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD AUG PY 2014 VL 16 IS 4 BP 761 EP 764 DI 10.1007/s10903-013-9862-0 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO9PG UT WOS:000341687100027 PM 23780349 ER PT J AU Bonds, DE AF Bonds, Denise E. TI DIGAMI 1: 20 years later SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION; INSULIN-GLUCOSE INFUSION; DIABETIC-PATIENTS; VASCULAR COMPLICATIONS; MORTALITY; MELLITUS; TRIAL C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Bonds, DE (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM bondsde@nhlbi.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD AUG PY 2014 VL 2 IS 8 BP 603 EP 604 DI 10.1016/S2213-8587(14)70106-8 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP1AX UT WOS:000341799900003 PM 24831991 ER PT J AU Capes-Davis, A Alston-Roberts, C Barrett, T Burnett, EC Cooper, JR Dirks, WG Freshney, RI Fuller, JR Healy, L Kerrigan, L Kniss, DA Kohara, A Korch, C MacLeod, RAF Masters, JRW Nakamura, Y Nardone, RM Nims, RW Reid, YA Storts, DR Drexler, HG AF Capes-Davis, Amanda Alston-Roberts, Christine Barrett, Tanya Burnett, Edward C. Cooper, Jim R. Dirks, Wilhelm G. Freshney, R. Ian Fuller, James R. Healy, Lyn Kerrigan, Liz Kniss, Douglas A. Kohara, Arihiro Korch, Christopher MacLeod, Roderick A. F. Masters, John R. W. Nakamura, Yukio Nardone, Roland M. Nims, Raymond W. Reid, Yvonne A. Storts, Douglas R. Drexler, Hans G. CA ICLAC TI Cell line cross-contamination: WSU-CLL is a known derivative of REH and is unsuitable as a model for chronic lymphocytic leukaemia SO LEUKEMIA RESEARCH LA English DT Editorial Material C1 [Capes-Davis, Amanda] CellBank Australia, Childrens Med Res Inst, Westmead, NSW, Australia. [Alston-Roberts, Christine; Kerrigan, Liz; Reid, Yvonne A.] ATCC, Manassas, VA USA. [Barrett, Tanya] NCBI, NLM, NIH, Bethesda, MD USA. [Burnett, Edward C.; Cooper, Jim R.] Culture Collect Publ Hlth England, Porton Down, Wiltshire, England. [Dirks, Wilhelm G.; Drexler, Hans G.] Leibniz Inst Deutsche Sammlung Mikrooraganismen &, Braunschweig, Germany. [Freshney, R. Ian] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland. [Fuller, James R.] Lab Corp Amer, DNA Identificat Testing Div, Burlington, NC USA. [Healy, Lyn] UK Stem Cell Bank, Natl Inst Biol Standards & Control, Potters Bar, Herts, England. [Kniss, Douglas A.] Ohio State Univ, Wexner Med Ctr, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Kniss, Douglas A.] Ohio State Univ, Wexner Med Ctr, Dept Biomed Engn, Columbus, OH 43210 USA. [Kohara, Arihiro] JCRB, Natl Inst Biomed Innovat, Osaka, Japan. [Korch, Christopher] Univ Colorado, Sch Med, DNA Sequencing & Anal Core, Aurora, CO USA. [Masters, John R. W.] Univ London Imperial Coll Sci Technol & Med, Prostate Canc Res Ctr, London, England. [Nakamura, Yukio] RIKEN, BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki, Japan. [Nardone, Roland M.] Catholic Univ Amer, Washington, DC 20064 USA. [Nims, Raymond W.] RMC Pharmaceut Solut, Longmont, CO USA. [Storts, Douglas R.] Promega Corp, Madison, WI USA. RP Capes-Davis, A (reprint author), CellBank Australia, Childrens Med Res Inst, Westmead, NSW, Australia. RI Nakamura, Yukio/A-5263-2016; OI Nardone, Raffaele/0000-0001-5243-6760; Capes-Davis, Amanda/0000-0003-4184-6339 NR 8 TC 1 Z9 1 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2014 VL 38 IS 8 BP 999 EP 1001 DI 10.1016/j.leukres.2014.05.003 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA AO4ZW UT WOS:000341350900024 ER PT J AU Hollevoet, K Mason-Osann, E Liu, XF Imhof-Jung, S Niederfellner, G Pastan, I AF Hollevoet, Kevin Mason-Osann, Emily Liu, Xiu-fen Imhof-Jung, Sabine Niederfellner, Gerhard Pastan, Ira TI In Vitro and In Vivo Activity of the Low-Immunogenic Antimesothelin Immunotoxin RG7787 in Pancreatic Cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SYNERGISTIC ANTITUMOR-ACTIVITY; RECOMBINANT IMMUNOTOXIN; PHASE-I; CELL-DEATH; MESOTHELIN; SS1P; THERAPY; TRIAL; TAXOL; ANTIGENICITY AB Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. RG7787 is a novel low-immunogenic antimesothelin recombinant immunotoxin (RIT), engineered to overcome the limitations of SS1P, a RIT now in clinical trials. In vitro activity was evaluated on five established PDAC cell lines (KLM-1, AsPC-1, BxPC-3, Panc 3.014, and PK-1) and on PDAC cells directly established from a patient tumor (GUMC108). RG7787 had subnanomolar IC(50)s in most cell lines, and was significantly more active than SS1P in GUMC108, KLM-1, and Panc 3.014 cells. GUMC108 was most sensitive, with RG7787 killing >99% of the cells. In a subcutaneous KLM-1 xenograft mouse model, two cycles of 3 x 2.5 mg/kg RG7787 QOD combined with two cycles of 1 x 50 mg/kg paclitaxel induced nearcomplete responses, with all tumors regressing below 5 mm 3 within 30 days after therapy was initiated (>95% decrease) and no significant growth increase for at least another 3 weeks. RG7787 alone gave limited but significant regressions and paclitaxel by itself arrested tumor growth. Quantifying the uptake of Alexa Fluor 647-labeled RG7787 in tumors showed that the RIT reached only 45% of KLM-1 cells, accounting in part for the limited responses. Paclitaxel did not improve RG7787 uptake, which thus cannot explain the beneficial effect of the combination therapy. In conclusion, RG7787 has high cytotoxic activity on PDAC cell lines as well as on primary patient cells. In vivo, this novel RIT gives durable near-complete tumor responses when combined with paclitaxel. RG7787 merits further evaluation for the treatment of PDAC. (C) 2014 AACR. C1 [Hollevoet, Kevin; Mason-Osann, Emily; Liu, Xiu-fen; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hollevoet, Kevin] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Therapeut & Diagnost Antibodies, Leuven, Belgium. [Imhof-Jung, Sabine; Niederfellner, Gerhard] Roche Innovat Ctr Penzberg, Pharmaceut Res & Early Dev pRED, Penzberg, Germany. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov OI Mason-Osann, Emily/0000-0003-0890-6440 FU Intramural Research Program of the NIH, NCI, Center for Cancer Research; NCI [2791]; Roche Pharmaceuticals [2791]; Fund for Scientific Research Flanders (FWO, Belgium) FX This work was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and by a Cooperative Research and Development Agreement (#2791) between the NCI and Roche Pharmaceuticals. K. Hollevoet was supported in part by the Fund for Scientific Research Flanders (FWO, Belgium). NR 34 TC 22 Z9 22 U1 1 U2 9 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 AUG PY 2014 VL 13 IS 8 BP 2040 EP 2049 DI 10.1158/1535-7163.MCT-14-0089-T PG 10 WC Oncology SC Oncology GA AO9EN UT WOS:000341658700006 PM 24928849 ER PT J AU Marchand, C Huang, SYN Dexheimer, TS Lea, WA Mott, BT Chergui, A Naumova, A Stephen, AG Rosenthal, AS Rai, G Murai, J Gao, R Maloney, DJ Jadhav, A Jorgensen, WL Simeonov, A Pommier, Y AF Marchand, Christophe Huang, Shar-yin N. Dexheimer, Thomas S. Lea, Wendy A. Mott, Bryan T. Chergui, Adel Naumova, Alena Stephen, Andrew G. Rosenthal, Andrew S. Rai, Ganesha Murai, Junko Gao, Rui Maloney, David J. Jadhav, Ajit Jorgensen, William L. Simeonov, Anton Pommier, Yves TI Biochemical Assays for the Discovery of TDP1 Inhibitors SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TYROSYL-DNA PHOSPHODIESTERASE; STRAND BREAK REPAIR; TOPOISOMERASE-I; SPINOCEREBELLAR ATAXIA; POLY(ADP-RIBOSE) POLYMERASE; COVALENT COMPLEXES; CLEAVAGE COMPLEXES; AXONAL NEUROPATHY; DAMAGE; CELLS AB Drug screening against novel targets is warranted to generate biochemical probes and new therapeutic drug leads. TDP1 and TDP2 are two DNA repair enzymes that have yet to be successfully targeted. TDP1 repairs topoisomerase I-, alkylation-, and chain terminator-induced DNA damage, whereas TDP2 repairs topoisomerase II-induced DNA damage. Here, we report the quantitative high-throughput screening (qHTS) of the NIH Molecular Libraries Small Molecule Repository using recombinant human TDP1. We also developed a secondary screening method using a multiple loading gel-based assay where recombinant TDP1 is replaced by whole cell extract (WCE) from genetically engineered DT40 cells. While developing this assay, we determined the importance of buffer conditions for testing TDP1, and most notably the possible interference of phosphate-based buffers. The high specificity of endogenous TDP1 in WCE allowed the evaluation of a large number of hits with up to 600 samples analyzed per gel via multiple loadings. The increased stringency of the WCE assay eliminated a large fraction of the initial hits collected from the qHTS. Finally, inclusion of a TDP2 counter-screening assay allowed the identification of two novel series of selective TDP1 inhibitors. (C) 2014 AACR. C1 [Marchand, Christophe; Huang, Shar-yin N.; Chergui, Adel; Naumova, Alena; Murai, Junko; Gao, Rui; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Marchand, Christophe; Huang, Shar-yin N.; Chergui, Adel; Naumova, Alena; Murai, Junko; Gao, Rui; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Dexheimer, Thomas S.; Lea, Wendy A.; Mott, Bryan T.; Rosenthal, Andrew S.; Rai, Ganesha; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton] NIH, NCATS, Bethesda, MD 20892 USA. [Stephen, Andrew G.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. [Jorgensen, William L.] Yale Univ, Dept Chem, New Haven, CT USA. RP Marchand, C (reprint author), NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM marchanc@mail.nih.gov; pommier@nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI, NIH [Z01BC006150]; NIH R03 grant [MH089814-01]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; NIH grant [GM32136] FX This study was supported in part by the Intramural Research Program of the Center for Cancer Research (Z01BC006150), NCI, NIH; by the NIH R03 grant MH089814-01 (to C. Marchand and Y. Pommier); by the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E; and by the NIH grant GM32136 (to W.L. Jorgensen). NR 49 TC 4 Z9 4 U1 0 U2 5 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 AUG PY 2014 VL 13 IS 8 BP 2116 EP 2126 DI 10.1158/1535-7163.MCT-13-0952 PG 11 WC Oncology SC Oncology GA AO9EN UT WOS:000341658700013 PM 25024006 ER PT J AU Babu, S Nutman, TB AF Babu, S. Nutman, T. B. TI Immunology of lymphatic filariasis SO PARASITE IMMUNOLOGY LA English DT Review DE B cells; cytokines; filariasis; helminths; parasites; T cells ID HUMAN BANCROFTIAN FILARIASIS; SELECTIVE UP-REGULATION; PARASITE BRUGIA-MALAYI; HUMAN DENDRITIC CELLS; REGULATORY T-CELLS; GROWTH FACTOR-A; HELMINTH-PARASITES; CHRONIC INFECTION; HOST PROTECTION; WUCHERERIA-BANCROFTI AB The immune responses to filarial parasites encompass a complex network of innate and adaptive cells whose interaction with the parasite underlies a spectrum of clinical manifestations. The predominant immunological feature of lymphatic filariasis is an antigen-specific Th2 response and an expansion of IL-10 producing CD4(+) T cells that is accompanied by a muted Th1 response. This antigen-specific T-cell hyporesponsiveness appears to be crucial for the maintenance of the sustained, long-standing infection often with high parasite densities. While the correlates of protective immunity to lymphatic filariasis are still incompletely understood, primarily due to the lack of suitable animal models to study susceptibility, it is clear that T cells and to a certain extent B cells are required for protective immunity. Host immune responses, especially CD4(+) T-cell responses clearly play a role in mediating pathological manifestations of LF, including lymphedema, hydrocele and elephantiasis. The main underlying defect in the development of clinical pathology appears to be a failure to induce T-cell hyporesponsiveness in the face of antigenic stimulation. Finally, another intriguing feature of filarial infections is their propensity to induce bystander effects on a variety of immune responses, including responses to vaccinations, allergens and to other infectious agents. The complexity of the immune response to filarial infection therefore provides an important gateway to understanding the regulation of immune responses to chronic infections, in general. C1 [Babu, S.] NIAID NIRT ICER, Madras, Tamil Nadu, India. [Nutman, T. B.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Natl Inst Res TB, 1 Mayor Sathiyamurthy Rd, Madras 600031, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 79 TC 14 Z9 14 U1 3 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0141-9838 EI 1365-3024 J9 PARASITE IMMUNOL JI Parasite Immunol. PD AUG PY 2014 VL 36 IS 8 SI SI BP 338 EP 346 DI 10.1111/pim.12081 PG 9 WC Immunology; Parasitology SC Immunology; Parasitology GA AP1JU UT WOS:000341826200003 PM 24134686 ER PT J AU Cui, Q Nussinov, R AF Cui, Qiang Nussinov, Ruth TI Making Biomolecular Simulations Accessible in the Post-Nobel Prize Era SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material ID DYNAMICS; CHARMM; GUI; PROTEINS C1 [Cui, Qiang] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA. [Cui, Qiang] Univ Wisconsin, Inst Theoret Chem, Madison, WI 53706 USA. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Cui, Q (reprint author), Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA. EM cui@chem.wisc.edu; nussinor@helix.nih.gov NR 11 TC 2 Z9 2 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2014 VL 10 IS 8 AR e1003786 DI 10.1371/journal.pcbi.1003786 PG 2 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AO8AE UT WOS:000341573600035 PM 25122142 ER PT J AU Textor, J Henrickson, SE Mandl, JN von Andrian, UH Westermann, J de Boer, RJ Beltman, JB AF Textor, Johannes Henrickson, Sarah E. Mandl, Judith N. von Andrian, Ulrich H. Westermann, Juergen de Boer, Rob J. Beltman, Joost B. TI Random Migration and Signal Integration Promote Rapid and Robust T Cell Recruitment SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID LYMPH-NODE; DENDRITIC CELLS; IN-VIVO; RECIRCULATING LYMPHOCYTES; 2-PHOTON MICROSCOPY; ANTIGEN CHALLENGE; NAIVE CD4(+); RAT SPLEEN; ACTIVATION; DYNAMICS AB To fight infections, rare T cells must quickly home to appropriate lymph nodes (LNs), and reliably localize the antigen (Ag) within them. The first challenge calls for rapid trafficking between LNs, whereas the second may require extensive search within each LN. Here we combine simulations and experimental data to investigate which features of random T cell migration within and between LNs allow meeting these two conflicting demands. Our model indicates that integrating signals from multiple random encounters with Ag-presenting cells permits reliable detection of even low-dose Ag, and predicts a kinetic feature of cognate T cell arrest in LNs that we confirm using intravital two-photon data. Furthermore, we obtain the most reliable retention if T cells transit through LNs stochastically, which may explain the long and widely distributed LN dwell times observed in vivo. Finally, we demonstrate that random migration, both between and within LNs, allows recruiting the majority of cognate precursors within a few days for various realistic infection scenarios. Thus, the combination of two-scale stochastic migration and signal integration is an efficient and robust strategy for T cell immune surveillance. C1 [Textor, Johannes; de Boer, Rob J.; Beltman, Joost B.] Univ Utrecht, Utrecht, Netherlands. [Henrickson, Sarah E.; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Mandl, Judith N.] NIH, Lymphocyte Biol Sect, Bethesda, MD 20892 USA. [Westermann, Juergen] Med Univ Lubeck, Inst Anat, D-23538 Lubeck, Germany. [Beltman, Joost B.] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. RP Textor, J (reprint author), Univ Utrecht, Utrecht, Netherlands. EM johannes.textor@gmx.de RI De Boer, Rob/B-6050-2011; Textor, Johannes/E-1792-2016 OI De Boer, Rob/0000-0002-2130-691X; Textor, Johannes/0000-0002-0459-9458 FU Netherlands Organisation for Scientific Research (NWO) grant [912.10.066]; German Academic Exchange Service (DAAD); NWO grants [916.86.080, 864.12.013]; [SFB 654]; [C4] FX JT was supported by the Netherlands Organisation for Scientific Research (NWO) grant 912.10.066 (to RJdB) and a postdoctoral scholarship from the German Academic Exchange Service (DAAD), and JBB was supported by NWO grants 916.86.080 and 864.12.013. JW was supported by SFB 654, C4. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 13 Z9 13 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2014 VL 10 IS 8 AR e1003752 DI 10.1371/journal.pcbi.1003752 PG 16 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AO8AE UT WOS:000341573600010 PM 25102014 ER PT J AU Eswaramoorthy, P Winter, PW Wawrzusin, P York, AG Shroff, H Ramamurthi, KS AF Eswaramoorthy, Prahathees Winter, Peter W. Wawrzusin, Peter York, Andrew G. Shroff, Hari Ramamurthi, Kumaran S. TI Asymmetric Division and Differential Gene Expression during a Bacterial Developmental Program Requires DivIVA SO PLOS GENETICS LA English DT Article ID BACILLUS-SUBTILIS DIVIVA; ANTI-SIGMA FACTOR; STRUCTURED-ILLUMINATION MICROSCOPY; TRANSCRIPTION FACTOR SIGMA(F); CELL-SPECIFIC TRANSCRIPTION; SPORULATION PROTEIN SPOIIE; CHROMOSOME SEGREGATION; MORPHOGENETIC PROTEIN; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI AB Sporulation in the bacterium Bacillus subtilis is a developmental program in which a progenitor cell differentiates into two different cell types, the smaller of which eventually becomes a dormant cell called a spore. The process begins with an asymmetric cell division event, followed by the activation of a transcription factor, sigma(F), specifically in the smaller cell. Here, we show that the structural protein DivIVA localizes to the polar septum during sporulation and is required for asymmetric division and the compartment-specific activation of sigma(F). Both events are known to require a protein called SpoIIE, which also localizes to the polar septum. We show that DivIVA copurifies with SpoIIE and that DivIVA may anchor SpoIIE briefly to the assembling polar septum before SpoIIE is subsequently released into the forespore membrane and recaptured at the polar septum. Finally, using super-resolution microscopy, we demonstrate that DivIVA and SpoIIE ultimately display a biased localization on the side of the polar septum that faces the smaller compartment in which sigma(F) is activated. C1 [Eswaramoorthy, Prahathees; Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Winter, Peter W.; Wawrzusin, Peter; York, Andrew G.; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD USA. RP Eswaramoorthy, P (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ramamurthiks@mail.nih.gov RI Ramamurthi, Kumaran/P-3516-2015; Shroff, Hari/E-7247-2016 OI Shroff, Hari/0000-0003-3613-8215 FU National Institutes of Health; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering FX This work was supported by the Intramural Research program of the National Institutes of Health, the National Cancer Institute (PE and KSR), and the National Institute of Biomedical Imaging and Bioengineering (PWW, PW, AGY, and HS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 94 TC 13 Z9 13 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2014 VL 10 IS 8 AR e1004526 DI 10.1371/journal.pgen.1004526 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA AO8BQ UT WOS:000341577800023 PM 25101664 ER PT J AU Haro, E Delgado, I Junco, M Yamada, Y Mansouri, A Oberg, KC Ros, MA AF Haro, Endika Delgado, Irene Junco, Marisa Yamada, Yoshihiko Mansouri, Ahmed Oberg, Kerby C. Ros, Marian A. TI Sp6 and Sp8 Transcription Factors Control AER Formation and Dorsal-Ventral Patterning in Limb Development SO PLOS GENETICS LA English DT Article ID APICAL ECTODERMAL RIDGE; SPLIT-HAND/FOOT MALFORMATION; HAND/SPLIT-FOOT MALFORMATION; CHICK LIMB; VERTEBRATE LIMB; CELL-DEATH; GENE-EXPRESSION; DORSOVENTRAL POLARITY; MOUSE LIMB; P63 GENE AB The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6; Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6(-/-); Sp8(+/-)) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/catenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning. C1 [Haro, Endika; Delgado, Irene; Junco, Marisa; Ros, Marian A.] Inst Biomed & Biotecnol Cantabria CSIC UC SODERCA, Santander, Spain. [Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Mansouri, Ahmed] Max Planck Inst Biophys Chem, Dept Mol Cell Biol, Gottingen, Germany. [Mansouri, Ahmed] Univ Gottingen, Dept Clin Neurophysiol, D-37073 Gottingen, Germany. [Mansouri, Ahmed] Erciyes Univ, Genome & Stem Cell Ctr, GENKOK, Kayseri, Turkey. [Oberg, Kerby C.] Loma Linda Univ, Dept Pathol & Human Anat, Loma Linda, CA 92350 USA. [Ros, Marian A.] Univ Cantabria, Fac Med, Dept Anat & Biol Celular, E-39005 Santander, Spain. RP Haro, E (reprint author), Inst Biomed & Biotecnol Cantabria CSIC UC SODERCA, Santander, Spain. EM rosm@unican.es RI Ros, Maria /K-8160-2014; Delgado, Irene/L-9424-2014; OI Ros, Maria /0000-0002-1224-7671; Delgado, Irene/0000-0002-0493-8261; Oberg, Kerby/0000-0002-1241-4273 FU Spanish Government [BFU2011-24972]; National Organization of Rare Diseases; National Institute of Dental and Craniofacial Research, NIH, USA FX Supported by grant BFU2011-24972 from the Spanish Government (MAR) and by National Organization of Rare Diseases (KCO) and by the Intramural Research Program at the National Institute of Dental and Craniofacial Research, NIH, USA (YY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 94 TC 5 Z9 5 U1 2 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2014 VL 10 IS 8 AR e1004468 DI 10.1371/journal.pgen.1004468 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AO8BQ UT WOS:000341577800003 PM 25166858 ER PT J AU Ng, MCY Shriner, D Chen, BH Li, J Chen, WM Guo, XQ Liu, JK Bielinski, SJ Yanek, LR Nalls, MA Comeau, ME Rasmussen-Torvik, LJ Jensen, RA Evans, DS Sun, YV An, P Patel, SR Lu, YC Long, JR Armstrong, LL Wagenknecht, L Yang, LY Snively, BM Palmer, ND Mudgal, P Langefeld, CD Keene, KL Freedman, BI Mychaleckyj, JC Nayak, U Raffel, LJ Goodarzi, MO Chen, YDI Taylor, HA Correa, A Sims, M Couper, D Pankow, JS Boerwinkle, E Adeyemo, A Doumatey, A Chen, GJ Mathias, RA Vaidya, D Singleton, AB Zonderman, AB Igo, RP Sedor, JR Kabagambe, EK Siscovick, DS McKnight, B Rice, K Liu, YM Hsueh, WC Zhao, W Bielak, LF Kraja, A Province, MA Bottinger, EP Gottesman, O Cai, QY Zheng, W Blot, WJ Lowe, WL Pacheco, JA Crawford, DC Grundberg, E Rich, SS Hayes, MG Shu, XO Loos, RJF Borecki, IB Peyser, PA Cummings, SR Psaty, BM Fornage, M Iyengar, SK Evans, MK Becker, DM Kao, WHL Wilson, JG Rotter, JI Sale, MM Liu, SM Rotimi, CN Bowden, DW AF Ng, Maggie C. Y. Shriner, Daniel Chen, Brian H. Li, Jiang Chen, Wei-Min Guo, Xiuqing Liu, Jiankang Bielinski, Suzette J. Yanek, Lisa R. Nalls, Michael A. Comeau, Mary E. Rasmussen-Torvik, Laura J. Jensen, Richard A. Evans, Daniel S. Sun, Yan V. An, Ping Patel, Sanjay R. Lu, Yingchang Long, Jirong Armstrong, Loren L. Wagenknecht, Lynne Yang, Lingyao Snively, Beverly M. Palmer, Nicholette D. Mudgal, Poorva Langefeld, Carl D. Keene, Keith L. Freedman, Barry I. Mychaleckyj, Josyf C. Nayak, Uma Raffel, Leslie J. Goodarzi, Mark O. Chen, Y-D Ida Taylor, Herman A., Jr. Correa, Adolfo Sims, Mario Couper, David Pankow, James S. Boerwinkle, Eric Adeyemo, Adebowale Doumatey, Ayo Chen, Guanjie Mathias, Rasika A. Vaidya, Dhananjay Singleton, Andrew B. Zonderman, Alan B. Igo, Robert P., Jr. Sedor, John R. Kabagambe, Edmond K. Siscovick, David S. McKnight, Barbara Rice, Kenneth Liu, Yongmei Hsueh, Wen-Chi Zhao, Wei Bielak, Lawrence F. Kraja, Aldi Province, Michael A. Bottinger, Erwin P. Gottesman, Omri Cai, Qiuyin Zheng, Wei Blot, William J. Lowe, William L. Pacheco, Jennifer A. Crawford, Dana C. Grundberg, Elin Rich, Stephen S. Hayes, M. Geoffrey Shu, Xiao-Ou Loos, Ruth J. F. Borecki, Ingrid B. Peyser, Patricia A. Cummings, Steven R. Psaty, Bruce M. Fornage, Myriam Iyengar, Sudha K. Evans, Michele K. Becker, Diane M. Kao, W. H. Linda Wilson, James G. Rotter, Jerome I. Sale, Michele M. Liu, Simin Rotimi, Charles N. Bowden, Donald W. CA FIND Consortium eMERGE Consortium DIAGRAM Consortium MuTHER Consortium MEta-Anal Type 2 Diabet TI Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes SO PLOS GENETICS LA English DT Article ID SUSCEPTIBILITY LOCI; TRANSGENIC MICE; HLA-B; CONFIRMATION; POPULATION; HAPLOTYPES; OBESITY; RISK; EXPRESSION; EFFICIENT AB Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15x10(-94) < P < 5x10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2x10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies. C1 [Ng, Maggie C. Y.; Palmer, Nicholette D.; Bowden, Donald W.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA. [Ng, Maggie C. Y.; Li, Jiang; Palmer, Nicholette D.; Mudgal, Poorva; Bowden, Donald W.] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA. [Shriner, Daniel; Adeyemo, Adebowale; Doumatey, Ayo; Chen, Guanjie; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Chen, Brian H.; Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Program Genom & Nutr, Los Angeles, CA 90024 USA. [Chen, Brian H.] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Metab Dis Prevent, Los Angeles, CA 90024 USA. [Chen, Wei-Min; Mychaleckyj, Josyf C.; Nayak, Uma; Rich, Stephen S.; Sale, Michele M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Chen, Wei-Min; Mychaleckyj, Josyf C.; Nayak, Uma] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Guo, Xiuqing; Chen, Y-D Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Liu, Jiankang] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Bielinski, Suzette J.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Yanek, Lisa R.; Mathias, Rasika A.; Vaidya, Dhananjay; Becker, Diane M.] Johns Hopkins Univ, Dept Med, GeneSTAR Res Program, Div Gen Internal Med,Sch Med, Baltimore, MD USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Comeau, Mary E.; Langefeld, Carl D.] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Publ Hlth Genom, Winston Salem, NC USA. [Comeau, Mary E.; Yang, Lingyao; Snively, Beverly M.; Langefeld, Carl D.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Jensen, Richard A.; Siscovick, David S.; McKnight, Barbara; Rice, Kenneth; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Jensen, Richard A.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Evans, Daniel S.; Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, Res Inst, San Francisco, CA USA. [Sun, Yan V.] Emory Univ, Dept Epidemiol & Biomed Informat, Atlanta, GA 30322 USA. [Kraja, Aldi; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Patel, Sanjay R.] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. [Lu, Yingchang; Bottinger, Erwin P.; Gottesman, Omri; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA. [Long, Jirong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Armstrong, Loren L.; Lowe, William L.; Hayes, M. Geoffrey] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Wagenknecht, Lynne] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Palmer, Nicholette D.; Bowden, Donald W.] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA. [Keene, Keith L.] E Carolina Univ, Dept Biol, Ctr Hlth Dispar, Greenville, NC USA. [Freedman, Barry I.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Raffel, Leslie J.; Goodarzi, Mark O.] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Taylor, Herman A., Jr.; Correa, Adolfo; Sims, Mario] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Tougaloo Coll, Jackson, MS USA. [Couper, David] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Boerwinkle, Eric; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Dept Med, Baltimore, MD USA. [Vaidya, Dhananjay; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Igo, Robert P., Jr.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Sedor, John R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Sedor, John R.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Kabagambe, Edmond K.] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [McKnight, Barbara; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Hsueh, Wen-Chi] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Zhao, Wei; Bielak, Lawrence F.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Pacheco, Jennifer A.] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Grundberg, Elin] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Child Hlth & Dev Inst, New York, NY USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Evans, Michele K.] NIA, Hlth Dispar Unit, Natl Inst Hlth, Baltimore, MD 21224 USA. [Becker, Diane M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Liu, Simin] Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02912 USA. RP Ng, MCY (reprint author), Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA. EM simin_liu@brown.edu; rotimic@mail.nih.gov; dbowden@wakehealth.edu RI Singleton, Andrew/C-3010-2009; Darbar, Dawood/C-9079-2015; Boehm, Bernhard/F-8750-2015; Meitinger, Thomas/O-1318-2015; Bielinski, Suzette/A-2238-2009; Burke, William/C-1203-2012; Aulchenko, Yurii/M-8270-2013; Rudan, Igor/I-1467-2012; Wijmenga, Cisca/D-2173-2009; OI Darbar, Dawood/0000-0002-4103-5977; Bielinski, Suzette/0000-0002-2905-5430; Aulchenko, Yurii/0000-0002-7899-1575; Rudan, Igor/0000-0001-6993-6884; Rasmussen, Luke/0000-0002-4497-8049; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Gieger, Christian/0000-0001-6986-9554; Adeyemo, Adebowale/0000-0002-3105-3231; Zeggini, Eleftheria/0000-0003-4238-659X; Patel, Sanjay/0000-0002-9142-5172; Navarro, Pau/0000-0001-5576-8584; Jorgensen, Torben/0000-0001-9453-2830; Small, Kerrin/0000-0003-4566-0005; Zonderman, Alan B/0000-0002-6523-4778; Vaidya, Dhananjay/0000-0002-7164-1601; Pankow, James/0000-0001-7076-483X; Hattersley, Andrew/0000-0001-5620-473X FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, HHSN268200782096C, S06GM008016-320107, S06GM008016-380111, 2M01RR010284, U01 NS041588, R01 DK084350, HHSC268200782096C]; National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]; NHLBI [N01-HC-65226, HL085251, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756, HL103612, HL120393, N02-HL-6-4278]; National Institute on Aging (NIA) [AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NHGRI; NIGMS [U01-HG-004610, U01-HG-004608, U01-HG-04599, U01HG004609, U01-HG-04603]; State of Washington Life Sciences Discovery Fund; National Center for Research Resources [UL1RR025741]; Vanderbilt CTSA from NCATS/NIH [UL1 TR000445]; NIH from NHLBI [R01-HL-087700, R01-HL-088215]; NIH from NIDDK [R01-DK-8925601, R01-DK-075681]; FIND [U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK57304]; NIH National Cancer Institute (NCI) [N01-CO-12400]; NIH-NCI Center for Cancer Research; National Center for Research Resources for the General Clinical Research Center [M01-RR-000080]; Wake Forest University [M01-RR-07122]; Harbor-University of California, Los Angeles Medical Center [M01-RR-00425]; College of Medicine, University of California, Irvine [M01-RR-00827-29]; University of New Mexico [HSC M01-RR-00997]; Agency for Healthcare Research and Quality, Rockville, MD [HS08365]; National Heart, Lung, and Blood Institute, Bethesda, MD [HL62985]; NIH through the National Heart, Lung, and Blood Institute [HL58625-01A1, HL59684, HL071025-01A1, U01HL72518, HL087698]; National Institute of Nursing Research [NR0224103]; National Institutes of Health from the National Heart, Lung, and Blood Institute [HL087660, HL100245, HL100185]; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; Andrea and Charles Bronfman Philanthropies; National Institute on Minority Health and Health Disparities; National Heart, Lung, and Blood Institute (NHLBI); US EPA -Science to Achieve Results (STAR) Program [RD831697]; National Center for Advancing Translational Sciences Grant [UL1TR000124]; Vanderbilt-Ingram Cancer Center [P30 CA68485]; U.S. NIH [R01CA92447]; NIH [K99 DK081350, R01 DK066358, R01 DK053591, R01 HL56266, R01 DK070941]; General Clinical Research Center of the Wake Forest School of Medicine [M01 RR07122]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01-WH-22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; NHLBI Contract [N02-HL-64278]; Burroughs Wellcome Fund Inter-school Training Program in Metabolic Diseases; UCLA Genomic Analysis Training Program (NHGRI) [T32-HG002536]; National Heart, Lung and Blood Institute [HL047887, HL047889, HL047890, HL47902, HL060944, HL060894, HL061210, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [N01-HC-48047]; [N01-HC-48048]; [N01-HC-48049]; [N01-HC-48050]; [N01-HC-95095]; [N01-HC-45204]; [N01-HC-45205]; [N01-HC-05187]; [N01-HC-45134]; [N01-HC-95100]; [NIH HL 46380]; [M01RR00080]; [M01-RR-01346]; [M01-RR000052]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [UL1-RR-024156] FX Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding for Coronary Artery Risk Development in Young Adults (CARDIA) include support to University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest School of Medicine (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California Irvine (N01-HC-45134, N01-HC-95100). Funding to Candidate-gene Association Resource (CARe) (http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx) include support to Massachusetts Institute of Technology - Broad Institute (N01-HC-65226). Cleveland Family Study (CFS) was supported by a grant to Case Western Reserve University (NIH HL 46380, M01RR00080). Cardiovascular Health Study (CHS) was supported by NHLBI contracts HL085251, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756, HL103612, and HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 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. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124, the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Electronic Medical Records and Genomics Network (eMERGE) Network was initiated and funded by NHGRI, with additional funding from NIGMS through the following grants: U01-HG-004610 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01-HG-04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01-HG-04603 (Vanderbilt University, also serving as the Coordinating Center), and the State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Medical Genetics. The Northwestern University Enterprise Data Warehouse was funded in part by a grant from the National Center for Research Resources, UL1RR025741. The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH.; Family Heart Study (FamHS) was supported by NIH grants R01-HL-087700 and R01-HL-088215 (MAP, Principal Investigator) from NHLBI; and R01-DK-8925601 and R01-DK-075681 (IBB, Principal Investigator) from NIDDK. Family Investigation of Nephropathy in Diabetes (FIND) was supported by FIND grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, and U01DK070657, U01DK57304. This project has been funded in whole or in part with federal funds from the NIH National Cancer Institute (NCI) under contract N01-CO-12400 and the Intramural Research Program of the NIH-NCI Center for Cancer Research. This work also was supported by the National Center for Research Resources for the General Clinical Research Center grants: Case Western Reserve University, M01-RR-000080; Wake Forest University, M01-RR-07122; Harbor-University of California, Los Angeles Medical Center, M01-RR-00425; College of Medicine, University of California, Irvine, M01-RR-00827-29; University of New Mexico, HSC M01-RR-00997; and Frederic C. Bartter, M01-RR-01346. The CHOICE Study was supported in part by HS08365 from the Agency for Healthcare Research and Quality, Rockville, MD, and HL62985 from the National Heart, Lung, and Blood Institute, Bethesda, MD. Genetic Study of Atherosclerosis Risk (GeneSTAR) was supported by NIH grants through the National Heart, Lung, and Blood Institute (HL58625-01A1, HL59684, HL071025-01A1, U01HL72518, and HL087698) and the National Institute of Nursing Research (NR0224103) and by M01-RR000052 to the Johns Hopkins General Clinical Research Center. Genetic Epidemiology Network of Arteriopathy (GENOA) study is supported by the National Institutes of Health grant numbers HL087660, HL100245 and HL100185 from the National Heart, Lung, and Blood Institute. Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS) was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (project # Z01-AG000513 and human subjects protocol # 2009-149). Health, Aging, and Body Composition Study (Health ABC Study) was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Howard University Family Study (HUFS) was supported by National Institutes of Health grants S06GM008016-320107 to CNR and S06GM008016-380111 to AA. Participant enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. Genotyping support was provided by the Coriell Institute for Medical Research. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362).; The Charles Bronfman Institute for Personalized Medicine (IPM) BioBank Program is supported by The Andrea and Charles Bronfman Philanthropies. Insulin Resistance Atherosclerosis Study (IRAS) was supported by the National Heart, Lung, and Blood Institute (HL047887, HL047889, HL047890, HL47902). IRAS Family Study was supported by the National Heart, Lung, and Blood Institute (HL060944, HL060894, HL061210). The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA), MESA Family, and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and UL1-RR-024156. Funding for MESA Family is provided by grants R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, and UL1-RR-025005. Funding for genotyping was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226. MESA Air is funded by the US EPA -Science to Achieve Results (STAR) Program Grant # RD831697. The project described was supported by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124. In Southern Community Cohort Study (SCCS), sample preparation was conducted at the Survey and Biospecimen Shared Resources, which is supported in part by Vanderbilt-Ingram Cancer Center (P30 CA68485). The SCCS dataset used for the present analyses was supported by U.S. NIH grant R01CA92447. In Sea Islands Genetic Network (SIGNET) - Reasons for Geographic And Racial Differences in Stroke (SIGNET-REGARDS), the REGARDS Study is supported by a cooperative agreement U01 NS041588 (PI George Howard) and SIGNET was supported by R01 DK084350 (MMS) from the National Institutes of Health. In Wake Forest School of Medicine (WFSM), genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. The work at Wake Forest was supported by NIH grants K99 DK081350 (NDP), R01 DK066358 (DWB), R01 DK053591 (DWB), R01 HL56266 (BIF), R01 DK070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest School of Medicine grant M01 RR07122. Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01-WH-22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. BHC was funded by the Burroughs Wellcome Fund Inter-school Training Program in Metabolic Diseases and UCLA Genomic Analysis Training Program (NHGRI T32-HG002536). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 37 Z9 38 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2014 VL 10 IS 8 AR e1004517 DI 10.1371/journal.pgen.1004517 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AO8BQ UT WOS:000341577800019 PM 25102180 ER PT J AU Wang, LF Zeng, XK Ryoo, HD Jasper, H AF Wang, Lifen Zeng, Xiankun Ryoo, Hyung Don Jasper, Heinrich TI Integration of UPRER and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation SO PLOS GENETICS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; INFLAMMATORY-BOWEL-DISEASE; ER-ASSOCIATED DEGRADATION; ENDOPLASMIC-RETICULUM; DROSOPHILA MIDGUT; RETINAL DEGENERATION; TISSUE HOMEOSTASIS; REDOX HOMEOSTASIS; LIFE-SPAN; ACTIVATION AB The Unfolded Protein Response of the endoplasmic reticulum (UPRER) controls proteostasis by adjusting the protein folding capacity of the ER to environmental and cell-intrinsic conditions. In metazoans, loss of proteostasis results in degenerative and proliferative diseases and cancers. The cellular and molecular mechanisms causing these phenotypes remain poorly understood. Here we show that the UPRER is a critical regulator of intestinal stem cell (ISC) quiescence in Drosophila melanogaster. We find that ISCs require activation of the UPRER for regenerative responses, but that a tissue-wide increase in ER stress triggers ISC hyperproliferation and epithelial dysplasia in aging animals. These effects are mediated by ISC-specific redox signaling through Jun-N-terminal Kinase (JNK) and the transcription factor CncC. Our results identify a signaling network of proteostatic and oxidative stress responses that regulates ISC function and regenerative homeostasis in the intestinal epithelium. C1 [Wang, Lifen; Jasper, Heinrich] Buck Inst Res Aging, Novato, CA 94945 USA. [Zeng, Xiankun] NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Ryoo, Hyung Don] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. RP Wang, LF (reprint author), Buck Inst Res Aging, Novato, CA 94945 USA. EM hjasper@buckinstitute.org FU National Institute on Aging [R01 AG028127]; National Institute on General Medical Sciences [R01 GM100196]; National Eye Institute [R01 EY020866]; Ellison Medical Foundation/AFAR postdoctoral Fellowship FX This work was funded by the National Institute on Aging (R01 AG028127 to HJ), the National Institute on General Medical Sciences (R01 GM100196 to HJ), the National Eye Institute (R01 EY020866 to HDR), and an Ellison Medical Foundation/AFAR postdoctoral Fellowship (LW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 13 Z9 13 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2014 VL 10 IS 8 AR e1004568 DI 10.1371/journal.pgen.1004568 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA AO8BQ UT WOS:000341577800052 PM 25166757 ER PT J AU Guagliardo, SA Barboza, JL Morrison, AC Astete, H Vazquez-Prokopec, G Kitron, U AF Guagliardo, Sarah Anne Barboza, Jose Luis Morrison, Amy C. Astete, Helvio Vazquez-Prokopec, Gonzalo Kitron, Uriel TI Patterns of Geographic Expansion of Aedes aegypti in the Peruvian Amazon SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MOSQUITOS DIPTERA; DENGUE VIRUS; GENE FLOW; VIET-NAM; CULICIDAE; VECTOR; DISPERSAL; INVASION; DISEASE; DYNAMICS AB Background and Objectives: In the Peruvian Amazon, the dengue vector Aedes aegypti is abundant in large urban centers such as Iquitos. In recent years, it has also been found in a number of neighboring rural communities with similar climatic and socioeconomic conditions. To better understand Ae. aegypti spread, we compared characteristics of communities, houses, and containers in infested and uninfested communities. Methods: We conducted pupal-demographic surveys and deployed ovitraps in 34 communities surrounding the city of Iquitos. Communities surveyed were located along two transects: the Amazon River and a 95km highway. We calculated entomological indices, mapped Ae. aegypti presence, and developed univariable and multivariable logistic regression models to predict Ae. aegypti presence at the community, household, or container level. Results: Large communities closer to Iquitos were more likely to be infested with Ae. aegypti. Within infested communities, houses with Ae. aegypti had more passively-filled containers and were more often infested with other mosquito genera than houses without Ae. aegypti. For containers, large water tanks/drums and containers with solar exposure were more likely to be infested with Ae. aegypti. Maps of Ae. aegypti presence revealed a linear pattern of infestation along the highway, and a scattered pattern along the Amazon River. We also identified the geographical limit of Ae. aegypti expansion along the highway at 19.3 km south of Iquitos. Conclusion: In the Peruvian Amazon, Ae. aegypti geographic spread is driven by human transportation networks along rivers and highways. Our results suggest that urban development and oviposition site availability drive Ae. aegypti colonization along roads. Along rivers, boat traffic is likely to drive long-distance dispersal via unintentional transport of mosquitoes on boats. C1 [Guagliardo, Sarah Anne; Vazquez-Prokopec, Gonzalo; Kitron, Uriel] Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. [Barboza, Jose Luis] Univ Nacl Amazonia Peruana, Iquitos, Peru. [Morrison, Amy C.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Astete, Helvio] Iquitos Lab, Naval Med Res Unit NAMRU 6 6, Iquitos, Peru. [Vazquez-Prokopec, Gonzalo; Kitron, Uriel] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Guagliardo, SA (reprint author), Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. EM sarah.guagliardo@gmail.com FU National Institutes of Health Training Grant in the Population Biology of Infectious Diseases through Emory University [T32 AI55404-10]; Emory Global Health Institute; NIH/NIAID [R01 AI069341-01] FX Funding for this study was provided by the National Institutes of Health Training Grant in the Population Biology of Infectious Diseases No. T32 AI55404-10 (L Real, PI) through Emory University and by the Emory Global Health Institute (www.globalhealth.emory.edu). Logistical support for this study was also provided by NIH/NIAID award No. R01 AI069341-01 (TW Scott, PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 9 Z9 13 U1 1 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3033 DI 10.1371/journal.pntd.0003033 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700019 PM 25101786 ER PT J AU Harrington, LC Fleisher, A Ruiz-Moreno, D Vermeylen, F Wa, CV Poulson, RL Edman, JD Clark, JM Jones, JW Kitthawee, S Scott, TW AF Harrington, Laura C. Fleisher, Andrew Ruiz-Moreno, Diego Vermeylen, Francoise Wa, Chrystal V. Poulson, Rebecca L. Edman, John D. Clark, John M. Jones, James W. Kitthawee, Sangvorn Scott, Thomas W. TI Heterogeneous Feeding Patterns of the Dengue Vector, Aedes aegypti, on Individual Human Hosts in Rural Thailand SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID VIRUS-INFECTION; PUERTO-RICO; HUMAN BLOOD; BORNE DISEASE; CULICIDAE; DIPTERA; IDENTIFICATION; TRANSMISSION; MOSQUITOS; ALBOPICTUS AB Background: Mosquito biting frequency and how bites are distributed among different people can have significant epidemiologic effects. An improved understanding of mosquito vector-human interactions would refine knowledge of the entomological processes supporting pathogen transmission and could reveal targets for minimizing risk and breaking pathogen transmission cycles. Methodology and principal findings: We used human DNA blood meal profiling of the dengue virus (DENV) vector, Aedes aegypti, to quantify its contact with human hosts and to infer epidemiologic implications of its blood feeding behavior. We determined the number of different people bitten, biting frequency by host age, size, mosquito age, and the number of times each person was bitten. Of 3,677 engorged mosquitoes collected and 1,186 complete DNA profiles, only 420 meals matched people from the study area, indicating that Ae. aegypti feed on people moving transiently through communities to conduct daily business. 10-13% of engorged mosquitoes fed on more than one person. No biting rate differences were detected between high-and low-dengue transmission seasons. We estimate that 43-46% of engorged mosquitoes bit more than one person within each gonotrophic cycle. Most multiple meals were from residents of the mosquito collection house or neighbors. People <= 25 years old were bitten less often than older people. Some hosts were fed on frequently, with three hosts bitten nine times. Interaction networks for mosquitoes and humans revealed biologically significant blood feeding hotspots, including community marketplaces. Conclusion and significance: High multiple-feeding rates and feeding on community visitors are likely important features in the efficient transmission and rapid spread of DENV. These results help explain why reducing vector populations alone is difficult for dengue prevention and support the argument for additional studies of mosquito feeding behavior, which when integrated with a greater understanding of human behavior will refine estimates of risk and strategies for dengue control. C1 [Harrington, Laura C.; Ruiz-Moreno, Diego; Wa, Chrystal V.; Poulson, Rebecca L.] Cornell Univ, Dept Entomol, Ithaca, NY 14853 USA. [Fleisher, Andrew; Edman, John D.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Vermeylen, Francoise] Cornell Univ, Cornell Stat Consulting Unit, Ithaca, NY USA. [Clark, John M.] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. [Jones, James W.] USAMC AFRIMS, Dept Enter Dis, Bangkok, Thailand. [Kitthawee, Sangvorn] Mahidol Univ, Fac Sci, Dept Biol, Bangkok 10400, Thailand. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Harrington, LC (reprint author), Cornell Univ, Dept Entomol, Ithaca, NY 14853 USA. EM lch27@cornell.edu FU National Institutes of Health [RO1 AI022119]; Cornell's Atkinson Center Climate Change and Disease Program; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; [NYC-2011-12-219] FX This research was supported by the National Institutes of Health grant RO1 AI022119, NYC-2011-12-219, Cornell's Atkinson Center Climate Change and Disease Program, and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 9 Z9 9 U1 2 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3048 DI 10.1371/journal.pntd.0003048 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700025 PM 25102306 ER PT J AU LaCon, G Morrison, AC Astete, H Stoddard, ST Paz-Soldan, VA Elder, JP Halsey, ES Scott, TW Kitron, U Vazquez-Prokopec, GM AF LaCon, Genevieve Morrison, Amy C. Astete, Helvio Stoddard, Steven T. Paz-Soldan, Valerie A. Elder, John P. Halsey, Eric S. Scott, Thomas W. Kitron, Uriel Vazquez-Prokopec, Gonzalo M. TI Shifting Patterns of Aedes aegypti Fine Scale Spatial Clustering in Iquitos, Peru SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DENGUE-VIRUS TRANSMISSION; GENETIC-STRUCTURE; KAMPHAENG PHET; PUERTO-RICO; VECTOR; CULICIDAE; DIPTERA; THAILAND; SURVEILLANCE; DISPERSAL AB Background: Empiric evidence shows that Aedes aegypti abundance is spatially heterogeneous and that some areas and larval habitats produce more mosquitoes than others. There is a knowledge gap, however, with regards to the temporal persistence of such Ae. aegypti abundance hotspots. In this study, we used a longitudinal entomologic dataset from the city of Iquitos, Peru, to (1) quantify the spatial clustering patterns of adult Ae. aegypti and pupae counts per house, (2) determine overlap between clusters, (3) quantify the temporal stability of clusters over nine entomologic surveys spaced four months apart, and (4) quantify the extent of clustering at the household and neighborhood levels. Methodologies/Principal Findings: Data from 13,662 household entomological visits performed in two Iquitos neighborhoods differing in Ae. aegypti abundance and dengue virus transmission was analyzed using global and local spatial statistics. The location and extent of Ae. aegypti pupae and adult hotspots (i.e., small groups of houses with significantly [p < 0.05] high mosquito abundance) were calculated for each of the 9 entomologic surveys. The extent of clustering was used to quantify the probability of finding spatially correlated populations. Our analyses indicate that Ae. aegypti distribution was highly focal (most clusters do not extend beyond 30 meters) and that hotspots of high vector abundance were common on every survey date, but they were temporally unstable over the period of study. Conclusions/Significance: Our findings have implications for understanding Ae. aegypti distribution and for the design of surveillance and control activities relying on household-level data. In settings like Iquitos, where there is a relatively low percentage of Ae. aegypti in permanent water-holding containers, identifying and targeting key premises will be significantly challenged by shifting hotspots of Ae. aegypti infestation. Focusing efforts in large geographic areas with historically high levels of transmission may be more effective than targeting Ae. aegypti hotspots. C1 [LaCon, Genevieve; Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. [Morrison, Amy C.; Stoddard, Steven T.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Astete, Helvio; Halsey, Eric S.] US Naval Med Res Unit 6, Lima, Peru. [Astete, Helvio; Halsey, Eric S.] US Naval Med Res Unit 6, Iquitos, Peru. [Stoddard, Steven T.; Scott, Thomas W.; Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Paz-Soldan, Valerie A.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Hlth Syst & Dev, New Orleans, LA USA. [Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. RP LaCon, G (reprint author), Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. EM gmvazqu@emory.edu FU U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases (NIH/NIAID) [R01 AI069341-01] FX Development of the ideas presented here was assisted by support from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. This research was funded by a grant from the U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases (NIH/NIAID) award number R01 AI069341-01 (to TWS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 5 Z9 5 U1 1 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3038 DI 10.1371/journal.pntd.0003038 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700022 PM 25102062 ER PT J AU Pak, BJ Vasquez-Camargo, F Kalinichenko, E Chiodini, PL Nutman, TB Tanowitz, HB McAuliffe, I Wilkins, P Smith, PT Ward, BJ Libman, MD Ndao, M AF Pak, Brian J. Vasquez-Camargo, Fabio Kalinichenko, Evgeniya Chiodini, Peter L. Nutman, Thomas B. Tanowitz, Herbert B. McAuliffe, Isabel Wilkins, Patricia Smith, Paul T. Ward, Brian J. Libman, Michael D. Ndao, Momar TI Development of a Rapid Serological Assay for the Diagnosis of Strongyloidiasis Using a Novel Diffraction-Based Biosensor Technology SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; STERCORALIS INFECTION; STOOL SPECIMENS; SPECIFICITY; HYPERINFECTION; SERODIAGNOSIS; SENSITIVITY; COMMUNITY; ELISA; IMMUNODIAGNOSIS AB Background: Strongyloidiasis is a persistent human parasitic infection caused by the intestinal nematode, Strongyloides stercoralis. The parasite has a world-wide distribution, particularly in tropical and subtropical regions with poor sanitary conditions. Since individuals with strongyloidiasis are typically asymptomatic, the infection can persist for decades without detection. Problems arise when individuals with unrecognized S. stercoralis infection are immunosuppressed, which can lead to hyper-infection syndrome and disseminated disease with an associated high mortality if untreated. Therefore a rapid, sensitive and easy to use method of diagnosing Strongyloides infection may improve the clinical management of this disease. Methodology/Principal Findings: An immunological assay for diagnosing strongyloidiasis was developed on a novel diffraction-based optical bionsensor technology. The test employs a 31-kDa recombinant antigen called NIE derived from Strongyloides stercoralis L3-stage larvae. Assay performance was tested using retrospectively collected sera from patients with parasitologically confirmed strongyloidiasis and control sera from healthy individuals or those with other parasitoses including schistosomiasis, trichinosis, echinococcosis or amebiasis who were seronegative using the NIE ELISA assay. If we consider the control group as the true negative group, the assay readily differentiated S. stercoralis-infected patients from controls detecting 96.3% of the positive cases, and with no cross reactivity observed in the control group These results were in excellent agreement (kappa = 0.98) with results obtained by an NIE-based enzyme-linked immunosorbent assay (ELISA). A further 44 sera from patients with suspected S. stercoralis infection were analyzed and showed 91% agreement with the NIE ELISA. Conclusions/Significance: In summary, this test provides high sensitivity detection of serum IgG against the NIE Strongyloides antigen. The assay is easy to perform and provides results in less than 30 minutes, making this platform amenable to rapid near-patient screening with minimal technical expertise. C1 [Pak, Brian J.; Kalinichenko, Evgeniya; Smith, Paul T.] Axela Inc, Toronto, ON, Canada. [Vasquez-Camargo, Fabio; Ward, Brian J.; Libman, Michael D.; Ndao, Momar] McGill Univ, Res Inst, Natl Reference Ctr Parasitol, Ctr Hlth, Montreal, PQ, Canada. [Chiodini, Peter L.] Univ Coll London Hosp, Hosp Trop Dis, Dept Clin Parasitol, London, England. [Chiodini, Peter L.] London Sch Hyg & Trop Med, London WC1, England. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Tanowitz, Herbert B.] Albert Einstein Coll Med, Dept Med Pathol, Bronx, NY 10467 USA. [McAuliffe, Isabel; Wilkins, Patricia] US Ctr Dis Control & Prevent, Atlanta, GA USA. [Ward, Brian J.; Libman, Michael D.; Ndao, Momar] McGill Univ, Dept Med, JD MacLean Ctr Trop Dis, Montreal, PQ, Canada. RP Pak, BJ (reprint author), Axela Inc, Toronto, ON, Canada. EM momar.ndao@mcgill.ca OI Chiodini, Peter/0000-0003-0317-7090 FU Public Health Agency of Canada/National Microbiology Laboratory [HT070-010033]; Foundation of the Montreal General Hospital; Research Institute of the McGill University Health Centre; National Institute for Health Research University College London Hospitals Biomedical Research Centre Infection Theme FX The National Reference Centre for Parasitology is supported by Public Health Agency of Canada/National Microbiology Laboratory grant HT070-010033. The study was supported by the Foundation of the Montreal General Hospital and the Research Institute of the McGill University Health Centre. PLC was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre Infection Theme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 6 Z9 7 U1 0 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3002 DI 10.1371/journal.pntd.0003002 PG 7 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700006 PM 25102174 ER PT J AU Whitehorn, J Yacoub, S Anders, KL Macareo, LR Cassetti, MC Van, VCN Shi, PY Wills, B Simmons, CP AF Whitehorn, James Yacoub, Sophie Anders, Katherine L. Macareo, Louis R. Cassetti, M. Cristina Vinh Chau Nguyen Van Shi, Pei-Yong Wills, Bridget Simmons, Cameron P. TI Dengue Therapeutics, Chemoprophylaxis, and Allied Tools: State of the Art and Future Directions SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Review ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; VIRUS-INFECTION; SHOCK SYNDROME; SEVERE THROMBOCYTOPENIA; PLATELET TRANSFUSION; DOUBLE-BLIND; ENDOTHELIAL FUNCTION; PROTECTIVE EFFICACY; FALCIPARUM-MALARIA AB Dengue is the most common arboviral disease of humans. There is an unmet need for a therapeutic intervention that reduces the duration and severity of dengue symptoms and diminishes the likelihood of severe complications. To this end, there are active discovery efforts in industry and academia to develop interventions, with a focus on small molecule inhibitors of dengue virus replication that are suitable for therapy or chemoprophylaxis. Advancements in animal models of dengue virus infection together with the possibility of a dengue human infection model have further enhanced the platform for dengue drug discovery. Whilst drug discovery efforts gestate, there are ongoing clinical research designed to benefit today's patients, including trials of supportive care interventions, and descriptive studies that should improve the ability of clinicians to make an accurate diagnosis early in the illness course and to identify patients most at risk of progression to severe disease. This review provides a state of the art summary of dengue drug discovery, clinical trials, and supportive allied research and reflects discussions at the 2nd International Dengue Therapeutics Workshop held in Ho Chi Minh City, Vietnam, in December 2013. C1 [Whitehorn, James] London Sch Hyg & Trop Med, Dept Clin Res, London WC1, England. [Whitehorn, James; Yacoub, Sophie; Anders, Katherine L.; Wills, Bridget; Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Yacoub, Sophie] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Macareo, Louis R.] US Army Med Component, Armed Forces Res Inst Med Sci, Bangkok, Thailand. [Cassetti, M. Cristina] NIAID, Bethesda, MD 20892 USA. [Vinh Chau Nguyen Van] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Shi, Pei-Yong] Novartis Inst Trop Dis, Singapore, Singapore. [Wills, Bridget; Simmons, Cameron P.] Univ Oxford, Ctr Trop Med, Oxford, England. [Simmons, Cameron P.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. RP Whitehorn, J (reprint author), London Sch Hyg & Trop Med, Dept Clin Res, London WC1, England. EM csimmons@oucru.org OI Simmons, Cameron P./0000-0002-9039-7392 FU Wellcome Trust of the United Kingdom [097430/Z/11/Z, 100562/Z/12/Z]; National Health and Medical Research Council, Australia (NHMRC) [1047282]; National Medical Research Council in Singapore FX JW and SY are supported by fellowships from the Wellcome Trust of the United Kingdom (grants 097430/Z/11/Z and 100562/Z/12/Z respectively). CPS is supported by the National Health and Medical Research Council, Australia (NHMRC ID: 1047282). PYS was partially supported by the TCR flagship "STOP Dengue'' program from National Medical Research Council in Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 17 Z9 18 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3025 DI 10.1371/journal.pntd.0003025 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700018 PM 25166493 ER PT J AU Bao, R Fordyce, A Chen, YX McVeigh, A Savarino, SJ Xia, D AF Bao, Rui Fordyce, April Chen, Yu-Xing McVeigh, Annette Savarino, Stephen J. Xia, Di TI Structure of CfaA Suggests a New Family of Chaperones Essential for Assembly of Class 5 Fimbriae SO PLOS PATHOGENS LA English DT Article ID ENTEROTOXIGENIC ESCHERICHIA-COLI; FACTOR ANTIGEN-I; CRYSTAL-STRUCTURE; YERSINIA-PESTIS; CS1 PILI; BIOGENESIS; MECHANISM; SUBUNIT; CAF1M; FIMC AB Adhesive pili on the surface of pathogenic bacteria comprise polymerized pilin subunits and are essential for initiation of infections. Pili assembled by the chaperone-usher pathway (CUP) require periplasmic chaperones that assist subunit folding, maintain their stability, and escort them to the site of bioassembly. Until now, CUP chaperones have been classified into two families, FGS and FGL, based on the short and long length of the subunit-interacting loops between its (F) under bar1 and (G) under bar1 beta-strands, respectively. CfaA is the chaperone for assembly of colonization factor antigen I (CFA/I) pili of enterotoxigenic E. coli (ETEC), a cause of diarrhea in travelers and young children. Here, the crystal structure of CfaA along with sequence analyses reveals some unique structural and functional features, leading us to propose a separate family for CfaA and closely related chaperones. Phenotypic changes resulting from mutations in regions unique to this chaperone family provide insight into their function, consistent with involvement of these regions in interactions with cognate subunits and usher proteins during pilus assembly. C1 [Bao, Rui; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fordyce, April; McVeigh, Annette; Savarino, Stephen J.] Naval Med Res Ctr, Enter Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. [Chen, Yu-Xing] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China. [Chen, Yu-Xing] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China. [Savarino, Stephen J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Savarino, SJ (reprint author), Naval Med Res Ctr, Enter Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. EM stephen.savarino@med.navy.mil; xiad@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Trans NIH/FDA Intramural Biodefense Program; U.S. Army Military Infectious Diseases Research Program Work Unit [A0307]; Henry M. Jackson Foundation for the Advancement of Military Medicine FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by a grant from the Trans NIH/FDA Intramural Biodefense Program (to DX). The research was also supported by the U.S. Army Military Infectious Diseases Research Program Work Unit Number A0307 (to SJS), and by the Henry M. Jackson Foundation for the Advancement of Military Medicine (SJS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 5 Z9 5 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004316 DI 10.1371/journal.ppat.1004316 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300037 PM 25122114 ER PT J AU Cheung, GYC Kretschmer, D Duong, AC Yeh, AJ Ho, TV Chen, Y Joo, HS Kreiswirth, BN Peschel, A Otto, M AF Cheung, Gordon Y. C. Kretschmer, Dorothee Duong, Anthony C. Yeh, Anthony J. Ho, Trung V. Chen, Yan Joo, Hwang-Soo Kreiswirth, Barry N. Peschel, Andreas Otto, Michael TI Production of an Attenuated Phenol-Soluble Modulin Variant Unique to the MRSA Clonal Complex 30 Increases Severity of Bloodstream Infection SO PLOS PATHOGENS LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; COMMUNITY-ASSOCIATED MRSA; SOFT-TISSUE INFECTION; VIRULENCE DETERMINANTS; SYSTEM; PEPTIDE; PROTEIN; BACTEREMIA; EXPRESSION AB Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSM alpha 3 peptide. We found that this variant, PSM alpha 3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSM alpha 3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms. C1 [Cheung, Gordon Y. C.; Duong, Anthony C.; Yeh, Anthony J.; Ho, Trung V.; Chen, Yan; Joo, Hwang-Soo; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Kretschmer, Dorothee; Peschel, Andreas] Univ Tubingen, Cellular & Mol Microbiol Div, Interfac Inst Microbiol & Infect Med, Tubingen, Germany. [Kreiswirth, Barry N.] Rutgers State Univ, Publ Hlth Res Inst, TB Ctr, New Jersey Med Sch, Newark, NJ 07102 USA. RP Cheung, GYC (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), The National Institutes of Health (NIH); German Research Foundation [SFB685, TR34]; German Ministry of Education and Research (Menage); Fortune program of the Medical Faculty, University of Tubingen FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), The National Institutes of Health (NIH) to MO, and grants from the German Research Foundation (SFB685 to AP, TR34 to AP and DK), the German Ministry of Education and Research (Menage, to AP), and the Fortune program of the Medical Faculty, University of Tubingen to DK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 17 Z9 17 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004298 DI 10.1371/journal.ppat.1004298 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300022 PM 25144687 ER PT J AU Cruz, R Huesgen, P Riley, SP Wlodawer, A Faro, C Overall, CM Martinez, JJ Simoes, I AF Cruz, Rui Huesgen, Pitter Riley, Sean P. Wlodawer, Alexander Faro, Carlos Overall, Christopher M. Martinez, Juan J. Simoes, Isaura TI RC1339/APRc from Rickettsia conorii Is a Novel Aspartic Protease with Properties of Retropepsin-Like Enzymes SO PLOS PATHOGENS LA English DT Article ID OUTER-MEMBRANE PROTEIN; VIRULENCE FACTORS; HIV-1 PROTEASE; ACTIVE-SITE; REDUCTIVE EVOLUTION; PEPTIDE LIBRARIES; MASS-SPECTROMETRY; GENOME EVOLUTION; HUMAN RENIN; PEPSIN-LIKE AB Members of the species Rickettsia are obligate intracellular, gram-negative, arthropod-borne pathogens of humans and other mammals. The life-threatening character of diseases caused by many Rickettsia species and the lack of reliable protective vaccine against rickettsioses strengthens the importance of identifying new protein factors for the potential development of innovative therapeutic tools. Herein, we report the identification and characterization of a novel membrane-embedded retropepsin-like homologue, highly conserved in 55 Rickettsia genomes. Using R. conorii gene homologue RC1339 as our working model, we demonstrate that, despite the low overall sequence similarity to retropepsins, the gene product of rc1339 APRc (for Aspartic Protease from Rickettsia conorii) is an active enzyme with features highly reminiscent of this family of aspartic proteases, such as autolytic activity impaired by mutation of the catalytic aspartate, accumulation in the dimeric form, optimal activity at pH 6, and inhibition by specific HIV-1 protease inhibitors. Moreover, specificity preferences determined by a high-throughput profiling approach confirmed common preferences between this novel rickettsial enzyme and other aspartic proteases, both retropepsins and pepsin-like. This is the first report on a retropepsin-like protease in gram-negative intracellular bacteria such as Rickettsia, contributing to the analysis of the evolutionary relationships between the two types of aspartic proteases. Additionally, we have also shown that APRc is transcribed and translated in R. conorii and R. rickettsii and is integrated into the outer membrane of both species. Finally, we demonstrated that APRc is sufficient to catalyze the in vitro processing of two conserved high molecular weight autotransporter adhesin/invasion proteins, Sca5/OmpB and Sca0/OmpA, thereby suggesting the participation of this enzyme in a relevant proteolytic pathway in rickettsial life-cycle. As a novel bona fide member of the retropepsin family of aspartic proteases, APRc emerges as an intriguing target for therapeutic intervention against fatal rickettsioses. C1 [Cruz, Rui; Faro, Carlos; Simoes, Isaura] Ctr Neurosci & Cell Biol CNC, Coimbra, Portugal. [Cruz, Rui; Faro, Carlos; Simoes, Isaura] Biocant, Biotechnol Innovat Ctr, Cantanhede, Portugal. [Huesgen, Pitter; Overall, Christopher M.] Univ British Columbia, Fac Dent, Ctr Blood Res, Vancouver, BC V5Z 1M9, Canada. [Huesgen, Pitter; Overall, Christopher M.] Univ British Columbia, Dept Biol & Med Sci, Fac Dent, Vancouver, BC V5Z 1M9, Canada. [Riley, Sean P.; Martinez, Juan J.] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Vector Borne Dis Labs, Baton Rouge, LA 70803 USA. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Overall, Christopher M.] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada. RP Martinez, JJ (reprint author), Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Vector Borne Dis Labs, Baton Rouge, LA 70803 USA. EM jmartinez@lsu.edu; isimoes@biocant.pt RI Simoes, Isaura/F-3239-2010; OI Simoes, Isaura/0000-0002-9331-6340; Cruz, Rui/0000-0003-1614-2399 FU Fundo Europeu de Desenvolvimento Regional (FEDER) Funds through the Operational Competitiveness Programme (COMPETE); National Funds through the Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/SAU-MII/107942/2008]; NIH/NIAID [AI072606]; FCT [SFRH/BD/47638/2008]; NIH, National Cancer Institute, Center for Cancer Research; [PEst-C/SAU/LA0001/2013-2014] FX This work was funded by Fundo Europeu de Desenvolvimento Regional (FEDER) Funds through the Operational Competitiveness Programme (COMPETE), by National Funds through the Fundacao para a Ciencia e a Tecnologia (FCT) under the project PTDC/SAU-MII/107942/2008 (to IS) and in part by NIH/NIAID award AI072606 (to JJM). RC was the recipient of a FCT PhD grant SFRH/BD/47638/2008. Authors would like to acknowledge grant PEst-C/SAU/LA0001/2013-2014. This project was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 4 Z9 4 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004324 DI 10.1371/journal.ppat.1004324 PG 18 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300042 PM 25144529 ER PT J AU Falzarano, D de Wit, E Feldmann, F Rasmussen, AL Okumura, A Peng, XX Thomas, MJ van Doremalen, N Haddock, E Nagy, L LaCasse, R Liu, TT Zhu, J McLellan, JS Scott, DP Katze, MG Feldmann, H Munster, VJ AF Falzarano, Darryl de Wit, Emmie Feldmann, Friederike Rasmussen, Angela L. Okumura, Atsushi Peng, Xinxia Thomas, Matthew J. van Doremalen, Neeltje Haddock, Elaine Nagy, Lee LaCasse, Rachel Liu, Tingting Zhu, Jiang McLellan, Jason S. Scott, Dana P. Katze, Michael G. Feldmann, Heinz Munster, Vincent J. TI Infection with MERS-CoV Causes Lethal Pneumonia in the Common Marmoset SO PLOS PATHOGENS LA English DT Article ID RESPIRATORY SYNDROME CORONAVIRUS; INNATE ANTIVIRAL RESPONSE; INTERFERON ANTAGONIST; ACCESSORY PROTEINS; RHESUS MACAQUES; MOUSE MODEL; RECEPTOR; RIBAVIRIN; BINDING; 4A AB The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS- CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS- CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS- CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS- CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies. C1 [Falzarano, Darryl; de Wit, Emmie; Haddock, Elaine; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Feldmann, Friederike; Nagy, Lee; LaCasse, Rachel; Scott, Dana P.] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Rasmussen, Angela L.; Okumura, Atsushi; Peng, Xinxia; Thomas, Matthew J.; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [van Doremalen, Neeltje; Munster, Vincent J.] NIAID, Virus Ecol Unit, Virol Lab, Div Intramural Res,NIH,Rocky Mt Labs, Hamilton, MT USA. [Liu, Tingting; Zhu, Jiang] Scripps Res Inst, Dept Immunol & Microbial Sci, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Falzarano, D (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov; munstervj@niaid.nih.gov RI Okumura, Atsushi/E-8012-2015; OI Okumura, Atsushi/0000-0002-7779-3059; Rasmussen, Angela/0000-0001-9462-3169; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) [R24OD011172-03]; Washington National Primate Research Center [P51OD010425] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) in addition to grants for the Development of Nonhuman Primate Reference Transcriptome Resources (R24OD011172-03) and the Washington National Primate Research Center (P51OD010425) to MGK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 61 Z9 66 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004250 DI 10.1371/journal.ppat.1004250 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300004 PM 25144235 ER PT J AU Handisurya, A Day, PM Thompson, CD Bonelli, M Lowy, DR Schiller, JT AF Handisurya, Alessandra Day, Patricia M. Thompson, Cynthia D. Bonelli, Michael Lowy, Douglas R. Schiller, John T. TI Strain-Specific Properties and T Cells Regulate the Susceptibility to Papilloma Induction by Mus musculus Papillomavirus 1 SO PLOS PATHOGENS LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; NONMELANOMA SKIN-CANCER; DENDRITIC CELLS; CUTANEOUS CARCINOGENESIS; IMMUNE-RESPONSES; VIRAL-INFECTION; IN-VIVO; CD4(+); REGRESSION; MICE AB The immunocytes that regulate papillomavirus infection and lesion development in humans and animals remain largely undefined. We found that immunocompetent mice with varying H-2 haplotypes displayed asymptomatic skin infection that produced L1 when challenged with 6 x 10(10) MusPV1 virions, the recently identified domestic mouse papillomavirus (also designated "MmuPV1''), but were uniformly resistant to MusPV1-induced papillomatosis. Broad immunosuppression with cyclosporin A resulted in variable induction of papillomas after experimental infection with a similar dose, from robust in Cr:ORL SENCAR to none in C57BL/6 mice, with lesional outgrowth correlating with early viral gene expression and partly with reported strain-specific susceptibility to chemical carcinogens, but not with H-2 haplotype. Challenge with 1 x 10(12) virions in the absence of immunosuppression induced small transient papillomas in Cr: ORL SENCAR but not in C57BL/6 mice. Antibody-induced depletion of CD3(+) T cells permitted efficient virus replication and papilloma formation in both strains, providing experimental proof for the crucial role of T cells in controlling papillomavirus infection and associated disease. In Cr: ORL SENCAR mice, immunodepletion of either CD4(+) or CD8(+) T cells was sufficient for efficient infection and papillomatosis, although deletion of one subset did not inhibit the recruitment of the other subset to the infected epithelium. Thus, the functional cooperation of CD4(+) and CD8(+) T cells is required to protect this strain. In contrast, C57BL/6 mice required depletion of both CD4(+) and CD8(+) T cells for infection and papillomatosis, and separate CD4 knock-out and CD8 knock-out C57BL/6 were also resistant. Thus, in C57BL/6 mice, either CD4(+) or CD8(+) T cell-independent mechanisms exist that can protect this particular strain from MusPV1-associated disease. These findings may help to explain the diversity of pathological outcomes in immunocompetent humans after infection with a specific human papillomavirus genotype. C1 [Handisurya, Alessandra; Day, Patricia M.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Bonelli, Michael] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Bonelli, Michael] Med Univ Vienna, Gen Hosp Vienna, Div Rheumatol, Vienna, Austria. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM schillej@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Austrian Science Fund FWF (Erwin Schroedinger Fellowship) [J3012-B13] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Austrian Science Fund FWF (Erwin Schroedinger Fellowship project no.: J3012-B13 to AH, www.fwf.ac.at). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 9 Z9 9 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004314 DI 10.1371/journal.ppat.1004314 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300035 PM 25121947 ER PT J AU Klatt, NR Bosinger, SE Peck, M Richert-Spuhler, LE Heigele, A Gile, JP Patel, N Taaffe, J Julg, B Camerini, D Torti, C Martin, JN Deeks, SG Sinclair, E Hecht, FM Lederman, MM Paiardini, M Kirchhoff, F Brenchley, JM Hunt, PW Silvestri, G AF Klatt, Nichole R. Bosinger, Steven E. Peck, Melicent Richert-Spuhler, Laura E. Heigele, Anke Gile, Jillian P. Patel, Nirav Taaffe, Jessica Julg, Boris Camerini, David Torti, Carlo Martin, Jeffrey N. Deeks, Steven G. Sinclair, Elizabeth Hecht, Frederick M. Lederman, Michael M. Paiardini, Mirko Kirchhoff, Frank Brenchley, Jason M. Hunt, Peter W. Silvestri, Guido TI Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS CONTROLLERS; SIV INFECTION; IMMUNE ACTIVATION; ANTIRETROVIRAL THERAPY; TYPE-1 INFECTION; SOOTY MANGABEYS; RHESUS MACAQUES; DISEASE; PERSISTENCE; RESPONSES AB A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated ("putative progressors'', PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = -0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (T-CM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ T-CM and T-SCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia. C1 [Klatt, Nichole R.; Richert-Spuhler, Laura E.; Gile, Jillian P.] Univ Washington, Dept Pharmaceut, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Klatt, Nichole R.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Bosinger, Steven E.; Patel, Nirav; Taaffe, Jessica; Paiardini, Mirko; Silvestri, Guido] Emory Univ, Yerkes Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Bosinger, Steven E.; Patel, Nirav; Taaffe, Jessica; Paiardini, Mirko; Silvestri, Guido] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. [Peck, Melicent; Martin, Jeffrey N.; Deeks, Steven G.; Sinclair, Elizabeth; Hecht, Frederick M.; Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Heigele, Anke; Kirchhoff, Frank] Univ Ulm, Med Ctr, Inst Mol Virol, D-89069 Ulm, Germany. [Julg, Boris] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Camerini, David] Univ Calif Irvine, Inst Immunol, Irvine, CA USA. [Torti, Carlo] Univ Brescia, Inst Infect & Trop Dis, Brescia, Italy. [Lederman, Michael M.] Case Western Reserve Univ, Div Infect Dis, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. RP Klatt, NR (reprint author), Univ Washington, Dept Pharmaceut, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. EM klattnr@uw.edu FU Hector Foundation; Deutsche Forschungsgemeinschaft; NIH/NIAID [P01 AI 076174, R01 AI110334, K22 AI098440]; University of Washington Center for AIDS Research [P30 AI027757]; University of California San Francisco Center for AIDS Research [P30 AI027763, R24 AI067039] FX This work was supported by: the Hector Foundation and the Deutsche Forschungsgemeinschaft (Leibniz award to FK), and NIH/NIAID grants P01 AI 076174 (Cleveland Immunopathogensis Program), R01 AI110334 (MPa), K22 AI098440 (NRK) and in part by University of Washington Center for AIDS Research, P30 AI027757 and University of California San Francisco Center for AIDS Research, P30 AI027763 and R24 AI067039. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 21 Z9 21 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004345 DI 10.1371/journal.ppat.1004345 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300053 PM 25167059 ER PT J AU Navis, M Tran, K Bale, S Phad, GE Guenaga, J Wilson, R Soldemo, M McKee, K Sundling, C Mascola, J Li, YX Wyatt, RT Hedestam, GBK AF Navis, Marjon Karen Tran Bale, Shridhar Phad, Ganesh E. Guenaga, Javier Wilson, Richard Soldemo, Martina McKee, Krisha Sundling, Christopher Mascola, John Li, Yuxing Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI HIV-1 Receptor Binding Site-Directed Antibodies Using a VH1-2 Gene Segment Orthologue Are Activated by Env Trimer Immunization SO PLOS PATHOGENS LA English DT Article ID NEUTRALIZING MONOCLONAL-ANTIBODIES; GP120 ENVELOPE GLYCOPROTEIN; MUCOSAL SHIV CHALLENGE; VIRUS TYPE-1 GP120; B-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS; PROTEIN DOCKING; STRUCTURAL BASIS; CD4 BINDING; BROAD NEUTRALIZATION AB Broadly neutralizing antibodies (bNAbs) isolated from chronically HIV-1 infected individuals reveal important information regarding how antibodies target conserved determinants of the envelope glycoprotein (Env) spike such as the primary receptor CD4 binding site (CD4bs). Many CD4bs-directed bNAbs use the same heavy (H) chain variable (V) gene segment, VH1-2*02, suggesting that activation of B cells expressing this allele is linked to the generation of this type of Ab. Here, we identify the rhesus macaque VH1.23 gene segment to be the closest macaque orthologue to the human VH1-2 gene segment, with 92% homology to VH1-2*02. Of the three amino acids in the VH1-2*02 gene segment that define a motif for VRC01-like antibodies (W50, N58, flanking the HCDR2 region, and R71), the two identified macaque VH1.23 alleles described here encode two. We demonstrate that immunization with soluble Env trimers induced CD4bs-specific VH1.23-using Abs with restricted neutralization breadth. Through alanine scanning and structural studies of one such monoclonal Ab (MAb), GE356, we demonstrate that all three HCDRs are involved in neutralization. This contrasts to the highly potent CD4bs-directed VRC01 class of bNAb, which bind Env predominantly through the HCDR2. Also unlike VRC01, GE356 was minimally modified by somatic hypermutation, its light (L) chain CDRs were of average lengths and it displayed a binding footprint proximal to the trimer axis. These results illustrate that the Env trimer immunogen used here activates B cells encoding a VH1-2 gene segment orthologue, but that the resulting Abs interact distinctly differently with the HIV-1 Env spike compared to VRC01. C1 [Navis, Marjon; Phad, Ganesh E.; Soldemo, Martina; Sundling, Christopher; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Karen Tran; Guenaga, Javier; Wilson, Richard; Li, Yuxing; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Bale, Shridhar; Wyatt, Richard T.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [McKee, Krisha; Mascola, John] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se OI Sundling, Christopher/0000-0002-6138-690X; Phad, Ganesh E/0000-0002-0047-6899 FU Swedish Research Council; Sida/SAREC; International AIDS Vaccine Initiative; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Karolinska Institutet FX This study was supported by grants from the Swedish Research Council, Sida/SAREC, the International AIDS Vaccine Initiative, the intramural program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health intramural research program and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 8 Z9 8 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004337 DI 10.1371/journal.ppat.1004337 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300049 PM 25166308 ER PT J AU Schiller, J Chackerian, B AF Schiller, John Chackerian, Bryce TI Why HIV Virions Have Low Numbers of Envelope Spikes: Implications for Vaccine Development SO PLOS PATHOGENS LA English DT Article ID B-CELL ANERGY; ANTIBODY-RESPONSES; SELF-ANTIGEN; VIRUS; INDUCTION; INFECTIVITY; PARTICLES C1 [Schiller, John] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Chackerian, Bryce] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. RP Schiller, J (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM schillej@mail.nih.gov FU U.S. National Institutes of Health through the University of New Mexico Sexually Transmitted Infectious Cooperative Research Center [U19A1084081]; Center for Cancer Research, National Cancer Institute FX Support to BC from U.S. National Institutes of Health (U19A1084081) through the University of New Mexico Sexually Transmitted Infectious Cooperative Research Center and to JS from the Center for Cancer Research, National Cancer Institute is acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 17 Z9 17 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004254 DI 10.1371/journal.ppat.1004254 PG 4 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300006 PM 25101974 ER PT J AU Simeon-Dubach, D Moore, HM AF Simeon-Dubach, Daniel Moore, Helen M. TI BIO Comes Into the Cold to Adopt BRISQ SO BIOPRESERVATION AND BIOBANKING LA English DT Editorial Material ID QUALITY BRISQ; BIOSPECIMEN C1 [Simeon-Dubach, Daniel] Medservice, CH-6318 Walchwil, Switzerland. [Moore, Helen M.] NCI, Bethesda, MD 20892 USA. RP Simeon-Dubach, D (reprint author), Medservice, Biobanking Consulting & Serv, Horndlirain 22, CH-6318 Walchwil, Switzerland. EM biobanking@medservice.ch RI Simeon-Dubach, Daniel/J-8276-2016 NR 10 TC 6 Z9 6 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD AUG PY 2014 VL 12 IS 4 BP 223 EP 224 DI 10.1089/bio.2014.1241 PG 2 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA AO7GJ UT WOS:000341520200001 PM 25162458 ER PT J AU Carrick, DM Mette, E Hoyle, B Rogers, SD Gillanders, EM Schully, SD Mechanic, LE AF Carrick, Danielle M. Mette, Eliza Hoyle, Brittany Rogers, Scott D. Gillanders, Elizabeth M. Schully, Sheri D. Mechanic, Leah E. TI The Use of Biospecimens in Population-Based Research: A Review of the National Cancer Institute's Division of Cancer Control and Population Sciences Grant Portfolio SO BIOPRESERVATION AND BIOBANKING LA English DT Review ID COLLECTION; STORAGE; EPIDEMIOLOGY; PERSPECTIVE; BIOMARKERS; SAMPLES; BLOOD AB Over the past two decades, researchers have increasingly used human biospecimens to evaluate hypotheses related to disease risk, outcomes and treatment. We conducted an analysis of population-science cancer research grants funded by the National Cancer Institute (NCI) to gain a more comprehensive understanding of biospecimens and common derivatives involved in those studies and identify opportunities for advancing the field. Data available for 1,018 extramural, peer-reviewed grants (active as of July 2012) supported by the Division of Cancer Control and Population Sciences (DCCPS), the NCI Division that supports cancer control and population-science extramural research grants, were analyzed. 455 of the grants were determined to involve biospecimens or derivatives. The most common specimen types included were whole blood (51% of grants), serum or plasma (40%), tissue (39%), and the biospecimen derivative, DNA (66%). While use of biospecimens in molecular epidemiology has become common, biospecimens for behavioral and social research is emerging, as observed in our analysis. Additionally, we found the majority of grants were using already existing biospecimens (63%). Grants that involved use of existing biospecimens resulted in lower costs (studies that used existing serum/plasma biospecimens were 4.2 times less expensive) and more publications per year (1.4 times) than grants collecting new biospecimens. This analysis serves as a first step at understanding the types of biospecimen collections supported by NCI DCCPS. There is room to encourage increased use of archived biospecimens and new collections of rarer specimen and cancer types, as well as for behavioral and social research. To facilitate these efforts, we are working to better catalogue our funded resources and make that data available to the extramural community. C1 [Carrick, Danielle M.; Mette, Eliza; Hoyle, Brittany; Rogers, Scott D.; Gillanders, Elizabeth M.; Schully, Sheri D.; Mechanic, Leah E.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. RP Carrick, DM (reprint author), 9609 Med Ctr Dr,Room 4E244, Rockville, MD 20850 USA. EM Danielle.Carrick@nih.gov NR 28 TC 1 Z9 1 U1 2 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD AUG PY 2014 VL 12 IS 4 BP 240 EP 245 DI 10.1089/bio.2014.0009 PG 6 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA AO7GJ UT WOS:000341520200004 PM 25162460 ER PT J AU Lawitschka, A Guclu, ED Varni, JW Putz, M Wolff, D Pavletic, S Greinix, H Peters, C Felder-Puig, R AF Lawitschka, A. Gueclue, E. D. Varni, J. W. Putz, M. Wolff, D. Pavletic, S. Greinix, H. Peters, C. Felder-Puig, R. TI Health-related quality of life in pediatric patients after allogeneic SCT: development of the PedsQL Stem Cell Transplant module and results of a pilot study SO BONE MARROW TRANSPLANTATION LA English DT Article ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; BONE-MARROW-TRANSPLANTATION; CLINICAL-TRIALS; FACT-BMT; CRITERIA; CHILDREN; CANCER; SCALE AB With increased survival after pediatric allogeneic hematopoietic SCT health-related quality of life (HRQL) has emerged as an essential health outcome. The impact of transplant and chronic GVHD (cGVHD)-associated morbidity remains a major obstacle. In 2005, the National Institutes of Health (NIH) Consensus Conference on Criteria for Clinical Trials in cGVHD recommended HRQL tools as an independent measure of the impact of disease burden. The NIH recommendations did not provide a cGVHD-specific tool for HRQOL measures in children. This report focuses on the development of an SCT-specific instrument to assess HRQL in children and adolescents. For the assessment of generic HRQL we chose the PedsQL (Pediatric Quality of Life Inventory) Generic Cores Scales, which have been used in a large number of healthy, acutely ill and chronically ill children and adolescents. To capture SCT- and, specifically, cGVHD-related problems, we developed the PedsQL Stem Cell Transplant module by reviewing the literature, taking over some items/scales of other PedsQL modules, interviewing patients, parents and members of the health-care team, and applying the PedsQL measurement methods. The final PedsQL Stem Cell Transplant module consists of the HRQL domains: pain and hurt, fatigue/sleeping problems/weakness, nausea, worry/anxiety about disease/treatment, nutritional problems, neurocognitive problems, communication about disease/treatment, loneliness, physical functioning and additional somatic complaints (pruritus, skin inflammation, oral problems, eyes or breathing) including patients' and parents' assessment. It was tested in 35 pediatric patients, who were referred to our SCT Outpatient Clinic about 100 days post SCT. Both the generic PedsQL and the SCT-specific scales showed high internal consistency, with Cronbach alpha levels of >= 0.70 in almost all scales. Most problems were detected within the HRQL domains of physical functioning and pain. The summary scores of the generic PedsQL and the PedsQL Stem Cell Transplant module showed high correlations (r=0.89 in patients' and r=0.81 in parents' assessments). Moreover, both tools discriminated between patients with and without cGVHD. The PedsQL Stem Cell Transplant module is practical for use and suitable across a broad age range (2-18 years) both in patients with and without cGVHD. However, it is still a pilot instrument and needs further development and testing in a larger patient population. C1 [Lawitschka, A.; Gueclue, E. D.; Putz, M.; Peters, C.; Felder-Puig, R.] Med Univ Vienna, St Anna Childrens Hosp, SCT Unit, A-1090 Vienna, Austria. [Varni, J. W.] Texas A&M Univ, Coll Architecture, College Stn, TX 77843 USA. [Varni, J. W.] Texas A&M Univ, Coll Med, College Stn, TX 77843 USA. [Wolff, D.] Univ Hosp Regensburg, Dept Med 3, Regensburg, Germany. [Pavletic, S.] NCI, NIH, Bethesda, MD 20892 USA. [Greinix, H.] Med Univ Vienna, BMT, Dept Internal Med, A-1090 Vienna, Austria. RP Lawitschka, A (reprint author), Med Univ Vienna, St Anna Childrens Hosp, Stem Cell Transplant Outpatient Clin, Kinderspitalgasse 6, A-1090 Vienna, Austria. EM anita.lawitschka@stanna.at FU Fonds der Stadt Wien fur Innovative Interdisziplinare Krebsforschung, Vienna, Austria FX This study was supported by a grant from Fonds der Stadt Wien fur Innovative Interdisziplinare Krebsforschung, Vienna, Austria NR 27 TC 4 Z9 4 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2014 VL 49 IS 8 BP 1093 EP 1097 DI 10.1038/bmt.2014.96 PG 5 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AO4CE UT WOS:000341283000017 PM 24820217 ER PT J AU Saleem, S McClure, EM Goudar, SS Patel, A Esamai, F Garces, A Chomba, E Althabe, F Moore, J Kodkany, B Pasha, O Belizan, J Mayansyan, A Derman, RJ Hibberd, PL Liechty, EA Krebs, NF Hambidge, KM Buekens, P Carlo, WA Wright, LL Koso-Thomas, M Jobe, AH Goldenberg, RL AF Saleem, Sarah McClure, Elizabeth M. Goudar, Shivaprasad S. Patel, Archana Esamai, Fabian Garces, Ana Chomba, Elwyn Althabe, Fernando Moore, Janet Kodkany, Bhalachandra Pasha, Omrana Belizan, Jose Mayansyan, Albert Derman, Richard J. Hibberd, Patricia L. Liechty, Edward A. Krebs, Nancy F. Hambidge, K. Michael Buekens, Pierre Carlo, Waldemar A. Wright, Linda L. Koso-Thomas, Marion Jobe, Alan H. Goldenberg, Robert L. CA Global Network Maternal Newborn TI A prospective study of maternal, fetal and neonatal deaths in low- and middle-income countries SO BULLETIN OF THE WORLD HEALTH ORGANIZATION LA English DT Article ID NEWBORN HEALTH; RURAL BANGLADESH; GLOBAL-NETWORK; MORTALITY; INTRAPARTUM; CHILD; INTERVENTIONS; MULTICOUNTRY; STILLBIRTH; REDUCTION AB Objective To quantify maternal, fetal and neonatal mortality in low- and middle-income countries, to identify when deaths occur and to identify relationships between maternal deaths and stillbirths and neonatal deaths. Methods A prospective study of pregnancy outcomes was performed in 106 communities at seven sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. Pregnant women were enrolled and followed until six weeks postpartum. Findings Between 2010 and 2012, 214 070 of 220235 enrolled women (97.2%) completed follow-up. The maternal mortality ratio was 168 per 100 000 live births, ranging from 69 per 100000 in Argentina to 316 per 100000 in Pakistan: Overall, 29% (98/336) of maternal deaths occurred around the time of delivery: most were attributed to haemorrhage (86/336), pre-eclampsia or eclampsia (55/336) or sepsis (39/336). Around 70% (4349/6213) of stillbirths were probably intrapartum; 34% (1804/5230) of neonates died on the day of delivery and 14% (755/5230) died the day after. Stillbirths were more common in women who died than in those alive six weeks postpartum (risk ratio, RR: 9.48; 95% confidence interval, CI: 7.97-11.27), as were perinatal deaths (RR: 4.30; 95% CI: 3.26-5.67) and 7-day (RR: 3.94; 95% CI: 2.74-5.65) and 28-day neonatal deaths (RR: 1.36; 95% CI: 5.54-9.77). Conclusion Most maternal, fetal and neonatal deaths occurred at or around delivery and were attributed to preventable causes. Maternal death increased the risk of perinatal and neonatal death. Improving obstetric and neonatal care around the time of birth offers the greatest chance of reducing mortality. C1 [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [McClure, Elizabeth M.; Moore, Janet] RTI Int, Durham, NC 27709 USA. [Goudar, Shivaprasad S.; Kodkany, Bhalachandra] KLE Univ JN Med Coll, Belgaum, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Esamai, Fabian] Moi Univ, Dept Pediat, Eldoret, Kenya. [Garces, Ana] Univ Francisco Marroquin, Guatemala City, Guatemala. [Chomba, Elwyn] Univ Zambia, Dept Pediat, Lusaka, Zambia. [Althabe, Fernando; Belizan, Jose] Inst Clin Effectiveness, Buenos Aires, DF, Argentina. [Mayansyan, Albert; Carlo, Waldemar A.] Univ N Carolina, Chapel Hill, NC USA. [Derman, Richard J.] Christiana Hlth Care, Dept Obstet & Gynecol, Newark, DE USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Dept Pediat, Boston, MA USA. [Liechty, Edward A.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Krebs, Nancy F.; Hambidge, K. Michael] Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. [Buekens, Pierre] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Wright, Linda L.; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP McClure, EM (reprint author), RTI Int, POB 12194,3040 East Cornwallis Rd, Durham, NC 27709 USA. EM mcclure@rti.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636] FX The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326 and U01 HD040636). NR 37 TC 22 Z9 22 U1 1 U2 14 PU WORLD HEALTH ORGANIZATION PI GENEVA 27 PA MARKETING AND DISSEMINATION, CH-1211 GENEVA 27, SWITZERLAND SN 0042-9686 EI 1564-0604 J9 B WORLD HEALTH ORGAN JI Bull. World Health Organ. PD AUG PY 2014 VL 92 IS 8 BP 605 EP 612 DI 10.2471/BLT.13.127464 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO3JN UT WOS:000341225600018 PM 25177075 ER PT J AU Zhang, H Zhang, YK Wang, YJ Kathawala, RJ Patel, A Zhu, H Sodani, K Talele, TT Ambudkar, SV Chen, ZS Fu, LW AF Zhang, Hui Zhang, Yun-Kai Wang, Yi-Jun Kathawala, Rishil J. Patel, Atish Zhu, Hua Sodani, Kamlesh Talele, Tanaji T. Ambudkar, Suresh V. Chen, Zhe-Sheng Fu, Li-Wu TI WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells SO CANCER SCIENCE LA English DT Article DE ABCG2 protein; ATP-binding cassette transporters; multidrug resistance; tyrosine kinase; WHI-P154 ID REVERSES MULTIDRUG-RESISTANCE; SUBFAMILY-B MEMBER-1; JANUS KINASE 3; DRUG-RESISTANCE; ABC-TRANSPORTERS; CANCER-CHEMOTHERAPY; CYTOTOXIC ACTIVITY; INHIBITION; APOPTOSIS; EFFLUX AB ATP-binding cassette (ABC) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of WHI-P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing ABC transporters-mediated drug resistance. We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [3H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10M). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function. C1 [Zhang, Hui; Fu, Li-Wu] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China. [Zhang, Hui; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J.; Patel, Atish; Sodani, Kamlesh; Talele, Tanaji T.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY USA. [Zhu, Hua] Ohio State Univ, Dept Internal Med, Wexner Med Ctr, Columbus, OH 43210 USA. [Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fu, LW (reprint author), Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China. EM chenz@stjohns.edu; fulw@mail.sysu.edu.cn RI Wang, Yi-Jun/K-3218-2016; Patel, Atish/J-4699-2014 OI Patel, Atish/0000-0002-5549-9166 FU St. John's University Research Seed grant [579-1110-7002]; Major science and technology project of the National National Natural Sciences Foundation of China [81072669, 81061160507]; Sun Yat-Sen University Ph. D. visiting scholar abroad program; international collaborative research project of Guangdong Province; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by St. John's University Research Seed grant (No. 579-1110-7002) to Z.S. Chen, the Major science and technology project of the National National Natural Sciences Foundation of China grant (No. 81072669 and No. 81061160507) for L. W. Fu, and Sun Yat-Sen University Ph. D. visiting scholar abroad program and international collaborative research project of Guangdong Province. Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research NR 39 TC 8 Z9 8 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD AUG PY 2014 VL 105 IS 8 BP 1071 EP 1078 DI 10.1111/cas.12462 PG 8 WC Oncology SC Oncology GA AO8XF UT WOS:000341638300019 PM 24903205 ER PT J AU Green, KY AF Green, K. Y. TI Norovirus infection in immunocompromised hosts SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Review DE Acquired immunodeficiency; chronic infection; immunocompromised; immunosuppressed; norovirus ID HEMATOPOIETIC STEM-CELL; RENAL-TRANSPLANT RECIPIENTS; MURINE NOROVIRUS; FELINE CALICIVIRUS; UNITED-STATES; NOSOCOMIAL TRANSMISSION; ACUTE GASTROENTERITIS; PEDIATRIC-PATIENTS; IN-VIVO; EVOLUTION AB Acute gastroenteritis caused by noroviruses often has a duration of 2-3 days and is characteristically self-limiting. In contrast, chronic infection caused by noroviruses in immunocompromised individuals can last from weeks to years, making clinical management difficult. The mechanisms by which noroviruses establish persistent infection, and the role of immunocompromised hosts as a reservoir for noroviruses in the general human population, are not known. However, study of this patient cohort may lead to new insights into norovirus biology and approaches to treatment. C1 NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kgreen@niaid.nih.gov FU NIAID, NIH, USA FX I would like to thank R. Prevots, S. Sosnovtsev and G. I. Parra of NIAID, NIH for critical reading and contributions to this manuscript. K. Green is supported by the Intramural Research Program of the NIAID, NIH, USA. NR 73 TC 25 Z9 26 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1198-743X EI 1469-0691 J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD AUG PY 2014 VL 20 IS 8 BP 717 EP 723 DI 10.1111/1469-0691.12761 PG 7 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA AO7FC UT WOS:000341516600015 PM 25040790 ER PT J AU Green, KY AF Green, K. Y. TI In Appreciation of Albert Z. Kapikian OBITUARY SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Biographical-Item C1 NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 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 1198-743X EI 1469-0691 J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD AUG PY 2014 VL 20 IS 8 DI 10.1111/1469-0691.12770 PG 1 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA AO7FC UT WOS:000341516600013 PM 25145949 ER PT J AU Feldman, SA Xu, H Black, MA Park, TS Robbins, PF Kochenderfer, JN Morgan, RA Rosenberg, SA AF Feldman, Steven A. Xu, Hui Black, Mary A. Park, Tristen S. Robbins, Paul F. Kochenderfer, James N. Morgan, Richard A. Rosenberg, Steven A. TI Use of the piggyBac Transposon to Create Stable Packaging Cell Lines for the Production of Clinical-Grade Self-Inactivating gamma-Retroviral Vectors SO HUMAN GENE THERAPY METHODS LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CHIMERIC-ANTIGEN-RECEPTOR; GENE-THERAPY; GAMMARETROVIRAL VECTORS; T-CELLS; LYMPHOCYTES; INTEGRATION; GENOTOXICITY; REGRESSION; IMMUNITY AB Efforts to improve the biosafety of gamma-retroviral-mediated gene therapy have resulted in a shift toward the use of self-inactivating (SIN) gamma-retroviral vectors. However, scale-up and manufacturing of such vectors requires significant optimization of transient transfection-based processes or development of novel platforms for the generation of stable producer cell clones. To that end, we describe the use of the piggybac transposon to generate stable producer cell clones for the production of SIN gamma-retroviral vectors. The piggybac transposon is a universal tool allowing for the stable integration of SIN gamma-retroviral constructs into murine (PG13) and human 293-based Phoenix (GALV and RD114, respectively) packaging cell lines without reverse transcription. Following transposition, a high-titer clone is selected for manufacture of a master cell bank and subsequent gamma-retroviral vector supernatant production. Packaging cell clones created using the piggybac transposon have comparable titers to non-SIN vectors generated via conventional methods. We describe herein the use of the piggybac transposon for the production of stable packaging cell clones for the manufacture of clinical-grade SIN gamma-retroviral vectors for ex vivo gene therapy clinical trials. C1 [Feldman, Steven A.; Xu, Hui; Black, Mary A.; Park, Tristen S.; Robbins, Paul F.; Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Morgan, Richard A.] Bluebird Bio Inc, Cambridge, MA 02141 USA. RP Feldman, SA (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,MSC 1201 ACRF,Off 1B37A, Bethesda, MD 20892 USA. EM feldmanst@mail.nih.gov NR 34 TC 1 Z9 1 U1 2 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 EI 1946-6544 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD AUG PY 2014 VL 25 IS 4 BP 253 EP 260 DI 10.1089/hgtb.2014.071 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AO8ID UT WOS:000341597000004 PM 25072603 ER PT J AU Anderson, WF Rosenberg, PS Prat, A Perou, CM Sherman, ME AF Anderson, William F. Rosenberg, Philip S. Prat, Aleix Perou, Charles M. Sherman, Mark E. TI How Many Etiological Subtypes of Breast Cancer: Two, Three, Four, Or More? SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ESTROGEN-RECEPTOR STATUS; FULL-TERM PREGNANCY; BASAL-LIKE SUBTYPE; CARCINOMA IN-SITU; DIFFERENT HISTOPATHOLOGIC TYPES; BIMODAL AGE DISTRIBUTION; GENOME-WIDE ASSOCIATION; PERIOD-COHORT ANALYSIS; HORMONAL RISK-FACTORS; END RESULTS DATABASE AB Breast cancer is a heterogeneous disease, divisible into a variable number of clinical subtypes. A fundamental question is how many etiological classes underlie the clinical spectrum of breast cancer? An etiological subtype reflects a grouping with a common set of causes, whereas a clinical subtype represents a grouping with similar prognosis and/or prediction. Herein, we review the evidence for breast cancer etiological heterogeneity. We then evaluate the etiological evidence with mRNA profiling data. A bimodal age distribution at diagnosis with peak frequencies near ages 50 and 70 years is a fundamental characteristic of breast cancer for important tumor features, clinical characteristics, risk factor profiles, and molecular subtypes. The bimodal peak frequencies at diagnosis divide breast cancer overall into a "mixture" of two main components in varying proportions in different cancer populations. The first breast cancer tends to arise early in life with modal age-at-diagnosis near 50 years and generally behaves aggressively. The second breast cancer occurs later in life with modal age near 70 years and usually portends a more indolent clinical course. These epidemiological and molecular data are consistent with a two-component mixture model and compatible with a hierarchal view of breast cancers arising from two main cell types of origin. Notwithstanding the potential added value of more detailed categorizations for personalized breast cancer treatment, we suggest that the development of better criteria to identify the two proposed etiologic classes would advance breast cancer research and prevention. C1 [Anderson, William F.; Rosenberg, Philip S.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Prat, Aleix] Vall dHebron Inst Oncol, Translat Genom Grp, Barcelona, Spain. [Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet & Pathol & Lab Med, Chapel Hill, NC 27599 USA. RP Anderson, WF (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, 9609 Med Ctr Dr,Rm 7E144, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov RI Prat, Aleix/P-8561-2014; OI Prat, Aleix/0000-0003-2377-540X; Perou, Charles/0000-0001-9827-2247 NR 190 TC 24 Z9 24 U1 3 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju165 DI 10.1093/jnci/dju165 PG 11 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800010 ER PT J AU Gage, JC Schiffman, M Katki, HA Castle, PE Fetterman, B Wentzensen, N Poitras, NE Lorey, T Cheung, LC Kinney, WK AF Gage, Julia C. Schiffman, Mark Katki, Hormuzd A. Castle, Philip E. Fetterman, Barbara Wentzensen, Nicolas Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Kinney, Walter K. TI Reassurance Against Future Risk of Precancer and Cancer Conferred by a Negative Human Papillomavirus Test SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CERVICAL-CANCER; 5-YEAR RISKS; HPV; GUIDELINES; WOMEN; PREVENTION; MANAGEMENT; CYTOLOGY AB Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing ("cotesting") every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1 011 092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided. Three-year risks following an HPV-negative result were lower than 3-year risks following a Pap-negative result (CIN3+ = 0.069% vs 0.19%, P < .0001; Cancer = 0.011% vs 0.020%, P < .0001) and 5-year risks following an HPV-negative/Pap-negative cotest (CIN3+ = 0.069% vs 0.11%, P < .0001; Cancer = 0.011% vs 0.014%, P = .21). These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening. C1 [Gage, Julia C.; Schiffman, Mark; Katki, Hormuzd A.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Gage, JC (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,MSC 9772, Bethesda, MD 20892 USA. EM gagej@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; OI Cheung, Li/0000-0003-1625-4331 FU BD; GE Healthcare; Roche; Gen-Probe/Hologic; Cepheid FX Dr. Schiffman and Dr. Gage have received HPV testing for research at no cost from Roche and BD. Dr. Castle has received compensation for serving as a member of a Data and Safety Monitoring Board for HPV vaccines for Merck. Dr. Castle has received HPV tests and testing for research at a reduced or no cost from Qiagen, Roche, MTM, and Norchip. Dr. Castle is a paid consultant for BD, GE Healthcare, Roche, Gen-Probe/Hologic, and Cepheid, and has received a speaker honorarium from Roche. No other authors report any conflicts of interest. NR 14 TC 20 Z9 20 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju153 DI 10.1093/jnci/dju153 PG 4 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800003 ER PT J AU Silverman, DT Lubin, JH Blair, AE Vermeulen, R Stewart, PA Schleiff, PL Attfield, MD AF Silverman, Debra T. Lubin, Jay H. Blair, Aaron E. Vermeulen, Roel Stewart, Patricia A. Schleiff, Patricia L. Attfield, Michael D. TI RE: The Diesel Exhaust in Miners Study (DEMS): A Nested Case-Control Study of Lung Cancer and Diesel Exhaust SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Silverman, Debra T.; Blair, Aaron E.; Vermeulen, Roel; Stewart, Patricia A.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Schleiff, Patricia L.; Attfield, Michael D.] NIOSH, Surveillance Branch, Div Resp Dis Studies, Morgantown, WV USA. RP Silverman, DT (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rm 6E142,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM silvermd@mail.nih.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 5 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju205 DI 10.1093/jnci/dju205 PG 3 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800032 ER PT J AU Galanter, JM Gignoux, CR Torgerson, DG Roth, LA Eng, C Oh, SS Nguyen, EA Drake, KA Huntsman, S Hu, DL Sen, S Davis, A Farber, HJ Avila, PC Brigino-Buenaventura, E LeNoir, MA Meade, K Serebrisky, D Borrell, LN Rodriguez-Cintron, W Estrada, AM Mendoza, KS Winkler, CA Klitz, W Romieu, I London, SJ Gilliland, F Martinez, F Bustamante, C Williams, LK Kumar, R Rodriguez-Santana, JR Burchard, EG AF Galanter, Joshua M. Gignoux, Christopher R. Torgerson, Dara G. Roth, Lindsey A. Eng, Celeste Oh, Sam S. Nguyen, Elizabeth A. Drake, Katherine A. Huntsman, Scott Hu, Donglei Sen, Saunak Davis, Adam Farber, Harold J. Avila, Pedro C. Brigino-Buenaventura, Emerita LeNoir, Michael A. Meade, Kelley Serebrisky, Denise Borrell, Luisa N. Rodriguez-Cintron, William Estrada, Andres Moreno Mendoza, Karla Sandoval Winkler, Cheryl A. Klitz, William Romieu, Isabelle London, Stephanie J. Gilliland, Frank Martinez, Fernando Bustamante, Carlos Williams, L. Keoki Kumar, Rajesh Rodriguez-Santana, Jose R. Burchard, Esteban G. TI Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: The Genes-environments & Admixture in Latino Americans study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; Latinos; admixture mapping; genome-wide association study; local ancestry; 17q21; 6p21 ID AFRICAN-AMERICAN; CHILDHOOD ASTHMA; UNITED-STATES; CANCER RISK; POPULATIONS; ANCESTRY; DISEASE; CHILDREN; INDIVIDUALS; IDENTIFICATION AB Background: Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent. Objective: We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. Methods: Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. Results: We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 x 10(-6)). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 x 10(-13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. Conclusions: Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21. C1 [Galanter, Joshua M.; Torgerson, Dara G.; Roth, Lindsey A.; Eng, Celeste; Oh, Sam S.; Huntsman, Scott; Hu, Donglei; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Galanter, Joshua M.; Gignoux, Christopher R.; Drake, Katherine A.; Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Nguyen, Elizabeth A.] St Louis Univ, Sch Med, St Louis, MO 63103 USA. [Sen, Saunak] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Davis, Adam; Meade, Kelley] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Farber, Harold J.] Baylor Coll Med, Dept Pediat, Sect Pulmonol, Houston, TX 77030 USA. [Farber, Harold J.] Texas Childrens Hosp, Houston, TX 77030 USA. [Avila, Pedro C.] Northwestern Univ, Div Allergy Immunol, Feinberg Sch Med, Chicago, IL 60611 USA. [Brigino-Buenaventura, Emerita] Kaiser Permanente Vallejo Med Ctr, Dept Allergy & Immunol, Vallejo, CA USA. [LeNoir, Michael A.] Bay Area Pediat, Oakland, CA USA. [Serebrisky, Denise] Jacobi Med Ctr, Pediat Pulm Div, Bronx, NY USA. [Borrell, Luisa N.] CUNY Herbert H Lehman Coll, Dept Hlth Sci, Grad Program Publ Hlth, Bronx, NY 10468 USA. [Rodriguez-Cintron, William] Vet Caribbean Hlth Care Syst, San Juan, PR USA. [Estrada, Andres Moreno; Mendoza, Karla Sandoval; Bustamante, Carlos] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Winkler, Cheryl A.] NIH, Frederick Natl Lab Canc Res, Frederick, MD USA. [Klitz, William] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Romieu, Isabelle] Int Agcy Res Canc, F-69372 Lyon, France. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Gilliland, Frank] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Martinez, Fernando] Univ Arizona, Dept Pediat, Tucson, AZ 85721 USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [Kumar, Rajesh] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Rodriguez-Santana, Jose R.] Ctr Neumol Pediat, San Juan, PR USA. RP Galanter, JM (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci & Med, UCSF Box 2911, San Francisco, CA 94143 USA. EM joshua.galanter@ucsf.edu OI Nguyen, Elizabeth/0000-0002-8070-6382; London, Stephanie/0000-0003-4911-5290 FU National Institutes of Health (NIH) [R01 ES015794, R01 HL088133, M01 RR000083, R01 HL078885, R01 HL104608, P60 MD006902, U19 AI077439, M01 RR00188]; ARRA grant [RC2 HL101651]; Flight Attendant Medical Research Institute (FAMRI); Sandler Foundation; American Asthma Foundation; NIH [K23HL004464]; NIH Training Grant [T32, GM007546, GM007175]; NHLBI [K23HL111636, K23HL093023]; NCATS KL2 [KL2TR000143]; Hewett Fellowship; UCSF Chancellor's Research Fellowship; Dissertation Year Fellowship; GCRC [RR00188]; Division of Intramural Research, National Institute of Environmental Health Sciences [ZIA ES49019]; NIH FX Supported in part by the National Institutes of Health (NIH; R01 ES015794, R01 HL088133, M01 RR000083, R01 HL078885, R01 HL104608, P60 MD006902, U19 AI077439, and M01 RR00188) and ARRA grant RC2 HL101651. E.G.B. was supported in part through grants from the Flight Attendant Medical Research Institute (FAMRI), the Sandler Foundation, the American Asthma Foundation and NIH (K23 HL004464). J.M.G. was supported in part by NIH Training Grant T32 (GM007546) and career development awards from the NHLBI K23 (K23HL111636) and NCATS KL2 (KL2TR000143), as well as the Hewett Fellowship. C.R.G. was supported in part by NIH Training Grant T32 (GM007175) and the UCSF Chancellor's Research Fellowship and Dissertation Year Fellowship. R. K. was supported with a career development award from the NHLBI (K23HL093023). H.J.F. was supported in part by the GCRC (RR00188). P.C.A. was supported in part by the Ernest S. Bazley Grant. S.J.L. was supported in part by the Division of Intramural Research, National Institute of Environmental Health Sciences (ZIA ES49019). This publication was supported by various institutes within the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 66 TC 29 Z9 29 U1 1 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2014 VL 134 IS 2 BP 295 EP 305 DI 10.1016/j.jaci.2013.08.055 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA AO5GB UT WOS:000341370800007 PM 24406073 ER PT J AU Salo, PM Arbes, SJ Jaramillo, R Calatroni, A Weir, CH Sever, ML Hoppin, JA Rose, KM Liu, AH Gergen, PJ Mitchell, HE Zeldin, DC AF Salo, Paeivi M. Arbes, Samuel J., Jr. Jaramillo, Renee Calatroni, Agustin Weir, Charles H. Sever, Michelle L. Hoppin, Jane A. Rose, Kathryn M. Liu, Andrew H. Gergen, Peter J. Mitchell, Herman E. Zeldin, Darryl C. TI Prevalence of allergic sensitization in the United States: Results from the National Health and Nutrition Examination Survey (NHANES) 2005-2006 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergen; allergy; allergic sensitization; serum IgE ID IMMEDIATE-TYPE HYPERSENSITIVITY; POPULATION-BASED COHORT; URBAN AIR-POLLUTION; CLIMATE-CHANGE; CROSS-REACTIVITY; RESPIRATORY ALLERGY; RISK-FACTORS; SURVEY I; ASTHMA; IGE AB Background: Allergic sensitization is an important risk factor for the development of atopic disease. The National Health and Nutrition Examination Survey (NHANES) 2005-2006 provides the most comprehensive information on IgE-mediated sensitization in the general US population. Objective: We investigated clustering, sociodemographic, and regional patterns of allergic sensitization and examined risk factors associated with IgE-mediated sensitization. Methods: Data for this cross-sectional analysis were obtained from NHANES 2005-2006. Participants aged 1 year or older (n = 9440) were tested for serum specific IgEs (sIgEs) to inhalant and food allergens; participants 6 years or older were tested for 19 sIgEs, and children aged 1 to 5 years were tested for 9 sIgEs. Serum samples were analyzed by using the ImmunoCAP System. Information on demographics and participants' characteristics was collected by means of questionnaire. Results: Of the study population aged 6 years and older, 44.6% had detectable sIgEs, whereas 36.2% of children aged 1 to 5 years were sensitized to 1 or more allergens. Allergen-specific IgEs clustered into 7 groups that might have largely reflected biological cross-reactivity. Although sensitization to individual allergens and allergen types showed regional variation, the overall prevalence of sensitization did not differ across census regions, except in early childhood. In multivariate modeling young age, male sex, non-Hispanic black race/ethnicity, geographic location (census region), and reported pet avoidance measures were most consistently associated with IgE-mediated sensitization. Conclusions: The overall prevalence of allergic sensitization does not vary across US census regions, except in early life, although allergen-specific sensitization differs based on sociodemographic and regional factors. Biological cross-reactivity might be an important but not the sole contributor to the clustering of allergen-specific IgEs. C1 [Salo, Paeivi M.; Hoppin, Jane A.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Arbes, Samuel J., Jr.; Calatroni, Agustin; Sever, Michelle L.; Mitchell, Herman E.] Rho Fed Syst Div, Chapel Hill, NC USA. [Jaramillo, Renee; Rose, Kathryn M.] Social & Sci Syst, Durham, England. [Weir, Charles H.] Univ N Carolina, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Gergen, Peter J.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Liu, Andrew H.] Univ Colorado, Sch Med, Aurora, CO USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Rm A214, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov RI Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 FU National Institutes of Health, National Institute of Environmental Health Sciences FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 58 TC 54 Z9 54 U1 2 U2 23 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2014 VL 134 IS 2 BP 350 EP 359 DI 10.1016/j.jaci.2013.12.1071 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA AO5GB UT WOS:000341370800014 PM 24522093 ER PT J AU Balenga, NA Jester, W Jiang, MQ Panettieri, RA Druey, KM AF Balenga, Nariman A. Jester, William Jiang, Meiqi Panettieri, Reynold A., Jr. Druey, Kirk M. TI Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; airway hyperresponsiveness; G proteins; regulator of G protein signaling proteins; Aspergillus fumigatus ID SMOOTH-MUSCLE CONTRACTION; INNATE LYMPHOID-CELLS; LIGHT-CHAIN KINASE; SEVERE ASTHMA; MOLECULAR-BIOLOGY; ATOPIC ASTHMA; RECEPTOR; ACTIVATION; RESPONSES; RGS5 AB Background: Although eosinophilic inflammation typifies allergic asthma, it is not a prerequisite for airway hyperresponsiveness (AHR), suggesting that underlying abnormalities in structural cells, such as airway smooth muscle (ASM), contribute to the asthmatic diathesis. Dysregulation of procontractile G protein-coupled receptor (GPCR) signaling in ASM could mediate enhanced contractility. Objective: We explored the role of a regulator of procontractile GPCR signaling, regulator of G protein signaling 5 (RGS5), in unprovoked and allergen-induced AHR. Methods: We evaluated GPCR-evoked Ca2+ signaling, precision-cut lung slice (PCLS) contraction, and lung inflammation in naive and Aspergillus fumigatus-challenged wild-type and Rgs5(-/-) mice. We analyzed lung resistance and dynamic compliance in live anesthetized mice using invasive plethysmography. Results: Loss of RGS5 promoted constitutive AHR because of enhanced GPCR-induced Ca2+ mobilization in ASM. PCLSs from naive Rgs5(-/-) mice contracted maximally at baseline independently of allergen challenge. RGS5 deficiency had little effect on the parameters of allergic inflammation, including cell counts in bronchoalveolar lavage fluid, mucin production, ASM mass, and subepithelial collagen deposition. Unexpectedly, induced IL-13 and IL-33 levels were much lower in challenged lungs from Rgs5(-/-) mice relative to those seen in wild-type mice. Conclusion: Loss of RGS5 confers spontaneous AHR in mice in the absence of allergic inflammation. Because it is selectively expressed in ASM within the lung and does not promote inflammation, RGS5 might be a therapeutic target for asthma. C1 [Balenga, Nariman A.; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Jester, William; Jiang, Meiqi; Panettieri, Reynold A., Jr.] Univ Penn, Pulm Allergy & Crit Care Div, Airways Biol Initiat, Philadelphia, PA 19104 USA. RP Druey, KM (reprint author), 10 Ctr Dr,Rm 11N242, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov OI Balenga, Nariman/0000-0002-2741-9595 FU National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH) [AI001746]; NIH [R01 HL097796, P30 ES013508] FX Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH; project no. AI001746, to K. M. D.) and NIH grants R01 HL097796 and P30 ES013508 (to R. A. P.). NR 54 TC 4 Z9 4 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2014 VL 134 IS 2 BP 451 EP + DI 10.1016/j.jaci.2014.01.019 PG 20 WC Allergy; Immunology SC Allergy; Immunology GA AO5GB UT WOS:000341370800026 PM 24666695 ER PT J AU Bowman, JJ Burbelo, PD Gill, RB Sauri, MA Schmitt, JM Cohen, JI AF Bowman, J. Jason Burbelo, Peter D. Gill, Rachel B. Sauri, Michael A. Schmitt, James M. Cohen, Jeffrey I. TI A seroprevalence study of primate workers for asymptomatic rhesus cytomegalovirus infection SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE Rhesus cytomegalovirus; Cytomegalovirus; Primate workers; Zoonosis ID RETROVIRUS; EMERGENCE; HUNTERS AB Background: Human cytomegalovirus (HCMV) infection can cause severe disease in neonates and immunocompromised persons, and infectious mononucleosis in healthy adults. While, rhesus CMV (RhCMV) infects human cells in culture, it is unknown whether the virus can infect humans. Objectives: We sought to determine whether primate workers, including those with injuries from animals, might be infected asymptomatically with RhCMV. Study design: We developed serologic assays that distinguish RhCMV from HCMV antibodies. We tested two groups of primate workers: those with documented injuries or mucosal splashes associated with rhesus macaques, and those with no documented exposure who worked with these animals. Results: None of over 200 primate workers, including 119 with injuries or mucosal splashes associated with exposures to macaques, were seropositive for RhCMV. Conclusions: The frequency of asymptomatic RhCMV infection in persons who work with rhesus macaques was <0.5% (<1/200 primate workers). Published by Elsevier B.V. C1 [Bowman, J. Jason; Gill, Rachel B.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Sauri, Michael A.] Occupat Hlth Consultants, Rockville, MD USA. [Schmitt, James M.] NIH, Occupat Med Serv, Div Occupat Safety & Hlth, Off Director, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, Bldg 50,Room 6134,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU intramural research programs of the National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; National Institutes of Health FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research and National Institutes of Health. NR 11 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD AUG PY 2014 VL 60 IS 4 BP 411 EP 413 DI 10.1016/j.jcv.2014.07.010 PG 3 WC Virology SC Virology GA AO5AS UT WOS:000341353200016 PM 24890818 ER PT J AU Sahasrabuddhe, VV Gravitt, PE Dunn, ST Robbins, D Brown, D Allen, RA Eby, YJ Smith, KM Zuna, RE Zhang, RR Gold, MA Schiffman, M Walker, JL Castle, PE Wentzensen, N AF Sahasrabuddhe, Vikrant V. Gravitt, Patti E. Dunn, S. Terence Robbins, David Brown, David Allen, Richard A. Eby, Yolanda J. Smith, Katie M. Zuna, Rosemary E. Zhang, Roy R. Gold, Michael A. Schiffman, Mark Walker, Joan L. Castle, Philip E. Wentzensen, Nicolas TI Evaluation of clinical performance of a novel urine-based HPV detection assay among women attending a colposcopy clinic SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE Human papillomavirus; Cervical cancer; Urine; Screening ID DNA AB Background: Human papillomavirus (HPV) testing in urine offers a convenient approach for cervical cancer screening but has previously suffered from limited clinical sensitivity. Objectives: We evaluated clinical performance of the prototype Trovagene HPV test, a novel polymerase chain reaction assay that targets the El region of the HPV genome and detects and amplifies short fragments of cell-free HPV DNA in urine. Study design: We conducted a pilot study among 72 women referred to colposcopy following abnormal screening. Participants provided a urine sample prior to clinician-collected cervical sampling and colposcopically-directed punch biopsy. Trovagene HPV test results on urine samples were compared with cervical and urine testing by Linear Array HPV Genotyping Test (LA-HPV) for detection of whistologically-confirmed cervical precancerous lesions. Results: There was high concordance between urine samples tested by the Trovagene HPV test and corresponding cervical (87.5%) and urine (81.9%) samples tested by LA-HPV. The Trovagene HPV test had high sensitivity (92.3% for detecting CIN2/3, and 100% for CIN3), comparable to LA-HPV testing on cervical samples (96.0% and 100%, respectively), and higher than LA-HPV testing on urine samples (80.8% and 90.0%, respectively). In this referral population, the specificity of the Trovagene urine HPV test was non-significantly lower (29% for CIN2/3 and 25% for CIN3) than corresponding estimates of LA-HPV testing on cervical (36% and 28%, respectively) and urine (42% and 38%, respectively) samples. Conclusions: This pilot study suggests that the Trovagene HPV test has high sensitivity for urine-based detection of cervical precancer and merits evaluation in larger studies. Published by Elsevier B.V. C1 [Sahasrabuddhe, Vikrant V.; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sahasrabuddhe, Vikrant V.] Vanderbilt Univ, Nashville, TN 37235 USA. [Gravitt, Patti E.; Eby, Yolanda J.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Dunn, S. Terence; Brown, David; Allen, Richard A.; Smith, Katie M.; Zuna, Rosemary E.; Zhang, Roy R.; Walker, Joan L.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Robbins, David] UTC Labs, New Orleans, LA USA. [Gold, Michael A.] Tulsa Canc Inst, Tulsa, OK USA. [Gold, Michael A.] Univ Oklahoma, Sch Community Med, Tulsa, OK USA. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. RP Sahasrabuddhe, VV (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E230 MSC 9774, Bethesda, MD 20892 USA. EM vikrant.sahasrabuddhe@nih.gov; pgravitt@jhsph.edu; terry-dunn@ouhsc.edu; drobbins@renrx.com; david-brown@ouhsc.edu; richard-allen@ouhsc.edu; yeby@jhsph.edu; katie-smith@ouhsc.edu; rosemary-zuna@ouhsc.edu; roy-zhang@ouhsc.edu; michael.gold@tciok.org; schiffmm@exchange.nih.gov; joan-walker@ouhsc.edu; castle.philip@gmail.com; wentzenn@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 10 TC 2 Z9 2 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD AUG PY 2014 VL 60 IS 4 BP 414 EP 417 DI 10.1016/j.jcv.2014.04.016 PG 4 WC Virology SC Virology GA AO5AS UT WOS:000341353200017 PM 24881489 ER PT J AU Stevens, TP Finer, NN Carlo, WA Szilagyi, PG Phelps, DL Walsh, MC Gantz, MG Laptook, AR Yoder, BA Faix, RG Newman, JE Das, A Do, BT Schibler, K Rich, W Newman, NS Ehrenkranz, RA Peralta-Carcelen, M Vohr, BR Wilson-Costello, DE Yolton, K Heyne, RJ Evans, PW Vaucher, YE Adams-Chapman, I McGowan, EC Bodnar, A Pappas, A Hintz, SR Acarregui, MJ Fuller, J Goldstein, RF Bauer, CR O'Shea, TM Myers, GJ Higgins, RD AF Stevens, Timothy P. Finer, Neil N. Carlo, Waldemar A. Szilagyi, Peter G. Phelps, Dale L. Walsh, Michele C. Gantz, Marie G. Laptook, Abbot R. Yoder, Bradley A. Faix, Roger G. Newman, Jamie E. Das, Abhik Do, Barbara T. Schibler, Kurt Rich, Wade Newman, Nancy S. Ehrenkranz, Richard A. Peralta-Carcelen, Myriam Vohr, Betty R. Wilson-Costello, Deanne E. Yolton, Kimberly Heyne, Roy J. Evans, Patricia W. Vaucher, Yvonne E. Adams-Chapman, Ira McGowan, Elisabeth C. Bodnar, Anna Pappas, Athina Hintz, Susan R. Acarregui, Michael J. Fuller, Janell Goldstein, Ricki F. Bauer, Charles R. O'Shea, T. Michael Myers, Gary J. Higgins, Rosemary D. CA Child Hlth Human Dev Neonatal Res TI Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial (SUPPORT) SO JOURNAL OF PEDIATRICS LA English DT Article ID LOW-BIRTH-WEIGHT; CHRONIC LUNG-DISEASE; EXTREMELY PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; PULMONARY-FUNCTION; DISTRESS SYNDROME; CHILDHOOD ASTHMA; EARLY CPAP; FOLLOW-UP; CHILDREN AB Objective To explore the early childhood pulmonary outcomes of infants who participated in the National Institute of Child Health and Human Development's Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), using a factorial design that randomized extremely preterm infants to lower vs higher oxygen saturation targets and delivery room continuous positive airway pressure (CPAP) vs intubation/surfactant. Study design The Breathing Outcomes Study, a prospective secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, assessed respiratory morbidity at 6-month intervals from hospital discharge to 18-22 months corrected age (CA). Two pre-specified primary outcomes-wheezing more than twice per week during the worst 2-week period and cough longer than 3 days without a cold-were compared for each randomized intervention. Results One or more interviews were completed for 918 of the 922 eligible infants. The incidences of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between the study arms of either randomized intervention. Infants randomized to lower vs higher oxygen saturation targets had a similar risk of death or respiratory morbidity (except for croup and treatment with oxygen or diuretics at home). Infants randomized to CPAP vs intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs 36.5%; P < .05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P < .05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P < .05) by 18-22 months CA. Conclusion Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18-22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates. C1 [Stevens, Timothy P.; Szilagyi, Peter G.; Phelps, Dale L.; Myers, Gary J.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. [Stevens, Timothy P.; Szilagyi, Peter G.; Phelps, Dale L.; Myers, Gary J.] Golisano Childrens Hosp, Rochester, NY USA. [Finer, Neil N.; Rich, Wade; Vaucher, Yvonne E.] Univ Calif San Diego, Div Neonatol, San Diego, CA 92103 USA. [Carlo, Waldemar A.; Peralta-Carcelen, Myriam] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Walsh, Michele C.; Newman, Jamie E.; Wilson-Costello, Deanne E.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Gantz, Marie G.; Newman, Jamie E.; Do, Barbara T.] RTI Int, Res Triangle Pk, NC USA. [Laptook, Abbot R.; Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Yoder, Bradley A.; Faix, Roger G.; Bodnar, Anna] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT USA. [Das, Abhik] RTI Int, Rockville, MD USA. [Schibler, Kurt; Yolton, Kimberly] Cincinnati Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH USA. [Schibler, Kurt; Yolton, Kimberly] Univ Cincinnati, Cincinnati, OH USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Heyne, Roy J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Evans, Patricia W.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Adams-Chapman, Ira] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Adams-Chapman, Ira] Childrens Healthcare Atlanta, Atlanta, GA USA. [McGowan, Elisabeth C.] Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Div Newborn Med, Boston, MA USA. [Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Hintz, Susan R.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Acarregui, Michael J.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Fuller, Janell] Univ New Mexico, Hlth Sci Ctr, Div Neonatol, Albuquerque, NM 87131 USA. [Goldstein, Ricki F.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Bauer, Charles R.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [O'Shea, T. Michael] Wake Forest Univ, Bowman Gray Sch Med, Div Neonatol, Winston Salem, NC USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Stevens, TP (reprint author), Univ Rochester, Div Neonatol, POB 651,601 Elmwood Ave, Rochester, NY 14642 USA. EM timothy_stevens@urmc.rochester.edu OI Stevens, Timothy/0000-0002-2959-3925 FU National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute; NICHD [K23 HD50646] FX Supported by the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Heart, Lung, and Blood Institute (recruitment 2004-2009; follow-up 2006-2011). T.S. was supported by the NICHD (SUPPORT Breathing Outcomes Secondary Protocol K23 HD50646). Data collected at participating sites of the NICHD Neonatal Research Network were transmitted to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study. The authors declare no conflicts of interest. NR 36 TC 18 Z9 19 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2014 VL 165 IS 2 BP 240 EP U65 DI 10.1016/j.jpeds.2014.02.054 PG 14 WC Pediatrics SC Pediatrics GA AO6CJ UT WOS:000341435800007 PM 24725582 ER PT J AU Affer, M Chesi, M Chen, WD Keats, JJ Demchenko, YN Tamizhmani, K Garbitt, VM Riggs, DL Brents, LA Roschke, AV Van Wier, S Fonseca, R Bergsagel, PL Kuehl, WM AF Affer, M. Chesi, M. Chen, W. D. Keats, J. J. Demchenko, Y. N. Tamizhmani, K. Garbitt, V. M. Riggs, D. L. Brents, L. A. Roschke, A. V. Van Wier, S. Fonseca, R. Bergsagel, P. L. Kuehl, W. M. TI Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma SO LEUKEMIA LA English DT Article ID PLASMA-CELL LEUKEMIA; C-MYC; MONOCLONAL GAMMOPATHIES; UNDETERMINED SIGNIFICANCE; MOLECULAR PATHOGENESIS; SMOLDERING MYELOMA; IGH LOCUS; TRANSLOCATIONS; RISK; PROGRESSION AB MYC locus rearrangements-often complex combinations of translocations, insertions, deletions and inversions-in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet, germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS (monoclonal gammopathy of undetermined significance)-prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have biallelic MYC expression at significantly higher levels than in MGUS. We also have shown that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is biallelic, but sometimes can be monoallelic if there is an MYC rearrangement. Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy. C1 [Affer, M.; Chesi, M.; Tamizhmani, K.; Garbitt, V. M.; Riggs, D. L.; Van Wier, S.; Fonseca, R.; Bergsagel, P. L.] Mayo Clin Arizona, Ctr Comprehens Canc, Dept Hematol Oncol, Scottsdale, AZ 85259 USA. [Chen, W. D.; Demchenko, Y. N.; Tamizhmani, K.; Brents, L. A.; Roschke, A. V.; Kuehl, W. M.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Keats, J. J.] Translat Genom Res Inst, Phoenix, AZ USA. RP Bergsagel, PL (reprint author), Mayo Clin Arizona, Ctr Comprehens Canc, Dept Hematol Oncol, 13400 East Shea Blvd, Scottsdale, AZ 85259 USA. EM bergsagel.leif@mayo.edu; kuehlw@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research [CA83724, ECOG CA21115T, CA136671, CA133966]; Predolin Foundation; Mayo Clinic Cancer Center; Mayo Foundation FX We thank the MMRC for their help in processing samples for this project and making available cytospin slides for FISH, the RNA for selective expression and with the help of Mike Chapman, the list of structural variations in the MYC locus from the MM Genomics Initiative.38 This work is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (WMK); Grants CA83724 (RF), ECOG CA21115T(RF), CA136671 (PLB), CA133966 (PLB), Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. NR 55 TC 55 Z9 55 U1 2 U2 5 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 AUG PY 2014 VL 28 IS 8 BP 1725 EP 1735 DI 10.1038/leu.2014.70 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA AO4TP UT WOS:000341334600016 PM 24518206 ER PT J AU Grkovic, T Blees, JS Bayer, MM Colburn, NH Thomas, CL Henrich, CJ Peach, ML McMahon, JB Schmid, T Gustafson, KR AF Grkovic, Tanja Blees, Johanna S. Bayer, Magdalena M. Colburn, Nancy H. Thomas, Cheryl L. Henrich, Curtis J. Peach, Megan L. McMahon, James B. Schmid, Tobias Gustafson, Kirk R. TI Tricyclic Guanidine Alkaloids from the Marine Sponge Acanthella cavernosa that Stabilize the Tumor Suppressor PDCD4 SO MARINE DRUGS LA English DT Article DE natural product; guanidine alkaloid; PDCD4; tumor suppressor ID TRANSLATION INHIBITOR; TRANSFORMATION SUPPRESSOR; BIEMNA-LABOUTEI; EXPRESSION; DEGRADATION; CANCER; CRYPTOCARYOLS; CARCINOMA; INVASION; PROTEIN AB A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 mu g/mL and 2.8 mu g/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions. C1 [Grkovic, Tanja; Blees, Johanna S.; Thomas, Cheryl L.; Henrich, Curtis J.; McMahon, James B.; Gustafson, Kirk R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Blees, Johanna S.; Bayer, Magdalena M.; Schmid, Tobias] Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, D-60590 Frankfurt, Germany. [Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, Curtis J.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Peach, Megan L.] Leidos Biomed Res Inc, Basic Sci Program, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Schmid, T (reprint author), Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, D-60590 Frankfurt, Germany. EM t.grkovic@griffith.edu.au; johanna.blees@gmail.com; M_Bajer@gmx.de; colburna@mail.nih.gov; cltterry@mail.nih.gov; henrichcj@mail.nih.gov; mpeach@helix.nih.gov; mcmahoja@mail.nih.gov; t.schmid@biochem.uni-frankfurt.de; gustafki@mail.nih.gov RI Grkovic, Tanja/B-8874-2012 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Deutsche Forschungsgemeinschaft (DFG) [GRK1172] FX We thank David Newman (NCI) and Thomas McCloud (SAIC-Frederick) for the sponge extracts and Marzena Dyba and Sergey Tarasov (Biophysics Resource, SBL, NCI-Frederick) for assistance with the HRLCMS studies. This research was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. This project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This work was further supported by the Deutsche Forschungsgemeinschaft (DFG) (GRK1172). NR 29 TC 4 Z9 4 U1 1 U2 7 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-3397 J9 MAR DRUGS JI Mar. Drugs PD AUG PY 2014 VL 12 IS 8 BP 4593 EP 4601 DI 10.3390/md12084593 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AO5ZL UT WOS:000341426100017 PM 25196934 ER PT J AU Qiao, J Wang, ZB Feng, HL Miao, YL Wang, Q Yu, Y Wei, YC Yan, J Wang, WH Shen, W Sun, SC Schatten, H Sun, QY AF Qiao, Jie Wang, Zhen-Bo Feng, Huai-Liang Miao, Yi-Liang Wang, Qiang Yu, Yang Wei, Yan-Chang Yan, Jie Wang, Wei-Hua Shen, Wei Sun, Shao-Chen Schatten, Heide Sun, Qing-Yuan TI The root of reduced fertility in aged women and possible therapentic options: Current status and future perspects SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Infertility; Maternal age; Oocyte; Ovary; Assited reproductive technology ID EMBRYONIC STEM-CELLS; IN-VITRO FERTILIZATION; PREIMPLANTATION GENETIC DIAGNOSIS; GERMINAL VESICLE TRANSFER; HUMAN OVARIAN TISSUE; HUMAN CHORIONIC-GONADOTROPIN; BONE-MARROW-TRANSPLANTATION; INTRACYTOPLASMIC SPERM INJECTION; RANDOMIZED CONTROLLED-TRIAL; POLARIZED-LIGHT MICROSCOPY AB It is well known that maternal ageing not only causes increased spontaneous abortion and reduced fertility, but it is also a high genetic disease risk Although assisted reproductive technologies (ARTs) have been widely used to treat infertility, the overall success is still low. The main reasons for age-related changes include reduced follicle number, compromised oocyte quality especially aneuploidy, altered reproductive endocrinology, and increased reproductive tract defect. Various approaches for improving or treating infertility in aged women including controlled ovarian hyperstimulation with intrauterine insemination (IUI), IVF/ICSI-ET, ovarian reserve testing, preimplantation genetic diagnosis and screening (PGD/PGS), oocyte selection and donation, oocyte and ovary tissue cryopreservation before ageing, miscarriage prevention, and caloric restriction are summarized in this review. Future potential reproductive techniques for infertile older women including oocyte and zygote micromanipulations, derivation of oocytes from germ stem cells, ES cells, and iPS cells, as well as through bone marrow transplantation are discussed. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Qiao, Jie; Yu, Yang; Yan, Jie] Peking Univ, Hosp 3, Dept Obstet & Gynecol, Ctr Reprod Med, Beijing 100191, Peoples R China. [Wang, Zhen-Bo; Wei, Yan-Chang; Sun, Qing-Yuan] Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing 100101, Peoples R China. [Feng, Huai-Liang] Cornell Univ, Weill Med Coll, New York Hosp Queens, Dept Lab Med, New York, NY 10021 USA. [Miao, Yi-Liang] NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Wang, Qiang] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Wang, Wei-Hua] Tomball Reg Hosp, Houston Fertil Inst, Tomball, TX 77375 USA. [Shen, Wei] Qingdao Agr Univ, Dept Anim Sci, Lab Germ Cell Biol, Qingdao 266109, Peoples R China. [Sun, Shao-Chen] Nanjing Agr Univ, Dept Anim Sci, Nanjing 210095, Jiangsu, Peoples R China. [Schatten, Heide] Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. RP Sun, QY (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, 1 Beichen West Rd, Beijing 100101, Peoples R China. EM sunqy@ioz.ac.cn FU Major State Basic Research Program [2011CB944500, 2012CB944404]; National Natural Science Foundation of China [30930065] FX This study was partially supported by by Major State Basic Research Program (2011CB944500, 2012CB944404) and National Natural Science Foundation of China (30930065). NR 393 TC 18 Z9 20 U1 5 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 EI 1872-9452 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD AUG PY 2014 VL 38 SI SI BP 54 EP 85 DI 10.1016/j.mam.2013.06.001 PG 32 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA AO7NA UT WOS:000341538700002 PM 23796757 ER PT J AU Rackwitz, L Djouad, F Janjanin, S Noth, U Tuan, RS AF Rackwitz, L. Djouad, F. Janjanin, S. Noeth, U. Tuan, R. S. TI Functional cartilage repair capacity of de-differentiated, chondrocyte- and mesenchymal stem cell-laden hydrogels in vitro SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Chondrocyte; Mesenchymal stem cell; Hydrogel; Cartilage repair; Integration ID TISSUE-ENGINEERED CARTILAGE; BONE MORPHOGENETIC PROTEIN-2; ARTICULAR-CARTILAGE; CHONDROGENIC DIFFERENTIATION; GENE-EXPRESSION; DEFECTS; TRANSPLANTATION; IMPLANTATION; CULTURE; MARROW AB Objective: The long-term performance of cell-seeded matrix-based cartilage constructs depends on (1) the development of sufficient biomechanical properties, and (2) lateral integration with host tissues, both of which require cartilage-specific matrix deposition within the scaffold. In this study, we have examined the potential of tissue-engineered cartilage analogs developed using different cell types, i.e., mesenchymal stem cells (MSCs) vs chondrocytes and de-differentiated chondrocytes, in an established "construct in cartilage ring" model. Design: Cell-laden constructs of differentiated chondrocytes, de-differentiated chondrocytes after two, five or eight population doublings, and MSCs were either implanted into a native cartilage ring immediately after fabrication (immature group) or pre-treated for 21 days in a transforming growth factor-beta 3 (TGF-beta 3) containing medium prior to implantation. After additional culture for 28 days in a serum-free, chemically defined medium, the extent of lateral integration, and biochemical and biomechanical characteristics of the implants as hybrid constructs were assessed. Results: The quality of integration, the amount of accumulated cartilage-specific matrix components and associated biomechanical properties were found to be highest when using differentiated chondrocytes. De-differentiation of chondrocytes negatively impacted the properties of the implants, as even two population doublings of the chondrocytes in culture significantly lowered cartilage repair capacity. In contrast, MSCs showed chondrogenic differentiation with TGF-beta 3 pre-treatment and superior integrational behavior. Conclusions: Chondrocyte expansion and de-differentiation impaired the cell response, resulting in inferior cartilage repair in vitro. With TGF-beta 3 pre-treatment, MSCs were able to undergo sustained chondrogenic differentiation and exhibited superior matrix deposition and integration compared to dedifferentiated chondrocytes. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. C1 [Rackwitz, L.; Djouad, F.; Janjanin, S.; Tuan, R. S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tuan, R. S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15219 USA. [Noeth, U.] Univ Wurzburg, Orthopaed Ctr Musculoskeletal Res, D-97070 Wurzburg, Germany. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM l.rackwitz@waldkrankenhaus.com; farida.djouad@inserm.fr; s_janjanin@yahoo.com; u.noeth@waldkrankenhaus.com; rst13@pitt.edu OI Djouad, Farida/0000-0001-8248-6822 FU NIH Intramural Research Program [Z01 AR41131]; Commonwealth of Pennsylvania Department of Health [SAP 4100050913] FX This study was supported in part by the NIH Intramural Research Program (Z01 AR41131) and the Commonwealth of Pennsylvania Department of Health (SAP 4100050913). NR 59 TC 6 Z9 6 U1 2 U2 16 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 AUG PY 2014 VL 22 IS 8 BP 1148 EP 1157 DI 10.1016/j.joca.2014.05.019 PG 10 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA AO4YV UT WOS:000341348200011 PM 24887551 ER PT J AU Roche, B Drake, JM Brown, J Stallknecht, DE Bedford, T Rohani, P AF Roche, Benjamin Drake, John M. Brown, Justin Stallknecht, David E. Bedford, Trevor Rohani, Pejman TI Adaptive Evolution and Environmental Durability Jointly Structure Phylodynamic Patterns in Avian Influenza Viruses SO PLOS BIOLOGY LA English DT Article ID A VIRUSES; PHYLOGENETIC ANALYSIS; WILD BIRDS; LOW-PATHOGENICITY; H3N2 VIRUSES; DYNAMICS; TRANSMISSION; WATER; H5N1; PERSISTENCE AB Avian influenza viruses (AIVs) have been pivotal to the origination of human pandemic strains. Despite their scientific and public health significance, however, there remains much to be understood about the ecology and evolution of AIVs in wild birds, where major pools of genetic diversity are generated and maintained. Here, we present comparative phylodynamic analyses of human and AIVs in North America, demonstrating (i) significantly higher standing genetic diversity and (ii) phylogenetic trees with a weaker signature of immune escape in AIVs than in human viruses. To explain these differences, we performed statistical analyses to quantify the relative contribution of several potential explanations. We found that HA genetic diversity in avian viruses is determined by a combination of factors, predominantly subtype-specific differences in host immune selective pressure and the ecology of transmission (in particular, the durability of subtypes in aquatic environments). Extending this analysis using a computational model demonstrated that virus durability may lead to long-term, indirect chains of transmission that, when coupled with a short host lifespan, can generate and maintain the observed high levels of genetic diversity. Further evidence in support of this novel finding was found by demonstrating an association between subtype-specific environmental durability and predicted phylogenetic signatures: genetic diversity, variation in phylogenetic tree branch lengths, and tree height. The conclusion that environmental transmission plays an important role in the evolutionary biology of avian influenza viruses-a manifestation of the "storage effect"-highlights the potentially unpredictable impact of wildlife reservoirs for future human pandemics and the need for improved understanding of the natural ecology of these viruses. C1 [Roche, Benjamin; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Roche, Benjamin] UMPC 209, Unite Modelisat Math & Informat Syst Complexes, IRD, Bondy, France. [Drake, John M.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Brown, Justin; Stallknecht, David E.] Univ Georgia, Coll Vet Med, Dept Populat Hlth, Southeastern Cooperat Wildlife Dis Study, Athens, GA USA. [Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Roche, B (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM benjamin.roche@ird.fr OI Bedford, Trevor/0000-0002-4039-5794; Roche, Benjamin/0000-0001-7975-4232; Drake, John/0000-0003-4646-1235 FU Centers for Disease Control and Prevention [5U19Cl000401]; James S. McDonnell Foundation; National Science Foundation [DEB-0917853]; Royal Society; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the Centers for Disease Control and Prevention (5U19Cl000401), the James S. McDonnell Foundation, and the National Science Foundation (DEB-0917853). TB was supported by the Royal Society. PR was also supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 12 Z9 12 U1 2 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD AUG PY 2014 VL 12 IS 8 AR e1001931 DI 10.1371/journal.pbio.1001931 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA AO7HI UT WOS:000341523000013 PM 25116957 ER PT J AU Ahmed, MM Guha, C Hodge, JW Jaffee, E AF Ahmed, Mansoor M. Guha, Chandan Hodge, James W. Jaffee, Elizabeth TI Immunobiology of Radiotherapy: New Paradigms SO RADIATION RESEARCH LA English DT Editorial Material C1 [Ahmed, Mansoor M.] NCI, Radiat Res Program, NIH, Rockville, MD 20850 USA. [Guha, Chandan] Albert Einstein Coll Med, Dept Radiat Oncol & Pathol, Bronx, NY 10461 USA. [Guha, Chandan] Montefiore Med Ctr, Bronx, NY 10461 USA. [Hodge, James W.] NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. [Jaffee, Elizabeth] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. RP Ahmed, MM (reprint author), NCI, Radiat Res Program, NIH, Rockville, MD 20850 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R01 CA078471] NR 13 TC 11 Z9 11 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2014 VL 182 IS 2 BP 123 EP 125 DI 10.1667/RR13849.1 PG 3 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LF UT WOS:000341308800001 PM 25036983 ER PT J AU Wattenberg, MM Fahim, A Ahmed, MM Hodge, JW AF Wattenberg, Max M. Fahim, Ahmed Ahmed, Mansoor M. Hodge, James W. TI Unlocking the Combination: Potentiation of Radiation-Induced Antitumor Responses with Immunotherapy SO RADIATION RESEARCH LA English DT Article ID SPATIALLY-FRACTIONATED RADIATION; CYTOTOXIC T-LYMPHOCYTES; TUMOR-CELLS; PROSTATE-CANCER; CALRETICULIN EXPOSURE; BEAM RADIATION; THERAPY; RADIOTHERAPY; VACCINE; CHEMOTHERAPY AB There is increasing evidence of the potential for radiation therapy to generate antitumor immune responses. The mechanisms of this immune-activating potential include actions on tumor cells such as immunogenic cell death and phenotypic change. Radiation modulates tumor cell surface expression of cell death receptors, tumor-associated antigens and adhesion molecules. This process of immunomodulation sensitizes tumor cells to immune-mediated killing. Radiation also affects immune compartments, including antigen-presenting cells, cytotoxic T lymphocytes and humoral immunity, leading to specific antitumor immune responses. Recognizing the importance of immunity as a potentiator of response to radiation leads to rational augmentation of antitumor immunity by combining radiation and immunotherapy. Targeted immunotherapy manipulates the immune system in a way that best synergizes with radiation. This article discusses the ability of radiation monotherapy to induce antitumor immunity, with a focus on the effect of radiation on antigen-presenting cells and cytotoxic T lymphocytes. We define two important responses generated by tumor cells, immunogenic cell death and immunomodulation, both of which are radiation dose-dependent. In conclusion, we describe the translation of several combination therapies from the preclinical to the clinical setting and identify opportunities for further exploration. (C) 2014 by Radiation Research Society C1 [Wattenberg, Max M.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fahim, Ahmed; Ahmed, Mansoor M.] NCI, Radiotherapy Dev Branch, Radiat Res Program, Div Canc Treatment & Diag,NIH, Rockville, MD USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B13, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH); NIH Medical Research Scholars Program; Pfizer Inc. FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH). This research was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program). The authors thank Bonnie L. Casey for editorial assistance in the preparation of this manuscript. NR 66 TC 15 Z9 15 U1 0 U2 4 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2014 VL 182 IS 2 BP 126 EP 138 DI 10.1667/RR13374.1 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LF UT WOS:000341308800002 PM 24960415 ER PT J AU Aryankalayil, MJ Makinde, AY Gameiro, SR Hodge, JW Rivera-Solis, PP Palayoor, ST Ahmed, MM Coleman, CN AF Aryankalayil, Molykutty J. Makinde, Adeola Y. Gameiro, Sofia R. Hodge, James W. Rivera-Solis, Patricia P. Palayoor, Sanjeewani T. Ahmed, Mansoor M. Coleman, C. Norman TI Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells SO RADIATION RESEARCH LA English DT Article ID LOCAL RADIATION-THERAPY; FRACTIONATED RADIATION; TUMOR-CELLS; IFN-GAMMA; ANTICANCER CHEMOTHERAPY; GENE-EXPRESSION; CARCINOMA-CELLS; DENDRITIC CELLS; IMMUNE-SYSTEM; PROTEINS AB To understand the impact of clinically relevant radiation therapy (RT) on tumor immune gene expression and to utilize the changes that occur during treatment to improve cancer treatment outcome, we examined how immune response genes are modulated in prostate cancer cells of varying p53 status. LNCaP (p53 wild-type), PC3 (p53 null) and DU145 (p53 mutant) cells received a 10 Gy single dose or 1 Gy x 10 multifractionated radiation dose to simulate hypofractionated and conventionally fractionated prostate radiotherapy. Total RNA was isolated 24 h after multifractionated radiation treatment and single-dose treatments and subjected to microarray analysis and later validated by RT-PCR. RT-PCR was utilized to identify total-dose inflection points for significantly upregulated genes in response to multifractionated radiation therapy. Radiation- induced damage-associated molecular pattern molecules (DAMPs) and cytokine analyses were performed using bioluminescence and ELISA. Multifractionated doses activated immune response genes more robustly than single-dose treatment, with a relatively larger number of immune genes upregulated in PC3 compared to DU145 and LNCaP cells. The inflection point of multifractionated radiation-induced immune genes in PC3 cells was observed in the range of 8-10 Gy total radiation dose. Although both multifractionated and single-dose radiation-induced pro-inflammatory DAMPs and positively modulated the cytokine environment, the changes were of higher magnitude with multifractionated therapy. The findings of this study together with the gene expression data suggest that cells subjected to multifractionated radiation treatment would promote productive immune cell-tumor cell interactions. (C) 2014 by Radiation Research Society C1 [Aryankalayil, Molykutty J.; Makinde, Adeola Y.; Rivera-Solis, Patricia P.; Palayoor, Sanjeewani T.; Coleman, C. Norman] NCI, Ctr Canc Res, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Gameiro, Sofia R.; Hodge, James W.] NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Ahmed, Mansoor M.; Coleman, C. Norman] NCI, Radiat Res Program, NIH, Rockville, MD USA. RP Coleman, CN (reprint author), NCI, Ctr Canc Res, Radiat Oncol Branch, Bethesda, MD 20892 USA. EM ccoleman@mail.nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX This study was supported by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. The authors would like to thank Momodou Jammeh for excellent technical assistance and Orieta Celiku, Radiation Oncology Branch of the NCI, for the help with statistical analysis. NR 57 TC 10 Z9 10 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2014 VL 182 IS 2 BP 139 EP 148 DI 10.1667/RR13731.1 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LF UT WOS:000341308800003 PM 25003313 ER PT J AU Kanagavelu, S Gupta, S Wu, X Philip, S Wattenberg, MM Hodge, JW Couto, MD Chung, KD Ahmed, MM AF Kanagavelu, Saravana Gupta, Seema Wu, Xiaodong Philip, Sakhi Wattenberg, Max M. Hodge, James W. Couto, Mariluz D. Chung, Kristina D. Ahmed, Mansoor M. TI In Vivo Effects of Lattice Radiation Therapy on Local and Distant Lung Cancer: Potential Role of Immunomodulation SO RADIATION RESEARCH LA English DT Article ID FRACTIONATED GRID RADIATION; TUMOR-GROWTH; IFN-GAMMA; ENDOTHELIAL-CELL; IMMUNE-RESPONSE; T-CELLS; ABSCOPAL; RADIOTHERAPY; ALPHA; ANGIOGENESIS AB Radiation is a potent immune-modulator that elicits cell death upon tumor, stromal and angiogenic compartments of tumor microenvironment. Here, we test a novel approach of high-dose radiation delivery using three dimensional volume based lattice radiation therapy (LRT) to understand the impact of different volume irradiation in eliciting both local and metastatic/distant tumor control through modulation of tumor immune micro-environment. To study such effects of LRT, tumors were implanted in both hind legs of C57BL/6 mice using Lewis lung carcinoma 1 (LLC1) cells. Mice were divided into five groups: untreated; partial tumor volume groups included two 10% vertices, one 20% vertex and one 50% vertex of the total tumor volume; and 100% open-field irradiation. Tumors implanted in the left flank were irradiated with a single dose of 20 Gy while the tumors in the right flank were unirradiated. Tumor growth and regression as well as immune responses (such as Th1 and Th2; T-cell infiltration) were determined after radiation treatment. Results demonstrated that both 100% open-field irradiation and 20% volume irradiation (in two 10% volumes) resulted in significant growth delay in the irradiated tumor. Further, all types of radiation exposures, partial or 100% volume, demonstrated distal effectiveness, however, 20% volume irradiation (in two 10% volumes) and 50% tumor volume irradiation led to maximum growth delay. Mice treated with partial tumor volume radiation induced a robust IFN-gamma and Th1 response when compared to whole-tumor irradiation and down-modulated Th2 functions. The presence of increased CD3(+) cells and TRAIL in partially irradiated tumor volumes correlated well with tumor growth delay. Further, serum obtained from any of the LRT treated mice caused growth inhibition of endothelial cells when compared to serum obtained from either untreated or open-field irradiated groups. These results indicate that high-dose partial volume irradiation can cause an improved distant effect than the total tumor volume irradiation through activating the host immune system. (C) 2014 by Radiation Research Society C1 [Kanagavelu, Saravana; Philip, Sakhi; Couto, Mariluz D.; Chung, Kristina D.] Univ Miami, Dept Radiat Oncol, Miami, FL 33136 USA. [Gupta, Seema; Wu, Xiaodong] Biophys Res Inst America, Boca Raton, FL 33179 USA. [Wattenberg, Max M.; Hodge, James W.] NCI, NIH, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Ahmed, Mansoor M.] NCI, NIH, RDB, RRP,DCTD, Rockville, MD 20850 USA. RP Ahmed, MM (reprint author), NCI, NIH, RDB, RRP,DCTD, 9609 Med Ctr Dr,Rm 3W224, Rockville, MD 20850 USA. EM ahmedmm@mail.nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 55 TC 3 Z9 3 U1 0 U2 5 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2014 VL 182 IS 2 BP 149 EP 162 DI 10.1667/RR3819.1 PG 14 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LF UT WOS:000341308800004 PM 25036982 ER PT J AU Sharon, E Polley, MY Bernstein, MB Ahmed, M AF Sharon, Elad Polley, Mei-Yin Bernstein, Michael B. Ahmed, Mansoor TI Immunotherapy and Radiation Therapy: Considerations for Successfully Combining Radiation into the Paradigm of Immuno-Oncology Drug Development SO RADIATION RESEARCH LA English DT Article ID CONTINUAL REASSESSMENT METHOD; I CLINICAL-TRIALS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; LATE-ONSET TOXICITIES; PHASE-I; SOLID TUMORS; T-CELLS; CANCER; DESIGN; PATIENT AB As the immunotherapy of cancer comes of age, adding immunotherapeutic agents to radiation therapy has the potential to improve the outcomes for patients with a wide variety of malignancies. Despite the enormous potential of such combination therapy, laboratory data has been lacking and there is little guidance for pursuing novel treatment strategies. Animal models have significant limitation in combining radiation therapy with immunotherapy and some of the limitations of preclinical models are discussed in this article. In addition to the preclinical challenges, radiation therapy and immunotherapy combinations may have overlapping toxicities, and for both types of therapy, early and late manifestations of toxicity are possible. Given these risks, special attention should be given to the design of the specific Phase I clinical trial that is chosen. In this article, we describe several Phase I design possibilities that may be employed, including the 3 + 3 design (also known as the cohort of 3 design), the continual reassessment method (CRM), and the time-to-event continual reassessment method (TITE-CRM). Efficacy end points for further development of combination therapy must be based on multiple factors, including disease type, stage of disease, the setting of therapy and the goal of therapy. While the designs for future clinical trials will vary, it is clear that these two successful modalities of therapy can and should be combined for the benefit of cancer patients. (C) 2014 by Radiation Research Society C1 [Sharon, Elad] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Polley, Mei-Yin] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Ahmed, Mansoor] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Bernstein, Michael B.] Albert Einstein Coll Med, Dept Radiat Oncol, Bronx, NY 10467 USA. [Bernstein, Michael B.] Montefiore Med Ctr, Bronx, NY 10467 USA. RP Sharon, E (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM sharone@mail.nih.gov NR 52 TC 6 Z9 6 U1 0 U2 4 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2014 VL 182 IS 2 BP 252 EP 257 DI 10.1667/RR13707.1 PG 6 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LF UT WOS:000341308800014 PM 25003314 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO SPINE JOURNAL LA English DT Article DE Low back pain; chronic low back pain; research standards; minimum dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses'' in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. PERSPECTIVE: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. This guideline article was first reported in the The Journal of Pain. (C) 2014 by the American Pain Society. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John; Weiner, Debra K.] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] Natl Inst Arthritis Musculoskeletal & Skin Dis, Bethesda, MD USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. NR 124 TC 6 Z9 6 U1 8 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD AUG PY 2014 VL 14 IS 8 BP 1375 EP 1391 DI 10.1016/j.spinee.2014.05.002 PG 17 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AO4JT UT WOS:000341304300002 PM 24950669 ER PT J AU Weng, LC Tang, WH Rich, SS Smith, NL Redline, S O'Donnell, CJ Basu, S Reiner, AP Delaney, JA Tracy, RP Palmer, CD Young, T Yang, Q Folsom, AR Cushman, M AF Weng, Lu-Chen Tang, Weihong Rich, Stephen S. Smith, Nicholas L. Redline, Susan O'Donnell, Christopher J. Basu, Saonli Reiner, Alexander P. Delaney, Joseph A. Tracy, Russell P. Palmer, Cameron D. Young, Taylor Yang, Qiong Folsom, Aaron R. Cushman, Mary TI A genetic association study of D-dimer levels with 50 K SNPs from a candidate gene chip in four ethnic groups SO THROMBOSIS RESEARCH LA English DT Article DE D-dimer; genetic association study; CARe consortium; single nucleotide polymorphisms ID FIBRIN D-DIMER; GENOME-WIDE ASSOCIATION; VENOUS THROMBOEMBOLISM; THR312ALA POLYMORPHISM; CARDIOVASCULAR HEALTH; ACTIVATION MARKERS; HEMOSTATIC FACTORS; LINKAGE ANALYSES; RESOURCE CARE; FACTOR-V AB Introduction: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations. Materials and Methods: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis. Results: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0 x 10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer. Conclusions: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Weng, Lu-Chen; Tang, Weihong; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Smith, Nicholas L.; Reiner, Alexander P.; Delaney, Joseph A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs Off Res & Dev, Seattle, WA USA. [Redline, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Sleep Med, Boston, MA USA. [Redline, Susan] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Basu, Saonli] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Biochem, Burlington, VT USA. [Palmer, Cameron D.; Young, Taylor] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA. [Yang, Qiong] NHLBIs Framingham Heart Study, Framingham, MA USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Cushman, Mary] Univ Vermont, Dept Pathol & Med, Burlington, VT USA. RP Tang, WH (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, 1300 S Second St,WBOB 300, Minneapolis, MN 55454 USA. EM tang0097@umn.edu FU National Heart, Lung, and Blood Institute; Broad Institute of Harvard University; Massachusetts Institute of Technology [N01-HC-65226]; University of Washington [N01-HC-85079, N01 HC-55222, U01 HL080295, N01-HC-95159]; Wake Forest University [N01-HC-85080, N01-HC-95165]; Johns Hopkins University [N01-HC-85081, N01 HC-15103, N01-HC-95162, N01-HC-95168]; University of Pittsburgh [N01-HC-85082]; University of California, Davis [N01-HC-85083]; University of California, Irvine [N01-HC-85084]; New England Medical Center [N01-HC-85085, N01-HC-95167]; University of Vermont [N01-HC-85086, N01-HC-95166]; Georgetown University [N01-HC-35129]; University of Wisconsin [N01-HC-75150]; Geisinger Clinic [N01-HC-45133]; Case Western Reserve University [RO1 HL46380-01-16]; Framingham Heart Study (FHS): Boston University [N01-HC25195]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; University of Minnesota [N01-HC-95163]; Northwestern University [N01-HC-95164]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; [R01-HL095603] FX CARe Acknowledgement: The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. The following four parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard University and the Massachusetts Institute of Technology (N01-HC-65226) to create this genotype/phenotype data base for this project:; Cardiovascular Health Study (CHS): University of Washington (N01-HC-85079), Wake Forest University (N01-HC-85080), Johns Hopkins University (N01-HC-85081), University of Pittsburgh (N01-HC-85082),University of California, Davis (N01-HC-85083), University of California, Irvine (N01-HC-85084), New England Medical Center (N01-HC-85085),University of Vermont (N01-HC-85086), Georgetown University (N01-HC-35129), Johns Hopkins University (N01 HC-15103), University of Wisconsin (N01-HC-75150), Geisinger Clinic (N01-HC-45133), University of Washington (N01 HC-55222, U01 HL080295);; Cleveland Family Study (CFS): Case Western Reserve University (RO1 HL46380-01-16); Framingham Heart Study (FHS): Boston University (N01-HC25195);; Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Johns Hopkins University (N01-HC-95168), Harbor-UCLA Research and Education Institute (N01-HC-95169);; Part of the work was supported by grant R01-HL095603. We would like to thank the University of Minnesota Supercomputing Institute for use of the Blade and Calhoun supercomputers. NR 37 TC 1 Z9 1 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD AUG PY 2014 VL 134 IS 2 BP 462 EP 467 DI 10.1016/j.thromres.2014.05.018 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AO4LI UT WOS:000341309200041 PM 24908450 ER PT J AU Gurnev, PA Nestorovich, EM AF Gurnev, Philip A. Nestorovich, Ekaterina M. TI Channel-Forming Bacterial Toxins in Biosensing and Macromolecule Delivery SO TOXINS LA English DT Review DE gramicidin A; alpha-hemolysin; anthrax toxin; biosensing; stochastic sensing; ion channel; biological nanopore; protein translocation; targeted toxins; drug delivery; polymer transport ID ANTHRAX PROTECTIVE ANTIGEN; AUREUS ALPHA-TOXIN; PLANAR LIPID-BILAYERS; SYMMETRICAL TETRAALKYLAMMONIUM IONS; BETA-CYCLODEXTRIN DERIVATIVES; PERFRINGENS EPSILON TOXIN; VIBRIO-CHOLERAE CYTOLYSIN; BOTULINUM C2 TOXIN; NONCOVALENT MOLECULAR ADAPTER; MESOSCOPIC PROTEIN NANOPORE AB To intoxicate cells, pore-forming bacterial toxins are evolved to allow for the transmembrane traffic of different substrates, ranging from small inorganic ions to cell-specific polypeptides. Recent developments in single-channel electrical recordings, X-ray crystallography, protein engineering, and computational methods have generated a large body of knowledge about the basic principles of channel-mediated molecular transport. These discoveries provide a robust framework for expansion of the described principles and methods toward use of biological nanopores in the growing field of nanobiotechnology. This article, written for a special volume on. Intracellular Traffic and Transport of Bacterial Protein Toxins., reviews the current state of applications of pore-forming bacterial toxins in small- and macromolecule-sensing, targeted cancer therapy, and drug delivery. We discuss the electrophysiological studies that explore molecular details of channel-facilitated protein and polymer transport across cellular membranes using both natural and foreign substrates. The review focuses on the structurally and functionally different bacterial toxins: gramicidin A of Bacillus brevis, a-hemolysin of Staphylococcus aureus, and binary toxin of Bacillus anthracis, which have found their. second life. in a variety of developing medical and technological applications. C1 [Gurnev, Philip A.] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Gurnev, Philip A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20008 USA. [Nestorovich, Ekaterina M.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. RP Nestorovich, EM (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. EM gurnev@physics.umass.edu; nestorovich@cua.edu FU National Science Foundation [1249199]; The Catholic University of America FX Philip A. Gurnev research is supported by the National Science Foundation EAGER award No. 1249199. Ekaterina M. Nestorovich research is supported by the startup funds from The Catholic University of America. The authors thank Adrian and Valerie Parsegian for their invaluable help with the manuscript proofreading. NR 370 TC 7 Z9 7 U1 9 U2 46 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD AUG PY 2014 VL 6 IS 8 BP 2483 EP 2540 DI 10.3390/toxins6082483 PG 58 WC Toxicology SC Toxicology GA AO5ZS UT WOS:000341427200018 PM 25153255 ER PT J AU Jarow, J Kluetz, PG Lerner, SP Liu, K Sridhara, R Bajorin, D Chang, S Dinney, CPN Groshen, S Morton, RA O'Donnell, M Quale, DZ Schoenberg, M Seigne, J Vikram, B AF Jarow, Jonathan Kluetz, Paul G. Lerner, Seth P. Liu, Ke Sridhara, Rajeshwari Bajorin, Dean Chang, Sam Dinney, Colin P. N. Groshen, Susan Morton, Ronald A. O'Donnell, Michael Quale, Diane Zipursky Schoenberg, Mark Seigne, John Vikram, Bhadrasain TI Re: Jarow JP et al.: Clinical Trial Design For the Development of New Therapies for Non-muscle-invasive Bladder Cancer: Report of a Food and Drug Administration and American Urological Association Public Workshop (Urology 2014;83:262-265) Reply SO UROLOGY LA English DT Letter C1 [Jarow, Jonathan; Kluetz, Paul G.] US FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. [Lerner, Seth P.] Baylor Coll Med, Med Ctr, Scott Dept Urol, Houston, TX 77030 USA. [Liu, Ke] Ctr Biol Evaluat & Res Food & Drug Adm, Off Cellular Tissue & Gene Therapies, Silver Spring, MD USA. [Sridhara, Rajeshwari] CDER Food & Drug Adm, Div Biometr 5, Off Biostat, Silver Spring, MD USA. [Bajorin, Dean] Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, New York, NY 10021 USA. [Chang, Sam] Vanderbilt Univ, Med Ctr, Dept Urol Surg, Nashville, TN USA. [Dinney, Colin P. N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Groshen, Susan] USC, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Morton, Ronald A.] Amer Med Syst, Minnetonka, MN USA. [O'Donnell, Michael] Univ Iowa, Iowa City, IA USA. [Quale, Diane Zipursky] Bladder Canc Advocacy Network, Bethesda, MD USA. [Schoenberg, Mark] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Seigne, John] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Seigne, John] Norris Cotton Canc Ctr, Lebanon, NH USA. [Vikram, Bhadrasain] NCI, Bethesda, MD 20892 USA. RP Jarow, J (reprint author), US FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD AUG PY 2014 VL 84 IS 2 BP 495 EP 496 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AO5EH UT WOS:000341365500079 PM 25065996 ER PT J AU Tuero, I Robert-Guroff, M AF Tuero, Iskra Robert-Guroff, Marjorie TI Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models SO VIRUSES-BASEL LA English DT Review DE HIV vaccine; mucosal immunity; non-human primate ID SIMIAN IMMUNODEFICIENCY VIRUS; CD8(+) T-CELLS; DEPENDENT CELLULAR CYTOTOXICITY; HUMORAL IMMUNE-RESPONSES; FEMALE RHESUS MACAQUES; HIGHLY PATHOGENIC SIV; GENITAL-TRACT; NEUTRALIZING ANTIBODIES; SHIV89.6P CHALLENGE; SIVMAC251 CHALLENGE AB An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials. C1 [Tuero, Iskra; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM iskra.tuero@nih.gov; guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 147 TC 3 Z9 3 U1 2 U2 11 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD AUG PY 2014 VL 6 IS 8 BP 3129 EP 3158 DI 10.3390/v6083129 PG 30 WC Virology SC Virology GA AO6AS UT WOS:000341430400010 PM 25196380 ER PT J AU Zhou, ZJ Zhao, ZH Zhang, H Wang, ZY Chen, XY Wang, RF Chen, Z Gao, JH AF Zhou, Zijian Zhao, Zhenghuan Zhang, Hui Wang, Zhenyu Chen, Xiaoyuan Wang, Ruifang Chen, Zhong Gao, Jinhao TI Interplay between Longitudinal and Transverse Contrasts in Fe3O4 Nanoplates with (111) Exposed Surfaces SO ACS NANO LA English DT Article DE T-1 and T-2 contrasts; magnetite nanoplates; Fe3O4(111); morphology ID IRON-OXIDE NANOPARTICLES; PAIR CORRELATION-FUNCTIONS; MAGNETIC NANOPARTICLES; SPIN RELAXATION; T-1 CONTRAST; TRANSLATIONAL DIFFUSION; BIOLOGICAL APPLICATIONS; BIOMEDICAL APPLICATIONS; AGENTS; RESONANCE AB Iron oxide has been developed as either T-1 or T-2 magnetic resonance imaging (MRI) contrast agents by controlling the size and composition; however, the underlying mechanism of T-1 and T-2 contrasts in one iron oxide entity is still not well understood. Herein, we report that freestanding superparamagnetic magnetite nanoplates with (111) exposed facets have significant but interactional T-1 and T-2 contrast effects. We demonstrate that the main contribution of the T-1 contrast of magnetic nanoplates is the chemical exchange on the iron-rich Fe3O4(111) surfaces, whereas the T-2 relaxation is dominated by the intrinsic superparamagnetism of the nanoplates with an enhanced perturbation effect We are able to regulate the balance of T-1 and T-2 contrasts by controlling structure and surface features, including morphology, exposed facets, and surface coating. This study provides an insightful understanding on the T-1 and T-2 contrast mechanisms, which is urgently needed to allow more sophisticated design of high-performance MRI contrast agents. C1 [Zhou, Zijian; Zhao, Zhenghuan; Zhang, Hui; Gao, Jinhao] Xiamen Univ, State Key Lab Phys Chem Solid Surfaces, Key Lab Chem Biol Fujian Prov, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. [Zhou, Zijian; Zhao, Zhenghuan; Zhang, Hui; Gao, Jinhao] Xiamen Univ, Coll Chem & Chem Engn, Dept Biol Chem, Xiamen 361005, Peoples R China. [Wang, Zhenyu; Wang, Ruifang; Chen, Zhong] Xiamen Univ, Dept Elect Sci, Xiamen 361005, Peoples R China. [Wang, Zhenyu; Wang, Ruifang; Chen, Zhong] Xiamen Univ, Fujian Key Lab Plasma & Magnet Resonance, Xiamen 361005, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Gao, JH (reprint author), Xiamen Univ, State Key Lab Phys Chem Solid Surfaces, Key Lab Chem Biol Fujian Prov, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. EM jhgao@xmu.edu.cn RI Gao, Jinhao/F-5092-2010; wang, ruifang/D-3037-2016; Chen, Zhong/G-4601-2010 OI Gao, Jinhao/0000-0003-3215-7013; wang, ruifang/0000-0002-8456-9776; FU National Key Basic Research Program of China [2013CB933901, 2014CB744502, 2014CB932004]; National Natural Science Foundation of China [21222106, 81370042, 81000662]; Natural Science Foundation of Fujian [2013J06005, IRT13036]; Fok Ying Tung Education Foundation [142012]; Program for New Century Excellent Talents in University [NCET-10-0709] FX This work was supported by the National Key Basic Research Program of China (2013CB933901, 2014CB744502, and 2014CB932004), National Natural Science Foundation of China (21222106, 81370042, and 81000662), Natural Science Foundation of Fujian (2013J06005), IRT13036, Fok Ying Tung Education Foundation (142012), and Program for New Century Excellent Talents in University (NCET-10-0709). We thank Dennis W. Hwang and Y.W. Chen for NMRD measurements, and E. Meggers, L.S. Zheng, and C.B. Cai for the fruitful discussions. NR 48 TC 28 Z9 28 U1 9 U2 108 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD AUG PY 2014 VL 8 IS 8 BP 7976 EP 7985 DI 10.1021/nn5038652 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA AO0IM UT WOS:000340992300043 PM 25093532 ER PT J AU Sun, XL Huang, XL Yan, XF Wang, Y Guo, JX Jacobson, O Liu, DB Szajek, LP Zhu, WL Niu, G Kiesewetter, DO Sun, SH Chen, XY AF Sun, Xiaolian Huang, Xinglu Yan, Xuefeng Wang, Yu Guo, Jinxia Jacobson, Orit Liu, Dingbin Szajek, Lawrence P. Zhu, Wenlei Niu, Gang Kiesewetter, Dale O. Sun, Shouheng Chen, Xiaoyuan TI Chelator-Free Cu-64-Integrated Gold Nanomaterials for Positron Emission Tomography Imaging Guided Photothermal Cancer Therapy SO ACS NANO LA English DT Article DE Cu-64 labeling; chelator free; PET; image-guided photothermal therapy ID TUMOR VASCULATURE; QUANTUM DOTS; NANOPARTICLES; PET; CLEARANCE; NANOCAGES; MICE AB Using positron emission tomography (PET) imaging to monitor and quantitatively analyze the delivery and localization of Au nanomaterials (NMs), a widely used photothermal agent, is essential to optimize therapeutic protocols to achieve individualized medicine and avoid side effects. Coupling radiometals to Au NMs via a chelator faces the challenges of possible detachment of the radiometals as well as surface property changes of the NMs. In this study, we reported a simple and general chelator-free Cu-64 radiolabeling method by chemically reducing Cu-64 on the surface of polyethylene glycol (PEG) stabilized Au NMs regardless of their shape and size. Our Cu-64 integrated NMs are proved to be radiochemically stable and can provide an accurate and sensitive localization of NMs through noninvasive PET imaging. We further integrated Cu-64 onto arginine-glycine-aspartic acid (RGD) peptide modified Au nanorods (NRs) for tumor theranostic application. These NRs showed high tumor targeting ability in a U87MG glioblastoma xenograft model and were successfully used for PET image-guided photothermal therapy. C1 [Sun, Xiaolian; Huang, Xinglu; Yan, Xuefeng; Wang, Yu; Guo, Jinxia; Jacobson, Orit; Liu, Dingbin; Niu, Gang; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Sun, Xiaolian; Guo, Jinxia] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 261005, Peoples R China. [Szajek, Lawrence P.] NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Zhu, Wenlei; Sun, Shouheng] Brown Univ, Dept Chem, Providence, RI 02912 USA. RP Sun, XL (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM xiaolian.sun@nih.gov; shawn.chen@nih.gov FU Intramural Research Program (IRP) of the NIBIB, NIH FX This work is supported by the Intramural Research Program (IRP) of the NIBIB, NIH. NR 33 TC 57 Z9 57 U1 9 U2 110 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD AUG PY 2014 VL 8 IS 8 BP 8438 EP 8446 DI 10.1021/nn502950t PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA AO0IM UT WOS:000340992300093 PM 25019252 ER PT J AU Gara, E Skopal, J Merkely, B Harding, SE Foldes, G AF Gara, E. Skopal, J. Merkely, B. Harding, S. E. Foldes, G. TI Angiogenic properties of human pluripotent stem cell-derived arterial and venous endothelial cells SO ACTA PHYSIOLOGICA LA English DT Meeting Abstract C1 [Gara, E.; Skopal, J.; Merkely, B.; Foldes, G.] Natl Heart & Lung Inst, Heart & Vasc Ctr, Bethesda, MD USA. [Harding, S. E.] Natl Heart & Lung Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD AUG PY 2014 VL 211 SU 697 SI SI MA S4-E8 BP 52 EP 52 PG 1 WC Physiology SC Physiology GA AN4VO UT WOS:000340586900136 ER PT J AU Szalay, CI Kokeny, G Erdelyi, K Lajtar, E Godo, M Sarkozy, M Kaucsar, T Csont, TB Krenacs, T Szenasi, G Pacher, P Hamar, P AF Szalay, Cs I. Koekeny, G. Erdelyi, K. Lajtar, E. Godo, M. Sarkoezy, M. Kaucsar, T. Csont, T. B. Krenacs, T. Szenasi, G. Pacher, P. Hamar, P. TI Less inflammation and oxidative damage is responsible for the resistance of Rowett rats against focal segmental glomerulosclerosis SO ACTA PHYSIOLOGICA LA English DT Meeting Abstract C1 [Szalay, Cs I.; Koekeny, G.; Lajtar, E.; Godo, M.; Kaucsar, T.; Krenacs, T.; Szenasi, G.; Hamar, P.] Semmelweis Univ, H-1085 Budapest, Hungary. [Erdelyi, K.; Pacher, P.] NIH, Bethesda, MD 20892 USA. [Sarkoezy, M.; Csont, T. B.] Univ Szeged, Szeged, Hungary. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD AUG PY 2014 VL 211 SU 697 SI SI MA P7.3 BP 118 EP 119 PG 2 WC Physiology SC Physiology GA AN4VO UT WOS:000340586900297 ER PT J AU Butali, A Mossey, PA Adeyemo, WL Mekonen, E Gaines, LA Braimoh, DR Aregbesola, TT Rigdon, J Emeka, CI James, OO Ogunlewe, MO Ladeinde, AL Abate, F Hailu, T Mohammed, I Gravem, PE Adeyemo, AA Murray, JC AF Butali, Azeez Mossey, P. A. Adeyemo, W. L. Mekonen, E. Gaines, L. A. Braimoh, D. R. Aregbesola, T. T. Rigdon, J. Emeka, C., I James, O. O. Ogunlewe, M. O. Ladeinde, A. L. Abate, Fikre Hailu, Taye Mohammed, Ibrahim Gravem, Paul Egl Adeyemo, A. A. Murray, J. C. TI Novel IRF6 mutations in families with Van Der Woude Syndrome and Popliteal Pterygium Syndrome from Sub-Saharan Africa SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 22, 2013 CL Boston, MA SP Soc Craniofacial Genet & Dev Biol C1 [Butali, Azeez; Gaines, L. A.; Rigdon, J.; Murray, J. C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Mossey, P. A.] Univ Dundee, Dundee DD1 4HN, Scotland. [Adeyemo, W. L.; Emeka, C., I; James, O. O.; Ogunlewe, M. O.; Ladeinde, A. L.] Univ Lagos, Lagos, Nigeria. [Mekonen, E.; Abate, Fikre; Hailu, Taye; Mohammed, Ibrahim; Gravem, Paul Egl] Univ Addis Ababa, Addis Ababa, Ethiopia. [Braimoh, D. R.; Aregbesola, T. T.] Obafemi Awolowo Univ, Ife, Nigeria. [Adeyemo, A. A.] NIH, Bethesda, MD 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 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2014 VL 164 IS 8 MA 10 BP 1878 EP 1878 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA AN5YD UT WOS:000340667900013 ER PT J AU Cesario, J Malt, AL Zhao, YG Rubenstein, J Jeong, J AF Cesario, Jeffry Malt, Andre Landin Zhao, Yangu Rubenstein, John Jeong, Juhee TI LHX transcription factors promote palate outgrowth through negative regulation of a cell cycle inhibitor p57Kip2 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 22, 2013 CL Boston, MA SP Soc Craniofacial Genet & Dev Biol C1 [Cesario, Jeffry; Malt, Andre Landin; Jeong, Juhee] NYU, Coll Dent, Dept Basic Sci & Craniofacial Biol, New York, NY 10010 USA. [Zhao, Yangu] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. [Rubenstein, John] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94148 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 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2014 VL 164 IS 8 MA 22 BP 1882 EP 1882 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA AN5YD UT WOS:000340667900025 ER PT J AU Knepper, MA Raghuram, V Bradford, D Chou, CL Hoffert, JD Pisitkun, T AF Knepper, Mark A. Raghuram, Viswanathan Bradford, Davis Chou, Chung-Lin Hoffert, Jason D. Pisitkun, Trairak TI Letter to the editor: "Systems biology versus reductionism in cell physiology" SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Letter ID IDENTIFY PROTEIN-KINASES; PHOSPHORYLATE AQUAPORIN-2; BAYES THEOREM; LC-MS/MS; SER(256); NETWORK; CANCER; FOCUS C1 [Knepper, Mark A.; Raghuram, Viswanathan; Bradford, Davis; Chou, Chung-Lin; Hoffert, Jason D.; Pisitkun, Trairak] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [Z01 HL001285, ZO1-HL-001285] NR 16 TC 0 Z9 0 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG 1 PY 2014 VL 307 IS 3 BP C308 EP C309 DI 10.1152/ajpcell.00175.2014 PG 2 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AO1QS UT WOS:000341088900010 PM 25088762 ER PT J AU Wang, DD Feng, XB Lu, L Konkel, JE Zhang, HY Chen, ZY Li, X Gao, X Lu, LW Shi, ST Chen, WJ Sun, LY AF Wang, Dandan Feng, Xuebing Lu, Lin Konkel, Joanne E. Zhang, Huayong Chen, Zhiyong Li, Xia Gao, Xiang Lu, Liwei Shi, Songtao Chen, Wanjun Sun, Lingyun TI A CD8 T Cell/Indoleamine 2,3-Dioxygenase Axis Is Required for Mesenchymal Stem Cell Suppression of Human Systemic Lupus Erythematosus SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID STROMAL CELLS; DENDRITIC CELLS; THERAPEUTIC TARGETS; NITRIC-OXIDE; B-CELLS; TRANSPLANTATION; ACTIVATION; TRYPTOPHAN; RESPONSES; GAMMA AB Objective. Allogeneic mesenchymal stem cells (MSCs) exhibit therapeutic effects in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain largely unknown. The aim of this study was to investigate how allogeneic MSCs mediate immunosuppression in lupus patients. Methods. The effects of allogeneic umbilical cord-derived MSCs (UC-MSCs) on inhibition of T cell proliferation were determined. MSC functional molecules were stimulated with peripheral blood mononuclear cells from healthy controls and SLE patients and examined by real-time polymerase chain reaction. CD4+ and CD8+ T cells were purified using microbeads to stimulate MSCs in order to determine cytokine expression by MSCs and to further determine which cell subset(s) or which molecule(s) is involved in inhibition of MSC-mediated T cell proliferation. The related signaling pathways were assessed. We determined levels of serum cytokines in lupus patients before and after UC-MSC transplantation. Results. Allogeneic UC-MSCs suppressed T cell proliferation in lupus patients by secreting large amounts of indoleamine 2,3-dioxygenase (IDO). We further found that interferon-gamma (IFN gamma), which is produced predominantly by lupus CD8+ T cells, is the key factor that enhances IDO activity in allogeneic MSCs and that it is associated with IFNGR1/JAK-2/STAT signaling pathways. Intriguingly, bone marrow-derived MSCs from patients with active lupus demonstrated defective IDO production in response to IFN gamma and allogeneic CD8+ T cell stimulation. After allogeneic UC-MSC transplantation, serum IDO activity increased in lupus patients. Conclusion. We found a previously unrecognized CD8+ T cell/IFN gamma/IDO axis that mediates the therapeutic effects of allogeneic MSCs in lupus patients. C1 [Wang, Dandan; Feng, Xuebing; Lu, Lin; Zhang, Huayong; Chen, Zhiyong; Li, Xia; Sun, Lingyun] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Nanjing 210008, Jiangsu, Peoples R China. [Konkel, Joanne E.; Chen, Wanjun] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Gao, Xiang] Nanjing Univ, Nanjing 210008, Jiangsu, Peoples R China. [Lu, Liwei] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Shi, Songtao] Univ So Calif, Los Angeles, CA USA. RP Sun, LY (reprint author), Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Rheumatol & Immunol, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China. EM wchen@mail.nih.gov; lingyunsun@nju.edu.cn FU Chinese Major International (Regional) Joint Research Project [81120108021]; National Natural Science Foundation of China [81273304]; Jiangsu Province 333 Talent Program of China; NIH FX Supported by grants from the Chinese Major International (Regional) Joint Research Project (grant 81120108021), the National Natural Science Foundation of China (grant 81273304), and the Jiangsu Province 333 Talent Program of China (to Dr. Sun), and the NIH (Intramural Research Program, National Institute of Dental and Craniofacial Research award to Drs. Konkel and W. Chen). NR 43 TC 20 Z9 22 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD AUG PY 2014 VL 66 IS 8 BP 2234 EP 2245 DI 10.1002/art.38674 PG 12 WC Rheumatology SC Rheumatology GA AN1WV UT WOS:000340375600028 PM 24756936 ER PT J AU Kahlenberg, JM Kaplan, MJ AF Kahlenberg, J. Michelle Kaplan, Mariana J. TI Requirements for "fire and ICE" differ between animal models of autoimmunity: comment on the article by Kahlenberg et al Reply SO ARTHRITIS & RHEUMATOLOGY LA English DT Letter ID INHIBITING NLRP3 INFLAMMASOME; MURINE LUPUS NEPHRITIS; I INTERFERON; MICE; ACTIVATION; PROTECTS; PATHWAY; DISEASE C1 [Kahlenberg, J. Michelle] Univ Michigan, Ann Arbor, MI 48109 USA. [Kaplan, Mariana J.] Natl Inst Arthrit & Musculoskeletal & Skin Disord, NIH, Bethesda, MD USA. RP Kahlenberg, JM (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. OI Kahlenberg, J. Michelle/0000-0002-4006-8945 NR 17 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD AUG PY 2014 VL 66 IS 8 BP 2311 EP 2312 DI 10.1002/art.38677 PG 3 WC Rheumatology SC Rheumatology GA AN1WV UT WOS:000340375600039 PM 24756988 ER PT J AU Lamm, C Benson, BE Guyer, AE Perez-Edgar, K Fox, NA Pine, DS Ernst, M AF Lamm, C. Benson, B. E. Guyer, A. E. Perez-Edgar, K. Fox, N. A. Pine, D. S. Ernst, M. TI Longitudinal study of striatal activation to reward and loss anticipation from mid-adolescence into late adolescence/early adulthood SO BRAIN AND COGNITION LA English DT Article DE Reward; Striatal; Longitudinal; Development; fMRI; Monetary incentive delay task (MID) ID BEHAVIORAL-INHIBITION; NUCLEUS-ACCUMBENS; DECISION-MAKING; BRAIN; FMRI; SENSITIVITY; AMYGDALA; SYSTEMS AB Adolescent risk-taking behavior has been associated with age-related changes in striatal activation to incentives. Previous cross-sectional studies have shown both increased and decreased striatal activation to incentives for adolescents compared to adults. The monetary incentive delay (MID) task, designed to assess functional brain activation in anticipation of reward, has been used extensively to examine striatal activation in both adult and adolescent populations. The current study used this task with a longitudinal approach across mid-adolescence and late adolescence/early adulthood. Twenty-two participants (13 male) were studied using the MID task at two time-points, once in mid-adolescence (mean age = 16.11; SD = 1.44) and a second time in late adolescence/early adulthood (mean age = 20.14; SD = .67). Results revealed greater striatal activation with increased age in high- compared to low-incentive contexts (incentive magnitude), for gain as well as for loss trials (incentive valence). Results extend cross-sectional findings and show reduced striatal engagement in adolescence compared to adulthood during preparation for action in an incentive context. (C) 2013 Elsevier Inc. All rights reserved. C1 [Lamm, C.] Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. [Benson, B. E.; Pine, D. S.; Ernst, M.] NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, Bethesda, MD USA. [Guyer, A. E.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. [Guyer, A. E.] Univ Calif Davis, Dept Human Ecol, Davis, CA 95616 USA. [Perez-Edgar, K.] Penn State Univ, Dept Psychol, Ctr Child Study, University Pk, PA 16802 USA. [Fox, N. A.] Univ Maryland, Child Dev Lab, Dept Human Dev & Quantitat Methodol, College Pk, MD USA. RP Lamm, C (reprint author), Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. EM clamm@uno.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU Intramural Research Program of the National Institutes of Health National Institute of Mental Health; National Institute of Mental Health [U01MH093349, P50MH078105, R00 MH080076] FX The project described was supported in part by the Intramural Research Program (Daniel S. Pine) of the National Institutes of Health National Institute of Mental Health, as well as by Grant Numbers U01MH093349 to Nathan A. Fox, P50MH078105 to Megan R. Gunnar, R00 MH080076 to Amanda E. Guyer, all from the National Institute of Mental Health. NR 35 TC 13 Z9 13 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD AUG PY 2014 VL 89 SI SI BP 51 EP 60 DI 10.1016/j.bandc.2013.12.003 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AO1KQ UT WOS:000341071400006 PM 24485273 ER PT J AU Crowley, MJ van Noordt, SJR Wu, J Hommer, RE South, M Fearon, RMP Mayes, LC AF Crowley, Michael J. van Noordt, Stefon J. R. Wu, Jia Hommer, Rebecca E. South, Mikle Fearon, R. M. P. Mayes, Linda C. TI Reward feedback processing in children and adolescents: Medial frontal theta oscillations SO BRAIN AND COGNITION LA English DT Article DE Theta oscillations; Reward; Adolescence; Event-related spectral analysis; Inter-trial phase coherence ID FALSE DISCOVERY RATE; RISK-TAKING; PREDICTION ERRORS; PREFRONTAL CORTEX; ELECTROPHYSIOLOGICAL RESPONSES; BRAIN OSCILLATIONS; NEGATIVITY; DYNAMICS; STRIATUM; TASK AB We examined event-related electroencephalography (EEG) oscillations, including event-related spectral perturbations (ERSP) and intertrial coherence (ITC), to compare feedback processing during a chance-based reward vs. non-reward task in groups of 10-12-year-old (n = 42), 13-14-year-old (n = 34) and 15-17-year-olds (n = 32). Because few, if any studies have applied these analytic methods to examine feedback processing in children or adolescents, we used a fine-grained approach that explored one half hertz by 16 ms increments during feedback (no win vs. win events) in the theta (4-8 Hz) frequency band. Complex wavelet frequency decomposition revealed that no win feedback was associated with enhanced theta power and phase coherence. We observed condition and age-based differences for both ERSP and ITC, with stronger effects for ITC. The transition from childhood to early adolescence (13-14 yrs.) was a point of increased differentiation of ITC favoring no win vs. wins feedback and also compared to children or older adolescents, a point of heightened ITC for no win feedback (quadratic effect). (C) 2013 Elsevier Inc. All rights reserved. C1 [Crowley, Michael J.; Wu, Jia; Mayes, Linda C.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Crowley, Michael J.] Yale Univ, Ctr Child Study, Ctr Translat Dev Neurosci, New Haven, CT 06520 USA. [van Noordt, Stefon J. R.] Brock Univ, Dept Psychol, Cognit & Affect Neurosci Lab, St Catharines, ON L2S 3A1, Canada. [Hommer, Rebecca E.] NIMH, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. [South, Mikle] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [South, Mikle] Brigham Young Univ, Dept Neurosci, Provo, UT 84602 USA. [Fearon, R. M. P.] UCL, Div Psychol & Language Sci, London WC1E 6BT, England. RP Crowley, MJ (reprint author), Yale Child Study Ctr, 230 South Frontage Rd, New Haven, CT 06473 USA. EM michael.crowley@yale.edu OI South, Mikle/0000-0003-0152-1257 FU NARSAD Young Investigator Award; Yale Interdisciplinary Research Consortium on Stress, Self-Control and Addiction Pilot project [1UL1RR024925-01]; NIDA [K01 DA034125, RO1-DA-06025, DA-017863, KO5]; Gustavus and Louise Pfeiffer Research Foundation; CTSA from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research [UL1 RR024139] FX This research was supported by NARSAD Young Investigator Award (MJC), Yale Interdisciplinary Research Consortium on Stress, Self-Control and Addiction Pilot project funding (MJC) through 1UL1RR024925-01 (R. Sinha); NIDA Grants K01 DA034125 (MJC), RO1-DA-06025 (LCM), DA-017863 (LCM) and KO5 (LCM), and a grant from the Gustavus and Louise Pfeiffer Research Foundation (LCM). This publication was also made possible by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 56 TC 4 Z9 4 U1 6 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD AUG PY 2014 VL 89 SI SI BP 79 EP 89 DI 10.1016/j.bandc.2013.11.011 PG 11 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AO1KQ UT WOS:000341071400009 PM 24360036 ER PT J AU Ernst, M AF Ernst, Monique TI The triadic model perspective for the study of adolescent motivated behavior SO BRAIN AND COGNITION LA English DT Article DE Systems model; Motivation; Regulation; Reward; Avoidance; Cognitive control striatum ID EARLY-LIFE STRESS; ANTERIOR CINGULATE CORTEX; MEDIAL FRONTAL-CORTEX; EVENT-RELATED FMRI; COGNITIVE CONTROL; RESPONSE-INHIBITION; BRAIN-DEVELOPMENT; HEALTHY ADOLESCENTS; WHITE-MATTER; RISK-TAKING AB The triadic neural systems model is a heuristic tool, which was developed with the goal of providing a framework for neuroscience research into motivated behaviors. Unlike dual models, that highlight dynamics between approach systems centered on striatal function and control systems centered on prefrontal cortex, the triadic model also includes an avoidance system, centered on amygdala-related circuits. A first application of this model has been to account for adolescent behavior. Published by Elsevier Inc. C1 NIMH, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 96 TC 34 Z9 35 U1 6 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD AUG PY 2014 VL 89 SI SI BP 104 EP 111 DI 10.1016/j.bandc.2014.01.006 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AO1KQ UT WOS:000341071400012 PM 24556507 ER PT J AU Ernst, M Hale, E O'Connell, K AF Ernst, Monique Hale, Elizabeth O'Connell, Katherine TI Response to commentaries regarding the Triadic Systems Model perspective SO BRAIN AND COGNITION LA English DT Editorial Material ID REWARD PREDICTION; MOTIVATED BEHAVIOR; ADOLESCENCE; ERRORS; BRAIN; ATTENTION; STRIATUM C1 [Ernst, Monique; Hale, Elizabeth; O'Connell, Katherine] NIMH, NIH, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, NIH, 15K North Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov NR 27 TC 3 Z9 3 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 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD AUG PY 2014 VL 89 SI SI BP 122 EP 126 DI 10.1016/j.bandc.2014.04.001 PG 5 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AO1KQ UT WOS:000341071400017 PM 24751185 ER PT J AU Freedman, LP Inglese, J AF Freedman, Leonard P. Inglese, James TI The Increasing Urgency for Standards in Basic Biologic Research SO CANCER RESEARCH LA English DT Article ID CELL-LINES; MECHANISM; DRUG; TARGETS AB Research advances build upon the validity and reproducibility of previously published data and findings. Yet irreproducibility in basic biologic and preclinical research is pervasive in both academic and commercial settings. Lack of reproducibility has led to invalidated research breakthroughs, retracted articles, and aborted clinical trials. Concerns and requirements for transparent, reproducible, and translatable research are accelerated by the rapid growth of "post-publication peer review," open access publishing, and data sharing that facilitate the identification of irreproducible data/studies; they are magnified by the explosion of high-throughput technologies, genomics, and other data-intensive disciplines. Collectively, these changes and challenges are decreasing the effectiveness of traditional research quality mechanisms and are contributing to unacceptable-and unsustainable-levels of irreproducibility. The global oncology and basic biologic research communities can no longer tolerate or afford widespread irreproducible research. This article discusses (i) how irreproducibility in preclinical research can ultimately be traced to an absence of a unifying life science standards framework, and (ii) makes an urgent case for the expanded development and use of consensus-based standards to both enhance reproducibility and drive innovations in cancer research. (C)2014 AACR. C1 [Freedman, Leonard P.] Global Biol Stand Inst, Washington, DC 20036 USA. [Inglese, James] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bethesda, MD 20892 USA. RP Freedman, LP (reprint author), Global Biol Stand Inst, 1020 19th St,Northwest,Suite 550, Washington, DC 20036 USA. EM lfreedman@gbsi.org FU Intramural NIH HHS [Z01 HG200319-05] NR 38 TC 17 Z9 17 U1 4 U2 21 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 AUG 1 PY 2014 VL 74 IS 15 BP 4024 EP 4029 DI 10.1158/0008-5472.CAN-14-0925 PG 6 WC Oncology SC Oncology GA AO2VM UT WOS:000341184400004 PM 25035389 ER PT J AU Seow, WJ Cawthon, RM Purdue, MP Hu, W Gao, YT Huang, WY Weinstein, SJ Ji, BT Virtamo, J Hosgood, HD Bassig, BA Shu, XO Cai, QY Xiang, YB Min, S Chow, WH Berndt, SI Kim, C Lim, U Albanes, D Caporaso, NE Chanock, S Zheng, W Rothman, N Lan, Q AF Seow, Wei Jie Cawthon, Richard M. Purdue, Mark P. Hu, Wei Gao, Yu-Tang Huang, Wen-Yi Weinstein, Stephanie J. Ji, Bu-Tian Virtamo, Jarmo Hosgood, H. Dean, III Bassig, Bryan A. Shu, Xiao-Ou Cai, Qiuyin Xiang, Yong-Bing Min, Shen Chow, Wong-Ho Berndt, Sonja I. Kim, Christopher Lim, Unhee Albanes, Demetrius Caporaso, Neil E. Chanock, Stephen Zheng, Wei Rothman, Nathaniel Lan, Qing TI Telomere Length in White Blood Cell DNA and Lung Cancer: A Pooled Analysis of Three Prospective Cohorts SO CANCER RESEARCH LA English DT Article ID MULTIPLEX QUANTITATIVE PCR; SHANGHAI WOMENS HEALTH; NON-HODGKIN-LYMPHOMA; RISK; ASSOCIATION; CARCINOMA; SURVIVAL; DYSFUNCTION; SENESCENCE; MELANOMA AB We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex qPCR assay. We used conditional logistic regression models to calculate ORs and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis [OR (95% CI) by quartile: 1.00; 1.24 (0.90-1.71); 1.27 (0.91-1.78); and 1.86 (1.33-2.62); P trend - 0.000022]. Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length [ OR (95% CI)] in the upper half of the fourth quartile were 2.41 (1.28-4.52), 2.16 (1.11-4.23), and 3.02(1.39-6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than 6 years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations. (C)2014 AACR. C1 [Seow, Wei Jie; Purdue, Mark P.; Hu, Wei; Huang, Wen-Yi; Weinstein, Stephanie J.; Ji, Bu-Tian; Bassig, Bryan A.; Min, Shen; Berndt, Sonja I.; Kim, Christopher; Albanes, Demetrius; Caporaso, Neil E.; Chanock, Stephen; Rothman, Nathaniel; Lan, Qing] NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Cawthon, Richard M.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Shu, Xiao-Ou; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lim, Unhee] Univ Hawaii Canc Ctr, Program Epidemiol, Honolulu, HI USA. [Gao, Yu-Tang] Shandong Jiaotong Univ, Renji Hosp, Shanghai Canc Inst, Sch Med,Dept Epidemiol, Shanghai, Peoples R China. [Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Seow, WJ (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 6E128, Rockville, MD 20850 USA. EM weijie.seow2@nih.gov RI Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU NCI; NCI, NIH [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; Department of Health and Human Services FX This work was supported by intramural funds from the NCI and extramural funds, including U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the NCI, NIH, and Department of Health and Human Services. NR 39 TC 30 Z9 31 U1 0 U2 22 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 AUG 1 PY 2014 VL 74 IS 15 BP 4090 EP 4098 DI 10.1158/0008-5472.CAN-14-0459 PG 9 WC Oncology SC Oncology GA AO2VM UT WOS:000341184400010 PM 24853549 ER PT J AU Li, XL Lu, X Parvathaneni, S Bilke, S Zhang, HE Thangavel, S Vindigni, A Hara, T Zhu, YL Meltzer, PS Lal, A Sharma, S AF Li, Xiao Ling Lu, Xing Parvathaneni, Swetha Bilke, Sven Zhang, Hongen Thangavel, Saravanabhavan Vindigni, Alessandro Hara, Toshifumi Zhu, Yuelin Meltzer, Paul S. Lal, Ashish Sharma, Sudha TI Identification of RECQ1-regulated transcriptome uncovers a role of RECQ1 in regulation of cancer cell migration and invasion SO CELL CYCLE LA English DT Article DE RecQ; helicase; gene expression; cell migration; cell invasion; transcription; cancer; G4 DNA ID RNA-POLYMERASE-II; WERNER-SYNDROME PROTEIN; G-QUADRUPLEX; DNA-DAMAGE; GENE-EXPRESSION; BREAST-CANCER; TOPOISOMERASE-I; RIBOSOMAL-RNA; HELICASE; REPLICATION AB The RECQ protein family of helicases has critical roles in protecting and stabilizing the genome. Three of the 5 known members of the human RecQ family are genetically linked with cancer susceptibility syndromes, but the association of the most abundant human RecQ homolog, RECQ1, with cellular transformation is yet unclear. RECQ1 is overexpressed in a variety of human cancers, indicating oncogenic functions. Here, we assessed genome-wide changes in gene expression upon knockdown of RECQ1 in HeLa and MDA-MB-231 cells. Pathway analysis suggested that RECQ1 enhances the expression of multiple genes that play key roles in cell migration, invasion, and metastasis, including EZR, ITGA2, ITGA3, ITGB4, SMAD3, and TGFBR2. Consistent with these results, silencing RECQ1 significantly reduced cell migration and invasion. In comparison to genome-wide annotated promoter regions, the promoters of genes downregulated upon RECQ1 silencing were significantly enriched for a potential G4 DNA forming sequence motif. Chromatin immunoprecipitation assays demonstrated binding of RECQ1 to the G4 motifs in the promoters of select genes downregulated upon RECQ1 silencing. In breast cancer patients, the expression of a subset of RECQ1-activated genes positively correlated with RECQ1 expression. Moreover, high RECQ1 expression was associated with poor prognosis in breast cancer. Collectively, our findings identify a novel function of RECQ1 in gene regulation and indicate that RECQ1 contributes to tumor development and progression, in part, by regulating the expression of key genes that promote cancer cell migration, invasion and metastasis. C1 [Li, Xiao Ling; Hara, Toshifumi; Lal, Ashish] NCI, Regulatory RNAs & Canc Sect, Gent Branch, NIH, Bethesda, MD 20892 USA. [Lu, Xing; Parvathaneni, Swetha; Sharma, Sudha] Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC USA. [Bilke, Sven; Zhang, Hongen; Zhu, Yuelin; Meltzer, Paul S.] NCI, Mol Genet Sect, Gent Branch, NIH, Bethesda, MD 20892 USA. [Thangavel, Saravanabhavan; Vindigni, Alessandro] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA. RP Lal, A (reprint author), NCI, Regulatory RNAs & Canc Sect, Gent Branch, NIH, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov; sudha.sharma@howard.edu OI Sharma, Sudha/0000-0003-2765-2482 FU NIGMS/NIH [5SC1GM093999-04]; National Institutes of Health, National Cancer Institute, and Center for Cancer Research; NIH [R01GM108648]; NIMHD/NIH [G12MD007597] FX This work was funded by the NIGMS/NIH grant 5SC1GM093999-04 to Sudha Sharma and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research to Ashish Lal. The work in Alessandro Vindigni's lab was supported by NIH grant R01GM108648. We acknowledge infrastructure support from the NIMHD/NIH under award number G12MD007597. NR 76 TC 12 Z9 12 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD AUG 1 PY 2014 VL 13 IS 15 BP 2431 EP 2445 DI 10.4161/cc.29419 PG 15 WC Cell Biology SC Cell Biology GA AN6QL UT WOS:000340720900018 PM 25483193 ER PT J AU Casida, JE Ford, B Jinsmaa, Y Sullivan, P Cooney, A Goldstein, DS AF Casida, John E. Ford, Breanna Jinsmaa, Yunden Sullivan, Patti Cooney, Adele Goldstein, David S. TI Benomyl, Aldehyde Dehydrogenase, DOPAL, and the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TOXIC DOPAMINE METABOLITE; PC12 CELLS; OXIDATIVE STRESS; 3,4-DIHYDROXYPHENYLACETALDEHYDE; MECHANISM; INHIBITION; CATECHOLS AB The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is detoxified mainly by aldehyde dehydrogenase (ALDH). We find that the fungicide benomyl potently and rapidly inhibits ALDH and builds up DOPAL in vivo in mouse striatum and in vitro in PC12 cells and human cultured fibroblasts and glial cells. The in vivo results resemble those noted previously with knockouts of the genes encoding ALDH1A1 and 2, a mouse model of aging-related Parkinson's disease (PD). Exposure to pesticides that inhibit ALDH may therefore increase PD risk via DOPAL buildup. This study lends support to the "catecholaldehyde hypothesis" that the autotoxic dopamine metabolite DOPAL plays a pathogenic role in PD. C1 [Casida, John E.; Ford, Breanna] Univ Calif Berkeley, Environm Chem & Toxicol Lab, Berkeley, CA 94720 USA. [Jinsmaa, Yunden; Sullivan, Patti; Cooney, Adele; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res, Bethesda, MD 20892 USA. RP Casida, JE (reprint author), Univ Calif Berkeley, Environm Chem & Toxicol Lab, Berkeley, CA 94720 USA. EM ectl@berkeley.edu; goldstein@ninds.nih.gov FU University of California, Berkeley; National Institute of Neurological Disorders and Stroke FX B.F. was supported by Sponsored Projects for Undergraduates Program at the University of California, Berkeley. Research at Bethesda was supported by Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 23 TC 7 Z9 7 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD AUG PY 2014 VL 27 IS 8 BP 1359 EP 1361 DI 10.1021/tx5002223 PG 3 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA AN4RS UT WOS:000340576800005 PM 25045800 ER PT J AU Carty, CL Bhattacharjee, S Haessler, J Cheng, I Hindorff, LA Aroda, V Carlson, CS Hsu, CN Wilkens, L Liu, SM Selvin, E Jackson, R North, KE Peters, U Pankow, JS Chatterjee, N Kooperberg, C AF Carty, Cara L. Bhattacharjee, Samsiddhi Haessler, Jeff Cheng, Iona Hindorff, Lucia A. Aroda, Vanita Carlson, Christopher S. Hsu, Chun-Nan Wilkens, Lynne Liu, Simin Selvin, Elizabeth Jackson, Rebecca North, Kari E. Peters, Ulrike Pankow, James S. Chatterjee, Nilanjan Kooperberg, Charles TI Analysis of Metabolic Syndrome Components in > 15 000 African Americans Identifies Pleiotropic Variants Results From the Population Architecture Using Genomics and Epidemiology Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE African continental ancestry group; genetic pleiotropy; genetic variation; high-density lipoprotein cholesterol; Hispanic Americans; hyperglycemia; metabolic syndrome ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; LIPID-LEVELS; TRAITS; RISK; DESIGN; LOCI; GENETICS AB Background-Metabolic syndrome (MetS) refers to the clustering of cardiometabolic risk factors, including dyslipidemia, central adiposity, hypertension, and hyperglycemia, in individuals. Identification of pleiotropic genetic factors associated with MetS traits may shed light on key pathways or mediators underlying MetS. Methods and Results-Using the Metabochip array in 15 148 African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study, we identify susceptibility loci and investigate pleiotropy among genetic variants using a subset-based meta-analysis method, ASsociation-analysis-based-on-subSETs (ASSET). Unlike conventional models that lack power when associations for MetS components are null or have opposite effects, Association-analysis-based-on-subsets uses 1-sided tests to detect positive and negative associations for components separately and combines tests accounting for correlations among components. With Association-analysis-based-on-subsets, we identify 27 single nucleotide polymorphisms in 1 glucose and 4 lipids loci (TCF7L2, LPL, APOA5, CETP, and APOC1/APOE/TOMM40) significantly associated with MetS components overall, all P<2.5e-7, the Bonferroni adjusted P value. Three loci replicate in a Hispanic population, n=5172. A novel African American-specific variant, rs12721054/APOC1, and rs10096633/LPL are associated with >= 3 MetS components. We find additional evidence of pleiotropy for APOE, TOMM40, TCF7L2, and CETP variants, many with opposing effects (eg, the same rs7901695/TCF7L2 allele is associated with increased odds of high glucose and decreased odds of central adiposity). Conclusions-We highlight a method to increase power in large-scale genomic association analyses and report a novel variant associated with all MetS components in African Americans. We also identify pleiotropic associations that may be clinically useful in patient risk profiling and for informing translational research of potential gene targets and medications. C1 [Carty, Cara L.; Haessler, Jeff; Carlson, Christopher S.; Peters, Ulrike; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Bhattacharjee, Samsiddhi] Natl Inst Biomed Genom, Netaji Subhas Sanat, Kalyani, W Bengal, India. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Aroda, Vanita] MedStar Hlth Res Inst, Hyattsville, MD USA. [Hsu, Chun-Nan] Univ Calif San Diego, Div Biomed Informat, La Jolla, CA 92093 USA. [Wilkens, Lynne] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Jackson, Rebecca] Ohio State Univ, Dept Internal Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Carty, CL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N-M3-A410, Seattle, WA 98109 USA. EM ccarty@fhcrc.org OI Pankow, James/0000-0001-7076-483X FU Population Architecture Using Genomics and Epidemiology (PAGE) program - National Human Genome Research Institute (NHGRI) [U01HG004803, U01HG004798, U01HG004802, U01HG004790, U01HG004801]; NHGRI PAGE program [U01HG004803, U01HG004790]; National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100 004C, HHSN271201100004C]; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; NHGRI [R01 HG006124] FX This work was supported by the Population Architecture Using Genomics and Epidemiology (PAGE) program which is funded by the National Human Genome Research Institute (NHGRI) (U01HG004803 [to the Genetic Epidemiology of Causal Variants Across the Life Course {CALiCo} program], U01HG004798 [to the Epidemiological Architecture of Genes Linked to Environment], U01HG004802 [to the Multi-Ethnic Cohort], U01HG004790 [to the Women's Health Initiative {WHI}], and U01HG004801 [to the PAGE Coordinating Center], and their respective NHGRI American Recovery and Reinvestment Act supplements. Funding support for the Epidemiology of putative genetic variants: The Women's Health Initiative (WHI) study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI American Recovery and Reinvestment Act supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100 004C, and HHSN271201100004C. Funding support for the Genetic Epidemiology of CALiCo program is provided through the NHGRI PAGE program (U01HG004803 and its NHGRI American Recovery and Reinvestment Act supplement). The following CALiCo studies contributed to this article and are funded by the following agencies: The Atherosclerosis Risk in Communities study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022). Assistance with phenotype harmonization, single nucleotide polymorphisms selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI American Recovery and Reinvestment Act supplement). The National Institutes of Mental Health also contributes to the support for the PAGE Coordinating Center. Additional support for this work was provided by the NHGRI through (R01 HG006124). NR 46 TC 5 Z9 5 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2014 VL 7 IS 4 BP 505 EP U303 DI 10.1161/CIRCGENETICS.113.000386 PG 13 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA AO2ZN UT WOS:000341197700013 PM 25023634 ER PT J AU Yang, XL Gu, DF He, J Hixson, JE Rao, DC Lu, FH Mu, JJ Jaquish, CE Chen, J Huang, JF Shimmin, LC Rice, TK Chen, JC Wu, XG Liu, DP Kelly, TN AF Yang, Xueli Gu, Dongfeng He, Jiang Hixson, James E. Rao, Dabeeru C. Lu, Fanghong Mu, Jianjun Jaquish, Cashell E. Chen, Jing Huang, Jianfeng Shimmin, Lawrence C. Rice, Treva K. Chen, Jichun Wu, Xigui Liu, Depei Kelly, Tanika N. TI Genome-Wide Linkage and Regional Association Study of Blood Pressure Response to the Cold Pressor Test in Han Chinese The Genetic Epidemiology Network of Salt Sensitivity Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE blood pressure; genetic association studies; linkage mapping ID SYSTEMATIC ANALYSIS; RISK-FACTORS; STRESS; VARIANTS; GENSALT; POLYMORPHISM; POPULATION; DISEASE; HYPERTENSION; REACTIVITY AB Background-Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT. Methods and Results-A total of 1961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds >= 2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8x10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response (P=0.03) and diastolic BP response (P=4.6x10(-5)). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with systolic BP response to CPT (P=4.0x10(-5) and 2.7x10(-4), respectively), and variants in genes MCM8 and STK35 were associated with mean arterial pressure response to CPT (P=1.5x10(-5) and 5.0x10(-5), respectively). Conclusions-Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2, and STK35 in this region. Additional work is warranted to confirm these findings. C1 [Yang, Xueli; He, Jiang; Chen, Jing; Kelly, Tanika N.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Yang, Xueli; Gu, Dongfeng; He, Jiang; Chen, Jing; Wu, Xigui] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis,Dept Epidemiol & Pop, Beijing 100037, Peoples R China. [Liu, Depei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100037, Peoples R China. Peking Union Med Coll, Beijing 100021, Peoples R China. [He, Jiang; Chen, Jing] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [Rao, Dabeeru C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Lu, Fanghong] Shandong Acad Med Sci, Inst Basic Med, Jinan, Shandong, Peoples R China. [Mu, Jianjun] Xi An Jiao Tong Univ, Coll Med, Affiliated Hosp 1, Dept Cardiol, Xian, Shaanxi, Peoples R China. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. RP Gu, DF (reprint author), Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, 167 Beilishi Rd, Beijing 100037, Peoples R China. EM gudongfeng@vip.sina.com; tkelly@tulane.edu FU National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD [U01HL072507, R01HL087263, R01HL090682]; High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China [2012AA02A516]; National Institutes of Health John E Fogarty International Center, Bethesda, MD [D43TW009107] FX The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by a cooperative agreement project grant (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. This study is also funded by a research grant (2012AA02A516) from the High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China. Dr Yang is supported by a research training grant (D43TW009107) from National Institutes of Health John E Fogarty International Center, Bethesda, MD. NR 50 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2014 VL 7 IS 4 BP 521 EP U325 DI 10.1161/CIRCGENETICS.113.000332 PG 13 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA AO2ZN UT WOS:000341197700015 PM 25028485 ER PT J AU Teepe, JD Schmitz, JE Hu, YY Yamada, Y Fajardo, RJ Smith, CE Chun, YHP AF Teepe, John D. Schmitz, James E. Hu, Yuanyuan Yamada, Yoshihiko Fajardo, Roberto J. Smith, Charles E. Chun, Yong-Hee P. TI Correlation of ameloblastin with enamel mineral content SO CONNECTIVE TISSUE RESEARCH LA English DT Article DE Ameloblastin; enamel; enamel biomineralization/formation; mineralized tissue/development; micro-computed tomography; mineralization front AB In enamel formation, the deposition of minerals as crystallites starts when the mineralization front first forms at the start of the secretory stage. During maturation, the enamel layer accumulates significant amounts of new mineral as the crystallites grow in volume. Inversely related to mineral gain is loss of protein and water from the forming enamel. Both ameloblastin (Ambn) and enamelin are essential components for formation of a functional enamel layer. The aim of this study was to quantify the proportion of mineral and non-mineral material present in developing enamel relative to Ambn concentration using Ambn mutant mice mated with others overexpressing full-length Ambn from the mouse amelogenin promoter at lower (+), similar (++) or higher (+++) concentration than normal. Mandibular incisors (age: 7 weeks, n = 8) were imaged by micro-computed tomography and the enamel was analyzed from the apical region to the incisal edge in sequential 1.0mm volumes of interest. Mineral density was determined using a series of hydroxyapatite (HA) phantoms to calibrate enamel density measurements. At the site where the mandibular incisor emerged into the oral cavity, the enamel volume, mineral weight, and mineral density were reduced when Tg Ambn was expressed at lower or higher levels than normal. While in wild-type the % mineral was >95%, it was negligible in Ambn-/-, 22.3% in Ambn-/-, Tg(+), 75.4% in Ambn-/-, Tg(++), and 45.2% in Ambn-/-, Tg(+++). These results document that the deposition of mineral and removal of non-mineral components are both very sensitive to expressed Ambn concentrations. C1 [Teepe, John D.] Dunn Dent Clin, Dept Periodont, San Antonio, TX USA. [Schmitz, James E.; Fajardo, Roberto J.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Orthopaed RAYO, Carlisle Ctr Bone & Mineral Imaging, San Antonio, TX 78229 USA. [Hu, Yuanyuan; Smith, Charles E.] Univ Michigan, Dept Biol & Mat Sci, Dent Res Lab, Ann Arbor, MI 48109 USA. [Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Smith, Charles E.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. [Chun, Yong-Hee P.] Univ Texas Hlth Sci Ctr San Antonio, Sch Dent, Dept Periodont, San Antonio, TX 78229 USA. RP Chun, YHP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sch Dent, Dept Periodont, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM chuny@uthscsa.edu FU National Institutes of Health, Bethesda [K08 DE022800, S10 RR025687]; UTHSCSA Department of Periodontics; UTHSCSA program for Research Core Laboratories FX This research was funded by the National Institutes of Health, Bethesda, K08 DE022800 (YPC), S10 RR025687 (RJF), the UTHSCSA Department of Periodontics and the UTHSCSA program for Research Core Laboratories. The authors have no conflicts of interest related to this study. NR 9 TC 2 Z9 3 U1 2 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-8207 EI 1607-8438 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD AUG PY 2014 VL 55 SU 1 BP 38 EP 42 DI 10.3109/03008207.2014.923871 PG 5 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA AO3LP UT WOS:000341231000010 PM 25158178 ER PT J AU Nam, AS Yin, Y von Marschall, Z Fisher, LW AF Nam, Anna S. Yin, Ying von Marschall, Zofia Fisher, Larry W. TI Efficient trafficking of acidic proteins out of the endoplasmic reticulum involves a conserved amino terminal IleProVal (IPV)-like tripeptide motif SO CONNECTIVE TISSUE RESEARCH LA English DT Article DE Cargo receptor; dentin dysplasia; dentinogenesis imperfecta; dentin sialophosphoprotein; DSPP; endoplasmic reticulum; trafficking ID DENTINOGENESIS IMPERFECTA; DENTIN DYSPLASIA; MATRIX; SHELL; DSPP AB Most of the proposed extracellular biomineralization processes include the secretion of proteins that interact with mineral ions and/or mineral surfaces. Typically these proteins are acidic or have acidic domains that interact with multivalent cations in the extracellular environment. We propose that most acidic, Ca2+-binding proteins challenge the cell's mechanisms for trafficking through the endoplasmic reticulum (ER) lumen due to lumenal mM calcium that cause them to form large aggregates. We have recently shown that >95% of the DSPP mutations that cause non-syndromic genetic dentin diseases start their dominant negative affects by failing to rapidly exit the ER likely by forming complexes that cannot be normally trafficked to the Golgi. The complexes of mutant DSPP then capture more (severe disease) or less (mild disease) of the DSPP translated from the normal allele. After searching genomic databases as well as the published literature, we found the IleProVal (IPV)-like motif at the predicted amino terminus of many acidic proteins made in the mineralizing as well as non-mineralizing tissues of many species including vertebrates, echinoderms, mollusks, and yeast. While we often focused on acidic proteins reported associated with mineralizing structures, proteins associated with hormones and their storage/secretion, digestion, blood functions, as well as milk and other secreted fluids started with variations of the motif. Our hypothesis is that the IPV-like motif interacts with a highly conserved cargo receptor in the ER that efficiently traffics the acidic proteins out of the organelle before they can form harmful aggregates in the Ca2+-rich lumen. C1 [Nam, Anna S.; Yin, Ying; von Marschall, Zofia; Fisher, Larry W.] NIDCR, Matrix Biochem Sect, CSDB, NIH, Bethesda, MD 20892 USA. RP Fisher, LW (reprint author), NIDCR, Matrix Biochem Sect, CSDB, NIH, Room 223,Bldg 30,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lfisher@dir.nidcr.nih.gov FU NIH Intramural Research Program (NIDCR) FX Research was supported by NIH Intramural Research Program (NIDCR). NR 7 TC 3 Z9 3 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-8207 EI 1607-8438 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD AUG PY 2014 VL 55 SU 1 BP 138 EP 141 DI 10.3109/03008207.2014.923852 PG 4 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA AO3LP UT WOS:000341231000031 PM 24844412 ER PT J AU Wu, XF Hammer, JA AF Wu, Xufeng Hammer, John A. TI Melanosome transfer: it is best to give and receive SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID MYOSIN-VA; RECYCLING ENDOSOME; MELANIN TRANSFER; LINKS RAB27A; TRANSPORT; MELANOCYTES; KERATINOCYTE; MELANOPHILIN; FILOPODIA; MEMBRANE AB The pigmentation of skin and hair in mammals is driven by the creation within melanocytes of melanosomes, a specialized pigment-producing organelle, and the subsequent intercellular transfer of this organelle to keratinocytes. This latter process is absolutely required for visible pigmentation and effective photo-protection because it serves to disperse the pigment in skin and hair. Therefore, the transfer of melanosomes from the melanocyte to the keratinocyte is as important for the biological endpoint of mammalian pigmentation as the biogenesis of this fascinating organelle. Here we review new findings that shed light on, and raise additional questions about, the mechanism of this enigmatic process. C1 [Wu, Xufeng; Hammer, John A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL000514-29] NR 39 TC 15 Z9 17 U1 1 U2 16 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD AUG PY 2014 VL 29 BP 1 EP 7 DI 10.1016/j.ceb.2014.02.003 PG 7 WC Cell Biology SC Cell Biology GA AO0IH UT WOS:000340991800002 PM 24662021 ER PT J AU Banfield, DK Prinz, W AF Banfield, David K. Prinz, Will TI Editorial overview: Cell organelles SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 [Banfield, David K.] Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Hong Kong, Peoples R China. [Prinz, Will] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Banfield, DK (reprint author), Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Hong Kong, Peoples R China. EM bodkb@ust.hk; williamp@intra.niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD AUG PY 2014 VL 29 BP V EP VI DI 10.1016/j.ceb.2014.07.001 PG 2 WC Cell Biology SC Cell Biology GA AO0IH UT WOS:000340991800001 PM 25062643 ER PT J AU Kozlov, MM Campelo, F Liska, N Chernomordik, LV Marrink, SJ McMahon, HT AF Kozlov, Michael M. Campelo, Felix Liska, Nicole Chernomordik, Leonid V. Marrink, Siewert J. McMahon, Harvey T. TI Mechanisms shaping cell membranes SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID TUBULAR ENDOPLASMIC-RETICULUM; SPONTANEOUS CURVATURE; AMPHIPATHIC HELICES; LIPID-MEMBRANES; COATED VESICLES; PROTEINS; FUSION; FORCE; BAR; PRINCIPLES AB Membranes of intracellular organelles are characterized by large curvatures with radii of the order of 10-30 nm. While, generally, membrane curvature can be a consequence of any asymmetry between the membrane monolayers, generation of large curvatures requires the action of mechanisms based on specialized proteins. Here we discuss the three most relevant classes of such mechanisms with emphasis on the physical requirements for proteins to be effective in generation of membrane curvature. We provide new quantitative estimates of membrane bending by shallow hydrophobic insertions and compare the efficiency of the insertion mechanism with those of the protein scaffolding and crowding mechanisms. C1 [Kozlov, Michael M.] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. [Campelo, Felix] CRG, Cell & Dev Biol Programme, Barcelona 08003, Spain. [Campelo, Felix] UPF, Barcelona 08003, Spain. [Liska, Nicole; McMahon, Harvey T.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. [Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Marrink, Siewert J.] Univ Groningen, Groningen Biomol Sci & Biotechnol Inst, NL-9747 AG Groningen, Netherlands. [Marrink, Siewert J.] Univ Groningen, Zernike Inst Adv Mat, NL-9747 AG Groningen, Netherlands. RP Kozlov, MM (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. EM michk@post.tau.ac.il; hmm@mrc-lmb.cam.ac.uk RI Marrink, Siewert /G-3706-2014 FU Israel Science Foundation (ISF) [758/11]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We thank Tom Rapoport for critical reading of the manuscript, Eva Schmid for the His-proteins (as in [44]) used for generation of the data presented in Figure 1, and Wai-Ching Hon for assembling the panels of Figure 3. MMK is supported by the Israel Science Foundation (ISF) (grant no. 758/11), and holds the Joseph Klafter Chair in Biophysics. The research of LVC is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 60 TC 44 Z9 44 U1 11 U2 69 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD AUG PY 2014 VL 29 BP 53 EP 60 DI 10.1016/j.ceb.2014.03.006 PG 8 WC Cell Biology SC Cell Biology GA AO0IH UT WOS:000340991800009 PM 24747171 ER PT J AU Pryor, SE Massa, V Savery, D Andre, P Yang, YZ Greene, NDE Copp, AJ AF Pryor, Sophie E. Massa, Valentina Savery, Dawn Andre, Philipp Yang, Yingzi Greene, Nicholas D. E. Copp, Andrew J. TI Vangl-dependent planar cell polarity signalling is not required for neural crest migration in mammals SO DEVELOPMENT LA English DT Article DE Cell migration; Embryo; Mouse; Neural crest; Neural tube; Planar cell polarity ID TUBE DEFECTS; LOOP-TAIL; BRANCHING MORPHOGENESIS; EMBRYONIC-DEVELOPMENT; TRACT DEVELOPMENT; GENE VANGL2; FAMILY; EXPRESSION; CLOSURE; PATTERNS AB The role of planar cell polarity (PCP) signalling in neural crest (NC) development is unclear. The PCP dependence of NC cell migration has been reported in Xenopus and zebrafish, but NC migration has not been studied in mammalian PCP mutants. Vangl2(Lp/Lp) mouse embryos lack PCP signalling and undergo almost complete failure of neural tube closure. Here we show, however, that NC specification, migration and derivative formation occur normally in Vangl2(Lp/Lp) embryos. The gene family member Vangl1 was not expressed in NC nor ectopically expressed in Vangl2(Lp/Lp) embryos, and doubly homozygous Vangl1/Vangl2 mutants exhibited normal NC migration. Acute downregulation of Vangl2 in the NC lineage did not prevent NC migration. In vitro, Vangl2(Lp/Lp) neural tube explants generated emigrating NC cells, as in wild type. Hence, PCP signalling is not essential for NC migration in mammals, in contrast to its essential role in neural tube closure. PCP mutations are thus unlikely to mediate NC-related birth defects in humans. C1 [Pryor, Sophie E.; Massa, Valentina; Savery, Dawn; Greene, Nicholas D. E.; Copp, Andrew J.] UCL, Inst Child Hlth, Newlife Birth Defects Res Ctr, London WC1N 1EH, England. [Andre, Philipp; Yang, Yingzi] Natl Human Genome Res Inst, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Copp, AJ (reprint author), UCL, Inst Child Hlth, Newlife Birth Defects Res Ctr, 30 Guilford St, London WC1N 1EH, England. EM a.copp@ucl.ac.uk OI Greene, Nicholas/0000-0002-4170-5248; Massa, Valentina/0000-0003-2246-9515; Copp, Andrew/0000-0002-2544-9117 FU Wellcome Trust [083361, 087259, 087525]; Medical Research Council [G0801124] FX This work was supported by the Wellcome Trust [grants 083361, 087259, 087525] and Medical Research Council [grant G0801124]. Deposited in PMC for immediate release. NR 37 TC 13 Z9 13 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD AUG PY 2014 VL 141 IS 16 BP 3153 EP 3158 DI 10.1242/dev.111427 PG 6 WC Developmental Biology SC Developmental Biology GA AO4KB UT WOS:000341305200007 PM 25038043 ER PT J AU Nogare, DD Somers, K Rao, S Matsuda, M Reichman-Fried, M Raz, E Chitnis, AB AF Nogare, Damian Dalle Somers, Katherine Rao, Swetha Matsuda, Miho Reichman-Fried, Michal Raz, Erez Chitnis, Ajay B. TI Leading and trailing cells cooperate in collective migration of the zebrafish posterior lateral line primordium SO DEVELOPMENT LA English DT Article DE FGF; Agent-based modeling; Chemokines; Collective migration; Lateral line; Zebrafish ID CHEMOKINE RECEPTOR; TISSUE MIGRATION; FGF; MORPHOGENESIS; CXCR7; REGENERATION; EXPRESSION; GRADIENT; LIGAND; CXCL12 AB Collective migration of cells in the zebrafish posterior lateral line primordium (PLLp) along a path defined by Cxcl12a expression depends on Cxcr4b receptors in leading cells and on Cxcr7b in trailing cells. Cxcr7b-mediated degradation of Cxcl12a by trailing cells generates a local gradient of Cxcl12a that guides PLLp migration. Agent-based computer models were built to explore how a polarized response to Cxcl12a, mediated by Cxcr4b in leading cells and prevented by Cxcr7b in trailing cells, determines unidirectional migration of the PLLp. These chemokine signaling-based models effectively recapitulate many behaviors of the PLLp and provide potential explanations for the characteristic behaviors that emerge when the PLLp is severed by laser to generate leading and trailing fragments. As predicted by our models, the bilateral stretching of the leading fragment is lost when chemokine signaling is blocked in the PLLp. However, movement of the trailing fragment toward the leading cells, which was also thought to be chemokine dependent, persists. This suggested that a chemokine-independent mechanism, not accounted for in our models, is responsible for this behavior. Further investigation of trailing cell behavior shows that their movement toward leading cells depends on FGF signaling and it can be re-oriented by exogenous FGF sources. Together, our observations reveal the simple yet elegant manner in which leading and trailing cells coordinate migration; while leading cells steer PLLp migration by following chemokine cues, cells further back play follow-the-leader as they migrate toward FGFs produced by leading cells. C1 [Nogare, Damian Dalle; Somers, Katherine; Rao, Swetha; Matsuda, Miho; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Matsuda, Miho] Rutgers State Univ, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07101 USA. [Reichman-Fried, Michal; Raz, Erez] Ctr Mol Biol Inflammat, Inst Cell Biol, D-48149 Munster, Germany. RP Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM chitnisa@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH) [HD001012] FX The Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institutes of Health (NIH) [HD001012] supported this work. Deposited in PMC for release after 12 months. NR 33 TC 10 Z9 11 U1 1 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD AUG PY 2014 VL 141 IS 16 BP 3188 EP 3196 DI 10.1242/dev.106690 PG 9 WC Developmental Biology SC Developmental Biology GA AO4KB UT WOS:000341305200011 ER PT J AU Kelly, NR Cotter, EW Mazzeo, SE AF Kelly, Nichole R. Cotter, Elizabeth W. Mazzeo, Suzanne E. TI Examining the role of distress tolerance and negative urgency in binge eating behavior among women SO EATING BEHAVIORS LA English DT Article DE Binge eating; Disordered eating attitudes; Depressive symptoms; Negative urgency; Impulsivity; Distress tolerance ID SELF-REPORT QUESTIONNAIRE; HANDLING MISSING DATA; DEPRESSIVE SYMPTOMS; COLLEGE-STUDENTS; ADOLESCENT GIRLS; RECIPROCAL RELATIONS; FEMALE ADOLESCENTS; DIETARY RESTRAINT; BULIMIC SYMPTOMS; SUBSTANCE-ABUSE AB The current study examined whether distress tolerance and negative urgency moderate the link between depressive symptoms and binge eating frequency, and between disordered eating attitudes and binge eating frequency. Young adult women (N = 186) completed questionnaires assessing depressive symptoms, cognitive restraint, eating, shape and weight concerns, distress tolerance, impulsivity (including negative urgency), and binge eating. After controlling for body mass index, race/ethnicity, and other domains of impulsivity, negative urgency was significantly associated with binge eating above and beyond the influence of disordered eating attitudes and depressive symptoms. Distress tolerance, in contrast, was not associated with binge eating. In addition, neither negative urgency nor distress tolerance moderated the associations between disordered eating attitudes and binge eating frequency, or between depressive symptoms and binge eating. Results support the additive role of difficulties responding adaptively to distress in binge eating frequency, above and beyond the influence of emotional distress. Findings highlight the potential value of focusing on negative urgency in targeted treatments for binge eating among women. Importantly, results from the current study differ from those of previous research; these discrepancies could be the result of variations in sample characteristics and approaches to the assessment of binge eating behavior. Additional research, including longitudinal studies and research using "real-time," assessment strategies, such as ecological momentary assessment, is necessary to elucidate further the role of various emotion regulation strategies in maintaining binge eating behavior in adult women. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kelly, Nichole R.; Mazzeo, Suzanne E.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Kelly, Nichole R.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, SGO, Bethesda, MD 20814 USA. [Kelly, Nichole R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Rockville, MD USA. [Cotter, Elizabeth W.] Amer Univ, Sch Educ Teaching & Hlth, Washington, DC 20016 USA. [Mazzeo, Suzanne E.] Virginia Commonwealth Univ, Dept Pediat, Richmond, VA 23284 USA. RP Kelly, NR (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, DoD, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM nichole.kelly@nih.gov NR 65 TC 6 Z9 6 U1 7 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD AUG PY 2014 VL 15 IS 3 BP 483 EP 489 DI 10.1016/j.eatbeh.2014.06.012 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AO0CI UT WOS:000340976300027 PM 25064303 ER PT J AU Medina-Echeverz, J Haile, LA Zhao, F Gamrekelashvili, J Ma, C Metais, JY Dunbar, CE Kapoor, V Manns, MP Korangy, F Greten, TF AF Medina-Echeverz, Jose Haile, Lydia A. Zhao, Fei Gamrekelashvili, Jaba Ma, Chi Metais, Jean-Yves Dunbar, Cynthia E. Kapoor, Veena Manns, Michael P. Korangy, Firouzeh Greten, Tim F. TI IFN-gamma regulates survival and function of tumor-induced CD11b(+)Gr-1(high) myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Bcl2a1; G-MDSC; GM-CSF; IFN-gamma; Immunotherapy; Vaccine ID NECROSIS-FACTOR-ALPHA; IMMUNOSUPPRESSIVE ACTIVITY; NEUTROPHIL APOPTOSIS; GENE-EXPRESSION; CANCER-THERAPY; BCL-2; FAMILY; MICE; INFLAMMATION; SUBSETS AB Myeloid derived suppressor cells (MDSCs) play a critical role in suppression of immune responses in cancer and inflammation. Here, we describe how regulation of Bcl2a1 by cytokines controls the suppressor function of CD11b(+)Gr-1(high) granulocytic MDSCs. Coculture of CD11b+Gr-1(high) granulocytic MDSCs with antigen-stimulated T cells and simultaneous blockade of IFN-gamma by the use of anti-IFN-gamma blocking antibody, IFN-gamma(-/-) effector T cells, IFN-gamma R-/- MDSCs or STAT1(-/-) MDSCs led to upregulation of Bcl2a1 in CD11b(+)Gr-1(high) cells, improved survival, and enhanced their suppressor function. Molecular studies revealed that GM-CSF released by antigen-stimulated CD8(+) T cells induced Bcl2a1 upregulation, which was repressed in the presence of IFN-gamma by a direct interaction of phosphorylated STAT-1 with the Bcl2a1 promotor. Bcl2a1 overexpressing granulocytic MDSCs demonstrated prolonged survival and enhanced suppressor function in vitro. Our data suggest that IFN-gamma/ STAT1-dependent regulation of Bcl2a1 regulates survival and thereby suppressor function of granulocytic MDSCs. C1 [Medina-Echeverz, Jose; Haile, Lydia A.; Zhao, Fei; Gamrekelashvili, Jaba; Ma, Chi; Korangy, Firouzeh; Greten, Tim F.] NCI, GI Malignancy Sect, Thorac & GI Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Metais, Jean-Yves; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kapoor, Veena] NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. RP Greten, TF (reprint author), NCI, Bldg 10 Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU Intramural Research Program of the NCI, NIH [ZIA BC 011345]; Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer FX This research was supported by the Intramural Research Program of the NCI, NIH (ZIA BC 011345) and the by the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer. NR 41 TC 11 Z9 12 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2014 VL 44 IS 8 BP 2457 EP 2467 DI 10.1002/eji.201444497 PG 11 WC Immunology SC Immunology GA AN4UU UT WOS:000340584800026 PM 24810636 ER PT J AU Yu, B Mumford, S Royster, GD Segars, J Armstrong, AY AF Yu, Bo Mumford, Sunni Royster, G. Donald Segars, James Armstrong, Alicia Y. TI Cost-effectiveness analysis comparing continuation of assisted reproductive technology with conversion to intrauterine insemination in patients with low follicle numbers SO FERTILITY AND STERILITY LA English DT Article DE Poor responders; intrauterine insemination; assisted reproductive technologies; cost effectiveness ID IN-VITRO FERTILIZATION; OVARIAN RESPONSE; POOR RESPONDERS; INVITRO FERTILIZATION; RESERVE; CYCLES; STIMULATION; PREDICTION; PREGNANCY; HORMONE AB Objective: To compare the cost effectiveness of proceeding with oocyte retrieval vs. converting to intrauterine insemination (IUI) in patients with <= 4 mature follicles during assisted reproductive technology (ART) cycles. Design: Probabilistic decision analysis. The cost effectiveness of completing ART cycles in poor responders was compared to that for converting the cycles to IUI. Setting: Not applicable. Patient(s): Not applicable. Intervention(s): Cost-effectiveness analysis. Main Outcome Measure(s): Cost effectiveness, which was defined as the average direct medical costs per ongoing pregnancy. Result(s): In patients with 1-3 mature follicles, completing ART was more cost effective if the cost of a single ART cycle was between $10,000 and $25,000. For patients with 4 mature follicles, if an ART cycle cost <$18,025, it was more cost effective to continue with oocyte retrieval than to convert to IUI. Conclusion(s): In patients with <= 4 mature follicles following ovarian stimulation in ART cycles, it was on average more cost effective to proceed with oocyte retrieval rather than convert to IUI. However, important factors, such as age, prior ART failures, other fertility factors, and medications used in each individual case need to be considered before this analysis model can be adapted by individual practices. ((C)2014 by American Society for Reproductive Medicine.) C1 [Yu, Bo] Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Mumford, Sunni] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. [Royster, G. Donald; Segars, James; Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod Adult Endocrinol, NIH, Bethesda, MD USA. RP Yu, B (reprint author), Dept Obstet Gynecol & Womens Hlth, Div Reprod Endocrinol & Infertil, Jack & Pearl Resnick Campus,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM boyumich2@gmail.com FU Intramural NIH HHS [Z99 HD999999] NR 26 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2014 VL 102 IS 2 BP 435 EP 439 DI 10.1016/j.fertnstert.2014.05.015 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AO4HX UT WOS:000341299000022 PM 24951366 ER PT J AU Lynch, KE Mumford, SL Schliep, KC Whitcomb, BW Zarek, SM Pollack, AZ Bertone-Johnson, ER Danaher, M Wactawski-Wende, J Gaskins, AJ Schisterman, EF AF Lynch, Kristine E. Mumford, Sunni L. Schliep, Karen C. Whitcomb, Brian W. Zarek, Shvetha M. Pollack, Anna Z. Bertone-Johnson, Elizabeth R. Danaher, Michelle Wactawski-Wende, Jean Gaskins, Audrey J. Schisterman, Enrique F. TI Assessment of anovulation in eumenorrheic women: comparison of ovulation detection algorithms SO FERTILITY AND STERILITY LA English DT Article DE Ovulation; menstrual cycles; progesterone; luteinizing hormone; estradiol ID LUTEINIZING-HORMONE SURGE; URINARY-EXCRETION RATES; MENSTRUAL-CYCLE; FERTILITY MONITOR; PREMENOPAUSAL WOMEN; ESTRONE GLUCURONIDE; OVARIAN ACTIVITY; LUTEAL-PHASE; PROGESTERONE; BIOCYCLE AB Objective: To compare previously used algorithms to identify anovulatory menstrual cycles in women self-reporting regular menses. Design: Prospective cohort study. Setting: Western New York. Patient(s): Two hundred fifty-nine healthy, regularly menstruating women followed for one (n = 9) or two (n = 250) menstrual cycles (2005-2007). Intervention(s): None. Main Outcome Measure(s): Prevalence of sporadic anovulatory cycles identified using 11 previously defined algorithms that use E-2, P, and LH concentrations. Result(s): Algorithms based on serum LH, E-2, and P levels detected a prevalence of anovulation across the study period of 5.5%-12.8% (concordant classification for 91.7%-97.4% of cycles). The prevalence of anovulatory cycles varied from 3.4% to 18.6% using algorithms based on urinary LH alone or with the primary E-2 metabolite, estrone-3-glucuronide, levels. Conclusion(s): The prevalence of anovulatory cycles among healthy women varied by algorithm. Mid-cycle LH surge urine-based algorithms used in over-the-counter fertility monitors tended to classify a higher proportion of anovulatory cycles compared with luteal-phase P serum-based algorithms. Our study demonstrates that algorithms based on the LH surge, or in conjunction with estrone-3-glucuronide, potentially estimate a higher percentage of anovulatory episodes. Addition of measurements of postovulatory serum P or urine pregnanediol may aid in detecting ovulation. (C) 2014 by American Society for Reproductive Medicine. C1 [Lynch, Kristine E.; Mumford, Sunni L.; Schliep, Karen C.; Zarek, Shvetha M.; Pollack, Anna Z.; Danaher, Michelle; Gaskins, Audrey J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH,US Dept HHS, Bethesda, MD USA. [Zarek, Shvetha M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, US Dept HHS, Bethesda, MD USA. [Lynch, Kristine E.] Westminster Coll, Dept Publ Hlth & Nursing, Salt Lake City, UT USA. [Whitcomb, Brian W.; Bertone-Johnson, Elizabeth R.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Pollack, Anna Z.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Gaskins, Audrey J.] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU National Institutes of Health, Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275200403394C]; National Institutes of Health [T32DK007703-16, T32HD060454] FX This research was supported by the National Institutes of Health, Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), contract HHSN275200403394C to the University at Buffalo; and National Institutes of Health training grants T32DK007703-16 and T32HD060454 (to A.J.G.). NR 39 TC 13 Z9 13 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2014 VL 102 IS 2 BP 511 EP U252 DI 10.1016/j.fertnstert.2014.04.035 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AO4HX UT WOS:000341299000033 PM 24875398 ER PT J AU Chauss, D Basu, S Rajakaruna, S Ma, ZW Gau, V Anastas, S Brennan, LA Hejtmancik, JF Menko, AS Kantorow, M AF Chauss, Daniel Basu, Subhasree Rajakaruna, Suren Ma, Zhiwei Gau, Victoria Anastas, Sara Brennan, Lisa A. Hejtmancik, J. Fielding Menko, A. Sue Kantorow, Marc TI Differentiation State-Specific Mitochondrial Dynamic Regulatory Networks Are Revealed by Global Transcriptional Analysis of the Developing Chicken Lens SO G3-GENES GENOMES GENETICS LA English DT Article DE RNA sequencing; eye; lens; differentiation; mitochondria; mitophagy; mitochondrial dynamics ID FIBER CELL-DIFFERENTIATION; ALPHA-B-CRYSTALLIN; OXIDATIVE STRESS; OCULAR LENS; EYE LENS; ORGANELLE DEGRADATION; VERTEBRATE LENS; GENE-EXPRESSION; CYTOCHROME-C; AUTOPHAGY AB The mature eye lens contains a surface layer of epithelial cells called the lens epithelium that requires a functional mitochondrial population to maintain the homeostasis and transparency of the entire lens. The lens epithelium overlies a core of terminally differentiated fiber cells that must degrade their mitochondria to achieve lens transparency. These distinct mitochondrial populations make the lens a useful model system to identify those genes that regulate the balance between mitochondrial homeostasis and elimination. Here we used an RNA sequencing and bioinformatics approach to identify the transcript levels of all genes expressed by distinct regions of the lens epithelium and maturing fiber cells of the embryonic Gallus gallus (chicken) lens. Our analysis detected more than 15,000 unique transcripts expressed by the embryonic chicken lens. Of these, more than 3000 transcripts exhibited significant differences in expression between lens epithelial cells and fiber cells. Multiple transcripts coding for separate mitochondrial homeostatic and degradation mechanisms were identified to exhibit preferred patterns of expression in lens epithelial cells that require mitochondria relative to lens fiber cells that require mitochondrial elimination. These included differences in the expression levels of metabolic (DUT, PDK1, SNPH), autophagy (ATG3, ATG4B, BECN1, FYCO1, WIPI1), and mitophagy (BNIP3L/NIX, BNIP3, PARK2, p62/SQSTM1) transcripts between lens epithelial cells and lens fiber cells. These data provide a comprehensive window into all genes transcribed by the lens and those mitochondrial regulatory and degradation pathways that function to maintain mitochondrial populations in the lens epithelium and to eliminate mitochondria in maturing lens fiber cells. C1 [Chauss, Daniel; Gau, Victoria; Anastas, Sara; Brennan, Lisa A.; Kantorow, Marc] Florida Atlantic Univ, Dept Biomed Sci, Boca Raton, FL 33431 USA. [Basu, Subhasree; Rajakaruna, Suren; Menko, A. Sue] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Ma, Zhiwei; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Kantorow, M (reprint author), Florida Atlantic Univ, Dept Biomed Sci, Charles E Schmidt Coll Med, 777 Glades Rd, Boca Raton, FL 33431 USA. EM mkantoro@fau.edu FU NIH/NEI [RO1 EY010577, EY13022] FX We appreciate the generous gift of Antibodies to BFSP1 and CP49 from Paul FitzGerald, Ph.D. (UC Davis, Davis, CA). This work was supported by NIH/NEI RO1 EY010577 (SM) and EY13022 (MK). NR 85 TC 10 Z9 10 U1 2 U2 6 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD AUG 1 PY 2014 VL 4 IS 8 BP 1515 EP 1527 DI 10.1534/g3.114.012120 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AO0PR UT WOS:000341013200014 PM 24928582 ER PT J AU Castellano, JF Fletcher, BR Patzke, H Long, JM Sewal, A Kim, DH Kelley-Bell, B Rapp, PR AF Castellano, James F. Fletcher, Bonnie R. Patzke, Holger Long, Jeffrey M. Sewal, Angila Kim, David H. Kelley-Bell, Bennett Rapp, Peter R. TI Reassessing the Effects of Histone Deacetylase Inhibitors on Hippocampal Memory and Cognitive Aging SO HIPPOCAMPUS LA English DT Article DE histone deacetylase inhibitor; epigenetics; hippocampus; aging ID LONG-TERM-MEMORY; SYNAPTIC PLASTICITY; SODIUM-BUTYRATE; AGED RATS; ALZHEIMERS-DISEASE; CONDITIONED FEAR; ACETYLATION; IMPAIRMENT; EXTINCTION; DEFICITS AB Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. (C) 2014 Wiley Periodicals, Inc. C1 [Castellano, James F.; Fletcher, Bonnie R.; Long, Jeffrey M.; Sewal, Angila; Kim, David H.; Kelley-Bell, Bennett; Rapp, Peter R.] NIA, Neurocognit Aging Sect, Baltimore, MD 21224 USA. [Castellano, James F.; Sewal, Angila] Icahn Sch Med Mt Sinai, Grad Program Neurosci, New York, NY 10029 USA. [Patzke, Holger] FORUM Pharmaceut, Watertown, MA USA. RP Rapp, PR (reprint author), NIA, Lab Behav Neurosci, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM rappp@mail.nih.gov RI Castellano, Jose Maria/L-8097-2014 OI Castellano, Jose Maria/0000-0003-3624-1298 FU Intramural Research Program of the National Institute on Aging; NIH [AG09973, AG032845] FX Grant sponsor: Intramural Research Program of the National Institute on Aging; Grant sponsor: NIH; Grant number: AG09973 and AG032845. NR 35 TC 8 Z9 8 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD AUG PY 2014 VL 24 IS 8 BP 1006 EP 1016 DI 10.1002/hipo.22286 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AN5WZ UT WOS:000340664100010 PM 24753063 ER PT J AU Lanitis, E Smith, JB Dangaj, D Flingai, S Poussin, M Xu, SW Czerniecki, BJ Li, YF Robbins, PF Powell, DJ AF Lanitis, Evripidis Smith, Jenessa B. Dangaj, Denarda Flingai, Seleeke Poussin, Mathilde Xu, Shuwen Czerniecki, Brian J. Li, Yong F. Robbins, Paul F. Powell, Daniel J., Jr. TI A Human ErbB2-Specific T-Cell Receptor Confers Potent Antitumor Effector Functions in Genetically Engineered Primary Cytotoxic Lymphocytes SO HUMAN GENE THERAPY LA English DT Article ID TUMOR-ASSOCIATED ANTIGENS; EARLY BREAST-CANCER; HUMAN RENAL-CELL; DENDRITIC CELLS; OVARIAN-CANCER; GENE-THERAPY; CYTOLYTIC ACTIVITY; IN-VIVO; HER-2/NEU; RECOGNITION AB The ErbB2 protein is a member of the tyrosine kinase family of growth factor receptors that is overexpressed in cancers of the breast, ovary, stomach, kidney, colon, and lung, and therefore represents an attractive candidate antigen for targeted cancer immunotherapy. Cytotoxic T lymphocytes specific for various immunogenic ErbB2 peptides have been described, but they often exhibit both poor functional avidity and tumor reactivity. In order to generate potent CD8(+) T cells with specificity for the ErbB2(369-377) peptide, we performed one round of in vitro peptide stimulation of CD8(+) T cells isolated from an HLA-A2(+) patient who was previously vaccinated with autologous dendritic cells pulsed with HLA class I ErbB2 peptides. Using this approach, we enriched highly avid ErbB2-reactive T cells with strong ErbB2-specific, antitumor effector functions. We then stimulated these ErbB2-reactive T cells with ErbB2(+) HLA-A2(+) tumor cells in vitro and sorted tumor-activated ErbB2(369-377) peptide T cells, which allowed for the isolation of a novel T-cell receptor (TCR) with ErbB2(369-377) peptide specificity. Primary human CD8(+) T cells genetically modified to express this ErbB2-specific TCR specifically bound ErbB2(369-377) peptide containing HLA-A2 tetramers, and efficiently recognized target cells pulsed with low nanomolar concentrations of ErbB2(369-377) peptide as well as nonpulsed ErbB2(+) HLA-A2(+) tumor cell lines in vitro. In a novel xenograft model, ErbB2-redirected T cells also significantly delayed progression of ErbB2(+) HLA-A2(+) human tumor in vivo. Together, these results support the notion that redirection of normal T-cell specificity by TCR gene transfer can have potential applications in the adoptive immunotherapy of ErbB2-expressing malignancies. C1 [Lanitis, Evripidis; Smith, Jenessa B.; Dangaj, Denarda; Flingai, Seleeke; Poussin, Mathilde; Powell, Daniel J., Jr.] Univ Penn, Dept Obstet & Gynecol, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. [Xu, Shuwen; Czerniecki, Brian J.] Univ Penn, Med Ctr, Dept Surg, Philadelphia, PA 19104 USA. [Li, Yong F.; Robbins, Paul F.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Powell, Daniel J., Jr.] Univ Penn, Dept Pathol & Lab Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Powell, DJ (reprint author), Univ Penn, 3400 Civ Ctr Blvd Bldg 421,TRC Room 8-103, Philadelphia, PA 19104 USA. EM poda@mail.med.upenn.edu FU Ovarian Cancer Research Fund; Sandy Rollman Ovarian Cancer Foundation; NIH [1R21CA152540]; Fox Chase Cancer Center [P50 CA083638]; University of Pennsylvania Ovarian Cancer SPORE [P50 CA083638]; Immunobiology of Normal and Neoplastic Lymphocytes T32 training grant [5T32CA009140-37] FX This work was supported in part by grants from the Ovarian Cancer Research Fund, Sandy Rollman Ovarian Cancer Foundation, NIH (1R21CA152540), the Joint Fox Chase Cancer Center and University of Pennsylvania Ovarian Cancer SPORE (P50 CA083638), and the Immunobiology of Normal and Neoplastic Lymphocytes T32 training grant (5T32CA009140-37). NR 44 TC 4 Z9 4 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD AUG PY 2014 VL 25 IS 8 BP 730 EP 739 DI 10.1089/hum.2014.006 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AN8AA UT WOS:000340821100008 PM 25003657 ER PT J AU Simpson, CL Goldenberg, AJ Culverhouse, R Daley, D Igo, RP Jarvik, GP Mandal, DM Mascalzoni, D Montgomery, CG Pierce, BL Plaetke, R Shete, S Goddard, KAB Stein, CM AF Simpson, Claire L. Goldenberg, Aaron J. Culverhouse, Rob Daley, Denise Igo, Robert P., Jr. Jarvik, Gail P. Mandal, Diptasri M. Mascalzoni, Deborah Montgomery, Courtney Gray Pierce, Brandon L. Plaetke, Rosemarie Shete, Sanjay Goddard, Katrina A. B. Stein, Catherine M. TI Practical Barriers and Ethical Challenges in Genetic Data Sharing SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE data sharing; identifiability; GWAS; ELSI; ethics; publication embargo; collaboration ID BLOOD-PRESSURE; ASSOCIATION; INFORMATION; VARIANTS AB The underlying ethos of dbGaP is that access to these data by secondary data analysts facilitates advancement of science. NIH has required that genome-wide association study data be deposited in the Database of Genotypes and Phenotypes (dbGaP) since 2003. In 2013, a proposed updated policy extended this requirement to next-generation sequencing data. However, recent literature and anecdotal reports suggest lingering logistical and ethical concerns about subject identifiability, informed consent, publication embargo enforcement, and difficulty in accessing dbGaP data. We surveyed the International Genetic Epidemiology Society (IGES) membership about their experiences. One hundred and seventy five (175) individuals completed the survey, a response rate of 27%. Of respondents who received data from dbGaP (43%), only 32% perceived the application process as easy but most (75%) received data within five months. Remaining challenges include difficulty in identifying an institutional signing official and an overlong application process. Only 24% of respondents had contributed data to dbGaP. Of these, 31% reported local IRB restrictions on data release; an additional 15% had to reconsent study participants before depositing data. The majority of respondents (56%) disagreed that the publication embargo period was sufficient. In response, we recommend longer embargo periods and use of varied data-sharing models rather than a one-size-fits-all approach. C1 [Simpson, Claire L.] Natl Human Genome Res Inst, Computat & Stat Genom Branch, Baltimore, MD 21224 USA. [Goldenberg, Aaron J.] Case Western Reserve Univ, Dept Bioeth, Cleveland, OH 44106 USA. [Culverhouse, Rob] Washington Univ, Dept Internal Med, St Louis, MO 63110 USA. [Daley, Denise] Univ British Columbia, Dept Med, Vancouver, BC V6Z 1Y6, Canada. [Igo, Robert P., Jr.; Stein, Catherine M.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Jarvik, Gail P.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Mandal, Diptasri M.] Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA 70112 USA. [Mascalzoni, Deborah] EURAC Inst Genet Med, I-39100 Bolzano, Italy. [Montgomery, Courtney Gray] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Pierce, Brandon L.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Plaetke, Rosemarie] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometry & Epidemiol, D-20246 Hamburg, Germany. [Shete, Sanjay] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Goddard, Katrina A. B.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97227 USA. RP Simpson, CL (reprint author), Natl Human Genome Res Inst, Computat & Stat Genom Branch, Baltimore, MD 21224 USA. EM claire.simpson@nih.gov; aaron.goldenberg@case.edu; rculverh@dom.wustl.edu; denise.daley@hli.ubc.ca; rpi@case.edu; gjarvik@medicine.washington.edu; dmanda@lsuhsc.edu; deborah.mascalzoni@eurac.edu; courtney-montgomery@omrf.org; bpierce@health.bsd.uchicago.edu; rplaetke@alaska.edu; sshete@mdanderson.org; Katrina.AB.Goddard@kpchr.org; cmj7@case.edu RI Jarvik, Gail/N-6476-2014; OI Jarvik, Gail/0000-0002-6710-8708; Pierce, Brandon/0000-0002-7829-952X FU International Genetic Epidemiology Society; Northwest Institute of Genetic Medicine (State of Washington Life Sciences Discovery Fund); National Human Genome Research Institute, National Institutes of Health; [PO1 HG004610] FX This survey was developed by members of the 2010-2011 IGES ELSI committee, and results were reviewed by the 2011-2012 IGES committee membership. Funding for the SurveyMonkey survey was provided by the International Genetic Epidemiology Society. Additional support was provided by the Northwest Institute of Genetic Medicine (State of Washington Life Sciences Discovery Fund awardee) and PO1 HG004610 (GPJ). CLS is supported by the intramural research program of the National Human Genome Research Institute, National Institutes of Health. NR 29 TC 4 Z9 4 U1 3 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD AUG PY 2014 VL 11 IS 8 BP 8383 EP 8398 DI 10.3390/ijerph110808383 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AO1UX UT WOS:000341101700050 PM 25153467 ER PT J AU Truog, RD Miller, FG AF Truog, Robert D. Miller, Franklin G. TI The Meaning of Brain Death SO JAMA INTERNAL MEDICINE LA English DT Editorial Material C1 [Truog, Robert D.] Boston Childrens Hosp, Div Crit Care Med, Boston, MA 02115 USA. [Truog, Robert D.] Harvard Univ, Sch Med, Div Med Eth, Boston, MA USA. [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Truog, RD (reprint author), Boston Childrens Hosp, Div Crit Care Med, 300 Longwood Ave,Bader 621, Boston, MA 02115 USA. EM robert.truog@childrens.harvard.edu NR 9 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1215 EP 1216 DI 10.1001/jamainternmed.2014.2272 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000002 PM 24911444 ER PT J AU Rodriguez, CJ Swett, K Agarwal, SK Folsom, AR Fox, ER Loehr, LR Ni, HY Rosamond, WD Chang, PP AF Rodriguez, Carlos J. Swett, Katrina Agarwal, Sunil K. Folsom, Aaron R. Fox, Ervin R. Loehr, Laura R. Ni, Hanyu Rosamond, Wayne D. Chang, Patricia P. TI Systolic Blood Pressure Levels Among Adults With Hypertension and Incident Cardiovascular Events The Atherosclerosis Risk in Communities Study SO JAMA INTERNAL MEDICINE LA English DT Article ID CONGESTIVE-HEART-FAILURE; ANTIHYPERTENSIVE DRUG-TREATMENT; INTERNATIONAL SOCIETY; CONSENSUS STATEMENT; OLDER PERSONS; WORKING GROUP; STROKE; PREVENTION; DISEASE; ASSOCIATION AB IMPORTANCE Studies document a progressive increase in heart disease risk as systolic blood pressure (SBP) rises above 115 mm Hg, but it is unknown whether an SBP lower than 120 mm Hg among adults with hypertension (HTN) lowers heart failure, stroke, and myocardial infarction risk. OBJECTIVE To examine the risk of incident cardiovascular (CV) events among adults with HTN according to 3 SBP levels: 140 mm Hg or higher; 120 to 139 mm Hg; and a reference level of lower than 120 mm Hg. DESIGN, SETTING, AND PARTICIPANTS A total of 4480 participants with HTN but without prevalent CV disease at baseline (years 1987-1989) from the Atherosclerosis Risk in Communities Study were included. Measurements of SBP were taken at baseline and at 3 triennial visits; SBP was treated as a time-dependent variable and categorized as elevated (>= 140 mm Hg), standard (120-139 mm Hg), and low (<120 mm Hg). Multivariable Cox regression models included baseline age, sex, diabetes status, BMI, high cholesterol level, smoking status, and alcohol intake. MAIN OUTCOMES AND MEASURES Incident composite CV events (heart failure, ischemic stroke, myocardial infarction, or death related to coronary heart disease). RESULTS After a median follow-up of 21.8 years, a total of 1622 incident CV events had occurred. Participants with elevated SBP developed incident CV events at a significantly higher rate than those in the low BP group (adjusted hazard ratio [HR], 1.46; 95% CI, 1.26-1.69). However, there was no difference in incident CV event-free survival among those in the standard vs low SBP group (adjusted HR, 1.00; 95% CI, 0.85-1.17). Further adjustment for BP medication use or diastolic BP did not significantly affect the results. CONCLUSIONS AND RELEVANCE Among patients with HTN, having an elevated SBP carries the highest risk for cardiovascular events, but in this categorical analysis, once SBP was below 140 mm Hg, an SBP lower than 120 mm Hg did not appear to lessen the risk of incident CV events. C1 [Rodriguez, Carlos J.; Swett, Katrina] Wake Forest Univ, Sch Med, Dept Med & Publ Hlth Sci, Winston Salem, NC 27157 USA. [Agarwal, Sunil K.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Agarwal, Sunil K.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Fox, Ervin R.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS USA. [Loehr, Laura R.; Rosamond, Wayne D.; Chang, Patricia P.] Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA. [Loehr, Laura R.; Rosamond, Wayne D.; Chang, Patricia P.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Ni, Hanyu] NHLBI, Bethesda, MD 20892 USA. RP Rodriguez, CJ (reprint author), Wake Forest Univ, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM crodrigu@wakehealth.edu FU National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) [R01 HL104199]; NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268200900048C] FX This study was supported in part by National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL104199 (Epidemiologic Determinants of Cardiac Structure and Function among Hispanics, Carlos J. Rodriguez, MD, MPH principal investigator). The ARIC Study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. Dr Rodriguez is also partially supported by the SPRINT clinical trial, NHLBI grant HHSN268200900048C. NR 39 TC 10 Z9 11 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1252 EP 1261 DI 10.1001/jamainternmed.2014.2482 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000012 PM 24935209 ER PT J AU Liu, JH Liu, XC Wang, W McCauley, L Pinto-Martin, J Wang, YJ Li, LD Yan, CH Rogan, WJ AF Liu, Jianghong Liu, Xianchen Wang, Wei McCauley, Linda Pinto-Martin, Jennifer Wang, Yingjie Li, Linda Yan, Chonghuai Rogan, Walter J. TI Blood Lead Concentrations and Children's Behavioral and Emotional Problems A Cohort Study SO JAMA PEDIATRICS LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; PORT-PIRIE COHORT; ENVIRONMENTAL LEAD; PRESCHOOL-CHILDREN; CHINESE CHILDREN; SOCIODEMOGRAPHIC FACTORS; GENDER-DIFFERENCES; EXPOSURE; LEVEL; INTELLIGENCE AB IMPORTANCE The association between lead exposure and children's IQ has been well studied, but few studies have examined the effects of blood lead concentrations on children's behavior. OBJECTIVE To evaluate the association between blood lead concentrations and behavioral problems in a community sample of Chinese preschool children with a mean blood lead concentration of less than 10 mu g/dL. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted at 4 preschools in Jintan, Jiangsu province of China. Participants included 1341 children aged 3 to 5 years. EXPOSURES Lead. MAIN OUTCOMES AND MEASURES Blood lead concentrations were measured in children aged 3 to 5 years. Behavioral problems were assessed using Chinese versions of the Child Behavior Checklist and Caregiver-Teacher Report Form when children were aged 6 years. RESULTS The mean (SD) blood lead concentration was 6.4 (2.6) mu g/dL, with the 75th and 90th percentiles being 7.5 and 9.4 mu g/dL, respectively. General linear modeling showed significant associations between blood lead concentrations and increased scores for teacher-reported behavioral problems. A 1-mu g/dL increase in the blood lead concentration resulted in a 0.322 (95% CI, 0.058 to 0.587), 0.253 (95% CI, 0.016 to 0.500), and 0.303 (95% CI, 0.046 to 0.560) increase of teacher-reported behavior scores on emotional reactivity, anxiety problems, and pervasive developmental problems, respectively (P < .05), with adjustment for parental and child variables. Spline modeling showed that mean teacher-reported behavior scores increased with blood lead concentrations, particularly for older girls. CONCLUSIONS AND RELEVANCE Blood lead concentrations, even at a mean concentration of 6.4 mu g/dL, were associated with increased risk of behavioral problems in Chinese preschool children, including internalizing and pervasive developmental problems. This association showed different patterns depending on age and sex. As such, continued monitoring of blood lead concentrations, as well as clinical assessments of mental behavior during regular pediatric visits, may be warranted. C1 [Liu, Jianghong; Pinto-Martin, Jennifer; Wang, Yingjie; Li, Linda] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Liu, Jianghong; Pinto-Martin, Jennifer] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Liu, Xianchen] Indiana Univ, Sch Med, Indianapolis, IN USA. [Liu, Xianchen] Shandong Univ, Sch Publ Hlth, Jinan 250100, Peoples R China. [Wang, Wei] Childrens Hosp Philadelphia, Ctr Outcomes Res, Philadelphia, PA 19104 USA. [McCauley, Linda] Emory Univ, Nell Hodgson Sch Nursing, Atlanta, GA 30322 USA. [Yan, Chonghuai] Shandong Jiaotong Univ, Sch Med, MOE Shanghai Key Lab Childrens Environm Hlth, Xinhua Hosp, Jinan, Peoples R China. [Rogan, Walter J.] NIEHS, NIH, Bethesda, MD USA. RP Liu, JH (reprint author), Univ Penn, Sch Nursing, 418 Curie Blvd,Room 426,Claire M Fagin Hall, Philadelphia, PA 19104 USA. EM jhliu@nursing.upenn.edu RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 FU National Institute of Environmental Health Sciences [RO1-ES018858, K01-ES015877, K02-ES019878, P30-ES013508]; University of Pennsylvania Center of Excellence in Environmental Toxicology; Wacker Foundation; Jintan city government; Jintan Hospital; National Institute of Environmental Health Sciences FX This work was supported by National Institute of Environmental Health Sciences grants RO1-ES018858, K01-ES015877, K02-E5019878, and P30-E5013508; the University of Pennsylvania Center of Excellence in Environmental Toxicology; the Wacker Foundation; the Jintan city government; and Jintan Hospital. Dr Rogan was supported by the Intramural Research Program at the National Institute of Environmental Health Sciences. NR 72 TC 11 Z9 11 U1 3 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD AUG PY 2014 VL 168 IS 8 BP 737 EP 745 DI 10.1001/jamapediatrics.2014.332 PG 9 WC Pediatrics SC Pediatrics GA AN0TZ UT WOS:000340298200013 PM 25090293 ER PT J AU Morriss, FH Saha, S Bell, EF Colaizy, TT Stoll, BJ Hintz, SR Shankaran, S Vohr, BR Hamrick, SEG Pappas, A Jones, PM Carlo, WA Laptook, AR Van Meurs, KP Sanchez, PJ Hale, EC Newman, NS Das, A Higgins, RD AF Morriss, Frank H., Jr. Saha, Shampa Bell, Edward F. Colaizy, Tarah T. Stoll, Barbara J. Hintz, Susan R. Shankaran, Seetha Vohr, Betty R. Hamrick, Shannon E. G. Pappas, Athina Jones, Patrick M. Carlo, Waldemar A. Laptook, Abbot R. Van Meurs, Krisa P. Sanchez, Pablo J. Hale, Ellen C. Newman, Nancy S. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst Human Dev Neonatal Res Network TI Surgery and Neurodevelopmental Outcome of Very Low-Birth-Weight Infants SO JAMA PEDIATRICS LA English DT Article ID PATENT DUCTUS-ARTERIOSUS; PRETERM INFANTS; NECROTIZING ENTEROCOLITIS; LEARNING-DISABILITIES; EARLY EXPOSURE; NEUROLOGIC-OUTCOMES; CHILDHOOD EXPOSURE; PROPENSITY SCORE; DEVELOPING BRAIN; CARDIAC-SURGERY AB IMPORTANCE Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine. OBJECTIVE To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months' corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12111 infants were included in analyses. EXPOSURES Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia). MAIN OUTCOMES AND MEASURES Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006. RESULTS A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower. CONCLUSIONS AND RELEVANCE Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months' corrected age. The role of general anesthesia is implicated but remains unproven. C1 [Morriss, Frank H., Jr.; Bell, Edward F.; Colaizy, Tarah T.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Saha, Shampa] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Stoll, Barbara J.; Hamrick, Shannon E. G.; Hale, Ellen C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.; Hamrick, Shannon E. G.; Hale, Ellen C.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Hintz, Susan R.; Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Hintz, Susan R.; Van Meurs, Krisa P.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Shankaran, Seetha; Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Vohr, Betty R.; Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Jones, Patrick M.] Univ Texas Med Sch, Dept Pediat, Houston, TX USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Sanchez, Pablo J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Newman, Nancy S.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Morriss, FH (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM frank-morriss@uiowa.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources (NCRR); National Center for Advancing Translational Sciences (NCATS) FX The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources (NCRR), and the National Center for Advancing Translational Sciences (NCATS) provided grant support for the Neonatal Research Network's Generic Database Study through cooperative agreements. NR 56 TC 19 Z9 20 U1 1 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD AUG PY 2014 VL 168 IS 8 BP 746 EP 754 DI 10.1001/jamapediatrics.2014.307 PG 9 WC Pediatrics SC Pediatrics GA AN0TZ UT WOS:000340298200014 PM 24934607 ER PT J AU MacKinnon-Lewis, C Lindsey, EW Frabutt, JM Chambers, JC AF MacKinnon-Lewis, Carol Lindsey, Eric W. Frabutt, James M. Chambers, Jessica Campbell TI Mother-Adolescent conflict in African American and European American families: The role of corporal punishment, adolescent aggression, and adolescents' hostile attributions of mothers' intent SO JOURNAL OF ADOLESCENCE LA English DT Article DE Corporal punishment; Mother-adolescent conflict; Hostile attribution of Intent; Adolescent aggression ID SOCIAL INFORMATION; BEHAVIOR PROBLEMS; PHYSICAL DISCIPLINE; LONGITUDINAL EXAMINATION; EXTERNALIZING BEHAVIORS; CHILD AGGRESSION; ADJUSTMENT; METAANALYSIS; MEDIATION; CONTEXT AB The present study examined mothers' use of corporal punishment and adolescents' aggression as predictors of mother-youth conflict during early adolescence. Particular attention was given to the potential mediating role that adolescents' hostile attributions of intent (HAI) regarding mothers' behavior might play in connections between corporal punishment, youth aggression, and mother adolescent conflict for European American (EA) and African American (AA) youth. Data were collected from 268 12- to 14-year-olds (154 European American; 114 African American; 133 girls; 135 boys) and their mothers over a period of 2 years. Questionnaires completed by both mothers and adolescents were used to assess maternal corporal punishment and adolescent aggression, and interviews concerning hypothetical situations were used to assess adolescent HAI in year one. In both year one and year two mother adolescent conflict was observed in a laboratory interaction session. Data revealed that adolescent HAI mediated the link between maternal corporal punishment and mother adolescent conflict for EA, but not AA youth. Adolescents' HAI mediated the link between adolescent aggression and mother adolescent conflict for both EA and AA families. (C) Published by Elsevier Ltd on behalf of The Foundation for Professionals in Services for Adolescents. C1 [MacKinnon-Lewis, Carol] Univ S Florida, Dept Child & Family Studies, Tampa, FL USA. [Lindsey, Eric W.] Penn State Berks, Dept Appl Psychol, Reading, PA 19610 USA. [Frabutt, James M.] Univ Notre Dame, Mary Ann Remick Leadership Program, Notre Dame, IN 46556 USA. [Chambers, Jessica Campbell] NIDA, Div Clin Neurosci Dev & Behav Res, Bethesda, MD 20892 USA. RP Lindsey, EW (reprint author), Penn State Berks, Dept Appl Psychol, 7009 Tulpehocken Rd, Reading, PA 19610 USA. EM EWL10@psu.edu NR 48 TC 3 Z9 3 U1 0 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0140-1971 EI 1095-9254 J9 J ADOLESCENCE JI J. Adolesc. PD AUG PY 2014 VL 37 IS 6 BP 851 EP 861 DI 10.1016/j.adolescence.2014.05.005 PG 11 WC Psychology, Developmental SC Psychology GA AO0JB UT WOS:000340993800009 PM 25086461 ER PT J AU Ghosh, D Mueller, GA Schramm, G Edwards, LL Petersen, A London, RE Haas, H Bhattacharya, SG AF Ghosh, Debajyoti Mueller, Geoffrey A. Schramm, Gabriele Edwards, Lori L. Petersen, Arnd London, Robert E. Haas, Helmut Bhattacharya, Swati Gupta TI Primary Identification, Biochemical Characterization, and Immunologic Properties of the Allergenic Pollen Cyclophilin Cat r 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETULA-VERRUCOSA POLLEN; CRYSTAL-STRUCTURE; CROSS-REACTIVITY; WEB SERVER; PLASMODIUM-FALCIPARUM; PROTEIN FAMILIES; NUCLEIC-ACIDS; HIGHER-PLANTS; L. POLLEN; IGE AB Cyclophilin (Cyp) allergens are considered pan-allergens due to frequently reported cross-reactivity. In addition to well studied fungal Cyps, a number of plant Cyps were identified as allergens (e. g. Bet v 7 from birch pollen, Cat r 1 from periwinkle pollen). However, there are conflicting data regarding their antigenic/allergenic cross-reactivity, with no plant Cyp allergen structures available for comparison. Because amino acid residues are fairly conserved between plant and fungal Cyps, it is particularly interesting to check whether they can cross-react. Cat r 1 was identified by immunoblotting using allergic patients' sera followed by N-terminal sequencing. Cat r 1 (similar to 91% sequence identity to Bet v 7) was cloned from a cDNA library and expressed in Escherichia coli. Recombinant Cat r 1 was utilized to confirm peptidyl-prolyl cis-trans-isomerase (PPIase) activity by a PPIase assay and the allergenic property by an IgE-specific immunoblotting and rat basophil leukemia cell (RBL-SX38) mediator release assay. Inhibition-ELISA showed cross-reactive binding of serum IgE from Cat r 1-allergic individuals to fungal allergenic Cyps Asp f 11 and Mala s 6. The molecular structure of Cat r 1 was determined by NMR spectroscopy. The antigenic surface was examined in relation to its plant, animal, and fungal homologues. The structure revealed a typical cyclophilin fold consisting of a compact beta-barrel made up of seven anti-parallel beta-strands along with two surrounding alpha-helices. This is the first structure of an allergenic plant Cyp revealing high conservation of the antigenic surface particularly near the PPIase active site, which supports the pronounced cross-reactivity among Cyps from various sources. C1 [Ghosh, Debajyoti; Bhattacharya, Swati Gupta] Bose Inst, Kolkata 700009, W Bengal, India. [Mueller, Geoffrey A.; Edwards, Lori L.; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Schramm, Gabriele; Haas, Helmut] Leibniz Ctr Med & Biosci, Res Ctr Borstel, D-23845 Borstel, Germany. [Petersen, Arnd] Airway Res Ctr North ARCN, Res Ctr Borstel, Div Clin & Mol Allergol, D-23845 Borstel, Germany. RP Ghosh, D (reprint author), Univ Cincinnati, Coll Med, Dept Internal Med, Div Allergy Immunol & Rheumatol, Cincinnati, OH 45267 USA. EM djghosh@yahoo.com; swati@jcbose.ac.in FU National Institutes of Health (NIEHS intramural program) [Z01-ES102885-01]; German Academic Exchange Service (DAAD) FX This work was supported, in whole or in part, by National Institutes of Health (NIEHS intramural program) Research Project Z01-ES102885-01 (to R. E. L.).; Supported by a fellowship from the German Academic Exchange Service (DAAD). To whom correspondence may be addressed: Division of Allergy, Immunology and Rheumatology, Dept. of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267. NR 58 TC 6 Z9 7 U1 0 U2 11 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 1 PY 2014 VL 289 IS 31 BP 21374 EP 21385 DI 10.1074/jbc.M114.559971 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4LC UT WOS:000340558300017 PM 24939849 ER PT J AU Mamais, A Chia, R Beilina, A Hauser, DN Hall, C Lewis, PA Cookson, MR Bandopadhyay, R AF Mamais, Adamantios Chia, Ruth Beilina, Alexandra Hauser, David N. Hall, Christine Lewis, Patrick A. Cookson, Mark R. Bandopadhyay, Rina TI Arsenite Stress Down-regulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2), Promoting Self-association and Cellular Redistribution SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PARKINSONS-DISEASE PATHOLOGY; KAPPA-B KINASE; CYTOPLASMIC LOCALIZATION; G2019S MUTATION; GTP-BINDING; ROC DOMAIN; G-PROTEINS; DEGRADATION; INHIBITION; LEUCINE-RICH-REPEAT-KINASE-2 AB Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson disease, but the mechanisms whereby LRRK2 is regulated are unknown. Phosphorylation of LRRK2 at Ser(910)/Ser(935) mediates interaction with 14-3-3. Pharmacological inhibition of its kinase activity abolishes Ser(910)/Ser(935) phosphorylation and 14-3-3 binding, and this effect is also mimicked by pathogenic mutations. However, physiological situations where dephosphorylation occurs have not been defined. Here, we show that arsenite or H2O2-induced stresses promote loss of Ser(910)/Ser(935) phosphorylation, which is reversed by phosphatase inhibition. Arsenite-induced dephosphorylation is accompanied by loss of 14-3-3 binding and is observed in wild type, G2019S, and kinase-dead D2017A LRRK2. Arsenite stress stimulates LRRK2 self-association and association with protein phosphatase 1 alpha, decreases kinase activity and GTP binding in vitro, and induces translocation of LRRK2 to centrosomes. Our data indicate that signaling events induced by arsenite and oxidative stress may regulate LRRK2 function. C1 [Mamais, Adamantios; Bandopadhyay, Rina] UCL, Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 1PJ, England. [Mamais, Adamantios; Hall, Christine; Lewis, Patrick A.; Bandopadhyay, Rina] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BJ, England. [Mamais, Adamantios; Chia, Ruth; Beilina, Alexandra; Hauser, David N.; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Chia, Ruth] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. [Hauser, David N.] Brown Univ, Dept Neurosci, Natl Inst Hlth Grad Partnership Program, Providence, RI 02912 USA. [Lewis, Patrick A.] Univ Reading, Sch Pharm, Reading RG6 6AP, Berks, England. RP Mamais, A (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM adamantios.mamais@nih.gov; rina.bandopadhyay@ucl.ac.uk RI Bandopadhyay, Rina /C-7926-2009; Hauser, David/I-4933-2012; OI Hauser, David/0000-0002-9500-5255; Lewis, Patrick/0000-0003-4537-0489 FU National Institutes of Health, NIA, Intramural Research Program; Michael J. Fox Foundation; Reta Lila Weston Institute of Neurological Studies; Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award [WT089698] FX This work was supported, in whole or in part, by the National Institutes of Health, NIA, Intramural Research Program. This work was also supported by grants from the Michael J. Fox Foundation (to R. B. and P. A. L.), funding from the Reta Lila Weston Institute of Neurological Studies, and the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (Grant WT089698) to the UK Parkinson's Disease Consortium whose members are from the University College London Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee. NR 66 TC 7 Z9 7 U1 1 U2 6 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 1 PY 2014 VL 289 IS 31 BP 21386 EP 21400 DI 10.1074/jbc.M113.528463 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4LC UT WOS:000340558300018 PM 24942733 ER PT J AU Hall, MD Marshall, TS Kwit, ADT Jenkins, LMM Dulcey, AE Madigan, JP Pluchino, KM Goldsborough, AS Brimacombe, KR Griffiths, GL Gottesman, MM AF Hall, Matthew D. Marshall, Travis S. Kwit, Alexandra D. T. Jenkins, Lisa M. Miller Dulcey, Andres E. Madigan, James P. Pluchino, Kristen M. Goldsborough, Andrew S. Brimacombe, Kyle R. Griffiths, Gary L. Gottesman, Michael M. TI Inhibition of Glutathione Peroxidase Mediates the Collateral Sensitivity of Multidrug-resistant Cells to Tiopronin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISATIN-BETA-THIOSEMICARBAZONES; BREAST-CANCER-CELLS; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; SELECTIVE ACTIVITY; DRUG-RESISTANCE; P-GLYCOPROTEIN; LINES; DETOXIFICATION; MECHANISMS AB Multidrug resistance (MDR) is a major obstacle to the successful chemotherapy of cancer. MDR is often the result of overexpression of ATP-binding cassette transporters following chemotherapy. A common ATP-binding cassette transporter that is overexpressed in MDR cancer cells is P-glycoprotein, which actively effluxes drugs against a concentration gradient, producing an MDR phenotype. Collateral sensitivity (CS), a phenomenon of drug hypersensitivity, is defined as the ability of certain compounds to selectively target MDR cells, but not the drug-sensitive parent cells from which they were derived. The drug tiopronin has been previously shown to elicit CS. However, unlike other CS agents, the mechanism of action was not dependent on the expression of P-glycoprotein in MDR cells. We have determined that the CS activity of tiopronin is mediated by the generation of reactive oxygen species (ROS) and that CS can be reversed by a variety of ROS-scavenging compounds. Specifically, selective toxicity of tiopronin toward MDR cells is achieved by inhibition of glutathione peroxidase (GPx), and the mode of inhibition of GPx1 by tiopronin is shown in this report. Why MDR cells are particularly sensitive to ROS is discussed, as is the difficulty in exploiting this hypersensitivity to tiopronin in the clinic. C1 [Hall, Matthew D.; Marshall, Travis S.; Kwit, Alexandra D. T.; Jenkins, Lisa M. Miller; Madigan, James P.; Pluchino, Kristen M.; Goldsborough, Andrew S.; Brimacombe, Kyle R.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dulcey, Andres E.; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program. NR 58 TC 11 Z9 11 U1 2 U2 18 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 1 PY 2014 VL 289 IS 31 BP 21473 EP 21489 DI 10.1074/jbc.M114.581702 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4LC UT WOS:000340558300025 PM 24930045 ER PT J AU Liu, J Han, L Li, B Yang, J Huen, MSY Pan, X Tsao, SW Cheung, ALM AF Liu, Jia Han, Liang Li, Bin Yang, Jie Huen, Michael S. Y. Pan, Xin Tsao, Sai Wah Cheung, Annie L. M. TI F-Box Only Protein 31 (FBXO31) Negatively Regulates p38 Mitogen-activated Protein Kinase (MAPK) Signaling by Mediating Lysine 48-linked Ubiquitination and Degradation of Mitogen-activated Protein Kinase Kinase 6 (MKK6) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIFFERENTIAL REGULATION; GENE-EXPRESSION; DNA-DAMAGE; PATHWAY; LIGASE; COMPLEX; PHOSPHORYLATION; UBIQUITYLATION; TRANSDUCTION; PHOSPHATASES AB The p38 MAPK signal transduction pathway plays an important role in inflammatory and stress responses. MAPKK6 (MKK6), a dual specificity protein kinase, is a p38 activator. Activation of the MKK6-p38 pathway is kept in check by multiple layers of regulations, including autoinhibition, dimerization, scaffold proteins, and Lys-63-linked polyubiquitination. However, the mechanisms underlying deactivation of MKK6-p38, which is crucial for maintaining the magnitude and duration of signal transduction, are not well understood. Lys-48-linked ubiquitination, which marks substrates for proteasomal degradation, is an important negative posttranslational regulatory machinery for signal pathway transduction. Here we report that the accumulation of F-box only protein 31 (FBXO31), a component of Skp1.Cul1.F-box protein E3 ligase, negatively regulated p38 activation in cancer cells upon genotoxic stresses. Our results show that FBXO31 binds to MKK6 and mediates its Lys-48-linked polyubiquitination and degradation, thereby functioning as a negative regulator of MKK6-p38 signaling and protecting cells from stress-induced cell apoptosis. Taken together, our findings uncover a new mechanism of deactivation of MKK6-p38 and substantiate a novel regulatory role of FBXO31 in stress response. C1 [Liu, Jia; Han, Liang; Li, Bin; Yang, Jie; Huen, Michael S. Y.; Tsao, Sai Wah; Cheung, Annie L. M.] Univ Hong Kong, Li Ka Shing Fac Med, Dept Anat, Pokfulam, Hong Kong, Peoples R China. [Pan, Xin] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Cheung, ALM (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, Dept Anat, Pokfulam, Hong Kong, Peoples R China. EM lmcheung@hku.hk OI /0000-0003-3217-1456 NR 35 TC 7 Z9 8 U1 1 U2 9 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 1 PY 2014 VL 289 IS 31 BP 21508 EP 21518 DI 10.1074/jbc.M114.560342 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4LC UT WOS:000340558300027 PM 24936062 ER PT J AU He, HY Ratnayake, AS Janso, JE He, M Yang, HY Loganzo, F Shor, B O'Donnell, CJ Koehn, FE AF He, Haiyin Ratnayake, Anokha S. Janso, Jeffrey E. He, Min Yang, Hui Y. Loganzo, Frank Shor, Boris O'Donnell, Christopher J. Koehn, Frank E. TI Cytotoxic Spliceostatins from Burkholderia sp and Their Semisynthetic Analogues SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID PRE-MESSENGER-RNA; ANTITUMOR SUBSTANCES; FR901464; SPLICEOSOME; INHIBITORS; TARGET; TUMORS; SF3B AB The spliceostatin class of natural products was reported to be potent cytotoxic agents via inhibition of the spliceosome, a key protein complex in the biosynthesis of mature mRNA. As part of an effort to discover novel leads for cancer chemotherapy, we re-examined this class of compounds from several angles, including fermentation of the producing strains, isolation and structure determination of new analogues, and semisynthetic modification. Accordingly, a group of spliceostatins were isolated from a culture broth of Burkholderia sp. FERM BP-3421, and their structures identified by analysis of spectroscopic data. Semisynthesis was performed on the major components 4 and 5 to generate ester and amide derivatives with improved in vitro potency. With their potent activity against tumor cells and unique mode of action, spliceostatins can be considered potential leads for development of cancer drugs. C1 [He, Haiyin; Ratnayake, Anokha S.; Janso, Jeffrey E.; O'Donnell, Christopher J.; Koehn, Frank E.] Pfizer Worldwide Res & Dev, Worldwide Med Chem, Nat Prod Lab, Groton, CT 06340 USA. [He, Min] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Yang, Hui Y.] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA. [Shor, Boris] Pfizer Oncol, Pearl River, NY 10965 USA. RP He, HY (reprint author), Pfizer Worldwide Res & Dev, Worldwide Med Chem, Nat Prod Lab, 558 Eastern Point Rd, Groton, CT 06340 USA. EM haiyin_he@yahoo.com NR 29 TC 14 Z9 16 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2014 VL 77 IS 8 BP 1864 EP 1870 DI 10.1021/np500342m PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA AN8NV UT WOS:000340861800014 PM 25098528 ER PT J AU Niciu, MJ Ionescu, DF Richards, EM Zarate, CA AF Niciu, Mark J. Ionescu, Dawn F. Richards, Erica M. Zarate, Carlos A., Jr. TI Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder SO JOURNAL OF NEURAL TRANSMISSION LA English DT Review DE Major depressive disorder; Glutamate; Glutamate receptor; NMDA receptor antagonist; Ketamine ID TREATMENT-RESISTANT DEPRESSION; MAGNETIC-RESONANCE-SPECTROSCOPY; D-ASPARTATE ANTAGONIST; RAPID ANTIDEPRESSANT RESPONSE; ANTERIOR CINGULATE CORTEX; GAMMA-AMINOBUTYRIC-ACID; LATE-LIFE DEPRESSION; TREATMENT ENHANCEMENT PROGRAM; RANDOMIZED CONTROLLED-TRIAL; SINGLE KETAMINE INFUSION AB Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is < 20 %. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-d-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants. C1 [Niciu, Mark J.; Ionescu, Dawn F.; Richards, Erica M.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, US Dept HHS,NIH, Bethesda, MD 20892 USA. RP Niciu, MJ (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, US Dept HHS,NIH, 10 Ctr Dr,Bldg 10-CRC,Room 7-5545, Bethesda, MD 20892 USA. EM mark.niciu@nih.gov RI Niciu, Mark/J-1766-2014; Ionescu, Dawn/K-5675-2015 OI Niciu, Mark/0000-0002-5612-3021; FU National Institute of Mental Health, National Institutes of Health; Department of Health and Human Services (IRP-NIMH-NIH-DHHS); NARSAD; Brain and Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services (IRP-NIMH-NIH-DHHS) and by a NARSAD Independent Investigator and the Brain and Behavior Mood Disorders Research Award (CAZ). NR 175 TC 23 Z9 25 U1 8 U2 31 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 EI 1435-1463 J9 J NEURAL TRANSM JI J. Neural Transm. PD AUG PY 2014 VL 121 IS 8 SI SI BP 907 EP 924 DI 10.1007/s00702-013-1130-x PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN6BU UT WOS:000340679500009 PM 24318540 ER PT J AU Alvey, NJ Pedley, A Rosenquist, KJ Massaro, JM O'Donnell, CJ Hoffmann, U Fox, CS AF Alvey, Nicholas J. Pedley, Alison Rosenquist, Klara J. Massaro, Joseph M. O'Donnell, Christopher J. Hoffmann, Udo Fox, Caroline S. TI Association of Fat Density With Subclinical Atherosclerosis SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; epidemiology; fat density; obesity ID CORONARY-ARTERY CALCIFICATION; ADIPOSE-TISSUE; INSULIN-RESISTANCE; RISK-FACTORS; VISCERAL ADIPOSITY; JAPANESE-AMERICANS; ABDOMINAL OBESITY; LIPID-METABOLISM; YOUNG-ADULTS; CELL-SIZE AB Background-Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis. Methods and Results-Participants were drawn from the Multi-Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable-adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age-/sex-specific cutoffs). Per 5-unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC. Conclusions-Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis. C1 [Alvey, Nicholas J.; Rosenquist, Klara J.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Alvey, Nicholas J.; Pedley, Alison; Rosenquist, Klara J.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rosenquist, Klara J.; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Rosenquist, Klara J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Rosenquist, Klara J.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res Cardiovasc Epidemiol & Human G, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU NHLBI's FHS [N01-HC-25195]; NHLBI Division of Intramural Research FX This research was, in part, supported by the NHLBI's FHS (Contract No. N01-HC-25195). Dr Fox is supported by the NHLBI Division of Intramural Research. NR 54 TC 11 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000788 DI 10.1161/JAHA.114.000788 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600012 ER PT J AU Kaplan, RC Aviles-Santa, L Parrinello, CM Hanna, DB Jung, M Castaneda, SF Hankinson, AL Isasi, CR Birnbaum-Weitzman, O Kim, RS Daviglus, ML Talavera, GA Schneiderman, N Cai, JW AF Kaplan, Robert C. Aviles-Santa, Larissa Parrinello, Christina M. Hanna, David B. Jung, Molly Castaneda, Sheila F. Hankinson, Arlene L. Isasi, Carmen R. Birnbaum-Weitzman, Orit Kim, Ryung S. Daviglus, Martha L. Talavera, Gregory A. Schneiderman, Neil Cai, Jianwen TI Body Mass Index, Sex, and Cardiovascular Disease Risk Factors Among Hispanic/Latino Adults: Hispanic Community Health Study/Study of Latinos SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE BMI; CVD risk factor; Hispanic/Latino; sex ID UNITED-STATES; MEXICAN-AMERICANS; OBESITY; PREVALENCE; MORTALITY; DESIGN; TRENDS AB Background-All major Hispanic/Latino groups in the United States have a high prevalence of obesity, which is often severe. Little is known about cardiovascular disease (CVD) risk factors among those at very high levels of body mass index (BMI). Methods and Results-Among US Hispanic men (N=6547) and women (N=9797), we described gradients across the range of BMI and age in CVD risk factors including hypertension, serum lipids, diabetes, and C-reactive protein. Sex differences in CVD risk factor prevalences were determined at each level of BMI, after adjustment for age and other demographic and socioeconomic variables. Among those with class II or III obesity (BMI >= 35 kg/m(2), 18% women and 12% men), prevalences of hypertension, diabetes, low high-density lipoprotein cholesterol level, and high C-reactive protein level approached or exceeded 40% during the fourth decade of life. While women had a higher prevalence of class III obesity (BMI >= 40 kg/m(2)) than did men (7% and 4%, respectively), within this highest BMI category there was a >50% greater relative prevalence of diabetes, hypertension, and hyperlipidemia in men versus women, while sex differences in prevalence of these CVD risk factors were approximate to 20% or less at other BMI levels. Conclusions-Elevated BMI is common in Hispanic/Latino adults and is associated with a considerable excess of CVD risk factors. At the highest BMI levels, CVD risk factors often emerge in the earliest decades of adulthood and they affect men more often than women. C1 [Kaplan, Robert C.; Parrinello, Christina M.; Hanna, David B.; Jung, Molly; Isasi, Carmen R.; Kim, Ryung S.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Parrinello, Christina M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Parrinello, Christina M.] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Hankinson, Arlene L.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Daviglus, Martha L.] Univ Illinois, Inst Minor Hlth Res, Chicago, IL 60680 USA. [Birnbaum-Weitzman, Orit; Schneiderman, Neil] Univ Miami, Dept Psychol, Miami, FL USA. [Castaneda, Sheila F.; Talavera, Gregory A.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Cai, Jianwen] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. RP Kaplan, RC (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave,Room 1315, Bronx, NY 10461 USA. EM robert.kaplan@einstein.yu.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, N01-HC65237]; National Institute on Minority Health and Health Disparities; National Institute of Deafness and Other Communications Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Office of Dietary Supplements FX The Hispanic Community Health Study/Study of Latinos was supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes/offices contribute to the HCHS/SOL baseline examination through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. NR 25 TC 7 Z9 7 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000923 DI 10.1161/JAHA.114.000923 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600027 ER PT J AU Kochukov, MY Balasubramanian, A Abramowitz, J Birnbaumer, L Marrelli, SP AF Kochukov, Mikhail Y. Balasubramanian, Adithya Abramowitz, Joel Birnbaumer, Lutz Marrelli, Sean P. TI Activation of Endothelial Transient Receptor Potential C3 Channel Is Required for Small Conductance Calcium-Activated Potassium Channel Activation and Sustained Endothelial Hyperpolarization and Vasodilation of Cerebral Artery SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cerebrovascular circulation; endothelium; endothelium-derived factors; ion channels; vasculature ID CA2+-ACTIVATED K+ CHANNELS; BRADYKININ-INDUCED VASODILATION; FACTOR-MEDIATED DILATIONS; TRPC3 CHANNELS; IKCA CHANNELS; RESISTANCE ARTERIES; PLASMA-MEMBRANE; COLLECTING DUCT; BLOOD-FLOW; IN-VIVO AB Background-Transient receptor potential C3 (TRPC3) has been demonstrated to be involved in the regulation of vascular tone through endothelial cell (EC) hyperpolarization and endothelium-dependent hyperpolarization-mediated vasodilation. However, the mechanism by which TRPC3 regulates these processes remains unresolved. We tested the hypothesis that endothelial receptor stimulation triggers rapid TRPC3 trafficking to the plasma membrane, where it provides the source of Ca2+ influx for small conductance calcium-activated K+ (SKCa) channel activation and sustained EC hyperpolarization. Methods and Results-Pressurized artery studies were performed with isolated mouse posterior cerebral artery. Treatment with a selective TRPC3 blocker (Pyr3) produced significant attenuation of endothelium-dependent hyperpolarization-mediated vasodilation and endothelial Ca2+ response (EC-specific Ca2+ biosensor) to intraluminal ATP. Pyr3 treatment also resulted in a reduced ATP-stimulated global Ca2+ and Ca2+ influx in primary cultures of cerebral endothelial cells. Patch-clamp studies with freshly isolated cerebral ECs demonstrated 2 components of EC hyperpolarization and K+ current activation in response to ATP. The early phase was dependent on intermediate conductance calcium-activated K+ channel activation, whereas the later sustained phase relied on SKCa channel activation. The SKCa channel-dependent phase was completely blocked with TRPC3 channel inhibition or in ECs of TRPC3 knockout mice and correlated with increased trafficking of TRPC3 (but not SKCa channel) to the plasma membrane. Conclusions-We propose that TRPC3 dynamically regulates SKCa channel activation through receptor-dependent trafficking to the plasma membrane, where it provides the source of Ca2+ influx for sustained SKCa channel activation, EC hyperpolarization, and endothelium-dependent hyperpolarization-mediated vasodilation. C1 [Kochukov, Mikhail Y.; Balasubramanian, Adithya; Marrelli, Sean P.] Baylor Coll Med, Dept Anesthesiol, Houston, TX 77030 USA. [Marrelli, Sean P.] Baylor Coll Med, Dept Physiol & Biophys, Houston, TX 77030 USA. [Marrelli, Sean P.] Baylor Coll Med, Grad Program Physiol, Houston, TX 77030 USA. [Abramowitz, Joel; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Div Intramural Res, Res Triangle Pk, NC USA. RP Marrelli, SP (reprint author), One Baylor Plaza,Suite 433D, Houston, TX 77030 USA. EM marrelli@bcm.edu RI Abramowitz, Joel/A-2620-2015 FU National Institutes of Health (NIH), National Heart, Lung, and Blood Institute [R01 HL088435]; NIH [Z01-ES101684] FX This study was supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute grant R01 HL088435 to Dr Marrelli and by the Intramural Research Program of the NIH (project Z01-ES101684 to Dr Birnbaumer). NR 60 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000913 DI 10.1161/JAHA.114.000913 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600025 ER PT J AU Sharma, RK Volpe, G Rosen, BD Ambale-Venkatesh, B Donekal, S Fernandes, V Wu, CO Carr, J Bluemke, DA Lima, JAC AF Sharma, Ravi K. Volpe, Gustavo Rosen, Boaz D. Ambale-Venkatesh, Bharat Donekal, Sirisha Fernandes, Veronica Wu, Colin O. Carr, Jeffrey Bluemke, David A. Lima, Joao A. C. TI Prognostic Implications of Left Ventricular Dyssynchrony for Major Adverse Cardiovascular Events in Asymptomatic Women and Men: The Multi-Ethnic Study of Atherosclerosis SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cardiac magnetic resonance imaging; cardiovascular events; left ventricular dyssynchrony; prognosis ID CARDIAC RESYNCHRONIZATION THERAPY; CONGESTIVE-HEART-FAILURE; MAGNETIC-RESONANCE; SYSTOLIC FUNCTION; MASS; GEOMETRY; HYPERTENSION; DISEASE; STRAIN; AGE AB Background-Left ventricular (LV) dyssynchrony is related to adverse outcomes in systolic heart failure, but its prognostic importance in asymptomatic population is not known. Our objective was to assess the prognostic implications of LV mechanical dyssynchrony in a large multiethnic population before the occurrence of global LV dysfunction. Methods and Results-A total of 1392 participants in the Multi-Ethnic Study of Atherosclerosis (MESA; mean age: 64.7 years; 46% were women) with cardiac magnetic resonance imaging at baseline were followed for a median duration of 8.3 years. Harmonic phase imaging analysis was used to derive systolic circumferential strain. Greater standard deviation of time to peak systolic strain (SD-TPS) indicates greater dyssynchrony. With SD-TPS as a continuous variable, Cox proportional hazards analysis was used to assess hazards ratio after adjusting for demographics, cardiovascular risk factors, LV mass-to-volume ratio, and ejection fraction. Using the 75th percentile of SD-TPS as a cutoff, Kaplan-Meier analysis was performed between 2 categorical groups for each gender. Higher values of dyssynchrony in women predicted major adverse cardiovascular events, defined as myocardial infarction, heart failure, stroke, and death (hazard ratio: 1.01 per 1-ms increment in SD-TPS, P=0.015), hard coronary events (hazard ratio: 1.05 per 1-ms increment in SD-TPS, P=0.026), and cerebrovascular events (hazard ratio: 1.03 per 1-ms increment in SD-TPS, P=0.013). In contrast, dyssynchrony in men was not predictive of events. Kaplan-Meier analyses in women revealed increased event occurrence in the higher dyssynchrony group, but this was not the case in men. Conclusions-In an asymptomatic cohort, greater LV dyssynchrony determined by cardiac magnetic resonance imaging predicts adverse cardiovascular outcome in women but not in men. C1 [Sharma, Ravi K.; Volpe, Gustavo; Rosen, Boaz D.; Ambale-Venkatesh, Bharat; Donekal, Sirisha; Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ Hosp, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. [Fernandes, Veronica] Mt Sinai Hosp, Dept Med, New York, NY 10029 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Carr, Jeffrey] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ Hosp, Dept Radiol, Baltimore, MD 21287 USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ Hosp, Blalock 524D,600 N Wolfe St, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU US National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC95168] FX This research was supported by contracts N01-HC-95159 through N01-HC95168 from the US National Heart, Lung, and Blood Institute. Bayer HealthCare provided Magnevist for the MESA cardiac magnetic resonance study. NR 29 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000975 DI 10.1161/JAHA.114.000975 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600037 ER PT J AU Waterworth, DM Li, L Scott, R Warren, L Gillson, C Aponte, J Sarov-Blat, L Sprecher, D Dupuis, J Reiner, A Psaty, BM Tracy, RP Lin, HH McPherson, R Chissoe, S Wareham, N Ehm, MG AF Waterworth, Dawn M. Li, Li Scott, Robert Warren, Liling Gillson, Christopher Aponte, Jennifer Sarov-Blat, Lea Sprecher, Dennis Dupuis, Josee Reiner, Alex Psaty, Bruce M. Tracy, Russell P. Lin, Honghuang McPherson, Ruth Chissoe, Stephanie Wareham, Nick Ehm, Margaret G. TI A Low-Frequency Variant in MAPK14 Provides Mechanistic Evidence of a Link With Myeloperoxidase: A Prognostic Cardiovascular Risk Marker SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE acute coronary syndrome; drug target gene; exome sequencing; myeloperoxidase; rare variation ID CORONARY-ARTERY-DISEASE; SERUM URIC-ACID; METABOLIC SYNDROME; EPIC-NORFOLK; DESIGN; ASSOCIATION; EPIDEMIOLOGY; INFLAMMATION; INDIVIDUALS; INJURY AB Background-Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits. Methods and Results-Investigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P = 2.3 x 10(-6)). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta-P = 0.003), leading to a meta-P value of 9.96 x 10(-7) in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population-based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case-control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P = 0.002) and risk of obesity (body mass index >= 30 kg/m(2), P = 0.004). Conclusions-As myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications. C1 [Waterworth, Dawn M.; Sarov-Blat, Lea; Sprecher, Dennis] GlaxoSmithKline, Philadelphia, PA USA. [Li, Li; Warren, Liling; Aponte, Jennifer; Chissoe, Stephanie; Ehm, Margaret G.] GlaxoSmithKline, Res Triangle Pk, NC USA. [Scott, Robert; Gillson, Christopher; Wareham, Nick] Univ Cambridge, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lin, Honghuang] Boston Univ, Framingham, MA USA. [Lin, Honghuang] NHLBI, Framingham Heart Study, Framingham, MA USA. [Dupuis, Josee] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Dupuis, Josee] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Dupuis, Josee] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Reiner, Alex] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Psaty, Bruce M.] Univ Vermont, Burlington, VT USA. [Tracy, Russell P.; Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [McPherson, Ruth] Univ Ottawa, Inst Heart, Lipoprotein & Atherosclerosis Res Grp, Ottawa, ON, Canada. RP Waterworth, DM (reprint author), 709 Swedeland Rd,UW2230, King Of Prussia, PA 19406 USA. EM Dawn.M.Waterworth@gsk.com RI Colaus, PsyColaus/K-6607-2013 FU GlaxoSmithKline; Swiss National Science Foundation [33CSCO-122661]; Faculty of Biology and Medicine of Lausanne; NHLBI [N01-HC-25195, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center FX The genotyping and analysis at the University of Cambridge was supported in part by funding from GlaxoSmithKline under a collaboration agreement. The GEMS study was sponsored in part by GlaxoSmithKline. The CoLaus study was supported by grants from GlaxoSmithKline, the Swiss National Science Foundation (Grant 33CSCO-122661), and the Faculty of Biology and Medicine of Lausanne. Framingham Heart Study (FHS) research was conducted in part using data and resources of the National Heart, Lung, and BloodInstitute (NHLBI) and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by NHLBI (contract no. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 33 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e001074 DI 10.1161/JAHA.114.001074 PG 19 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600051 ER PT J AU Vaughn, S Zumeta, R Wanzek, J Cook, B Klingner, JK AF Vaughn, Sharon Zumeta, Rebecca Wanzek, Jeanne Cook, Bryan Klingner, Janette K. TI Intensive Interventions for Students with Learning Disabilities in the RTI Era: Position Statement of the Division for Learning Disabilities Council for Exceptional Children SO LEARNING DISABILITIES RESEARCH & PRACTICE LA English DT Article AB Response to intervention (RTI) reforms have changed the structure of many aspects of special education for students with and at risk for learning disabilities (LD). Regardless of the structure of services, the core of special education for students with LD remains intensive instruction. Many students with LD are not being provided with appropriate instruction that consists of intensive, individualized interventions based on the best available evidence. To encourage schools and districts to examine the intensity, individualization, and research base of their instructional approaches for students with LD, the Council for Exceptional Children's Division for Learning Disabilities offers the following position statement: RTI reforms provide a structure for delivering instruction to students with and at risk for LD. Students with LD require appropriate instruction that includes intensive, individualized interventions based on the best available evidence to help them improve in their areas of need, successfully access the general education curriculum, and make progress toward standards. Special education for students with LD should not be either accommodations/adaptations OR intensive interventions, but both. We suggest that the design and implementation of these intensive, individualized, research-based interventions will likely require changes in how schooling is now provided to the vast majority of students with LD. C1 [Vaughn, Sharon] US DOE, Washington, DC 20585 USA. [Vaughn, Sharon] NICHHD, Inst Sci Educ, Bethesda, MD USA. [Zumeta, Rebecca] Amer Inst Res, Washington, DC USA. [Wanzek, Jeanne] Florida State Univ, Tallahassee, FL 32306 USA. [Cook, Bryan] Univ Hawaii, Honolulu, HI 96822 USA. [Klingner, Janette K.] Univ Colorado, Boulder, CO 80309 USA. RP Vaughn, S (reprint author), Univ Texas Austin, Austin, TX 78712 USA. EM srvaughn@austin.utexas.edu NR 1 TC 1 Z9 1 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0938-8982 EI 1540-5826 J9 LEARN DISABIL RES PR PD AUG PY 2014 VL 29 IS 3 BP 90 EP 92 DI 10.1111/ldrp.12039 PG 3 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA AN6CB UT WOS:000340680200002 ER PT J AU Manasanch, EE Korde, N Zingone, A Tageja, N de Larrea, CF Bhutani, M Wu, P Roschewski, M Landgren, O AF Manasanch, Elisabet E. Korde, Neha Zingone, Adriana Tageja, Nishant Fernandez de Larrea, Carlos Bhutani, Manisha Wu, Peter Roschewski, Mark Landgren, Ola TI The proteasome: mechanisms of biology and markers of activity and response to treatment in multiple myeloma SO LEUKEMIA & LYMPHOMA LA English DT Review DE Myeloma; cell cycle and apoptosis changes; prognostication ID DEPENDENT PROTEOLYTIC SYSTEM; CIRCULATING 20S PROTEASOME; UNFOLDED PROTEIN RESPONSE; NF-KAPPA-B; ENDOPLASMIC-RETICULUM; THERAPEUTIC TARGET; BORTEZOMIB RESISTANCE; CELL DIFFERENTIATION; INDUCTION THERAPY; PEPTIDE-TRANSPORT AB Since the early 1990s, the synthesis and subsequent clinical application of small molecule inhibitors of the ubiquitin proteasome pathway (UPP) has revolutionized the treatment and prognosis of multiple myeloma. In this review, we summarize important aspects of the biology of the UPP with a focus on its structure and key upstream/downstream regulatory components. We then review current knowledge of plasma cell sensitivity to proteasome inhibition and highlight new proteasome inhibitors that have recently entered clinical development. Lastly, we address the putative role of circulating proteasomes as a novel biomarker in multiple myeloma and provide guidance for future clinical trials using proteasome inhibitors. C1 [Manasanch, Elisabet E.; Korde, Neha; Zingone, Adriana; Tageja, Nishant; Bhutani, Manisha; Wu, Peter; Roschewski, Mark; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. [Fernandez de Larrea, Carlos] IDIBAPS, Hosp Clin, Dept Hematol, Amyloidosis & Myeloma Unit, Barcelona, Catalonia, Spain. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 10-Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov NR 90 TC 7 Z9 7 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2014 VL 55 IS 8 BP 1707 EP 1714 DI 10.3109/10428194.2013.828351 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA AM9TO UT WOS:000340224100005 PM 24261677 ER PT J AU Park, JW Jang, SH Park, DM Lim, NJ Deng, CX Kim, DY Green, JE Kim, HK AF Park, Jun Won Jang, Seok Hoon Park, Dong Min Lim, Na Jung Deng, Chuxia Kim, Dae Yong Green, Jeffrey E. Kim, Hark Kyun TI Cooperativity of E-cadherin and Smad4 Loss to Promote Diffuse-Type Gastric Adenocarcinoma and Metastasis SO MOLECULAR CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR ACTIVITY; CONDITIONAL MOUSE MODEL; BETA-CATENIN; COLORECTAL-CANCER; BREAST-CANCER; MICE LACKING; EXPRESSION; CARCINOMA; GENE; TUMORIGENESIS AB Loss of E-cadherin (CDH1), Smad4, and p53 has been shown to play an integral role in gastric, intestinal, and breast cancer formation. Compound conditional knockout mice for Smad4, p53, and E-cadherin were generated to define and compare the roles of these genes in gastric, intestinal, and breast cancer development by crossing with Pdx-1-Cre, Villin-Cre, and MMTV-Cre transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice than in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(+/+) mice, demonstrating that Cdh1 heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice developed gastric adenocarcinomas without E-cadherin expression. However, intestinal and mammary adenocarcinomas with the same genetic background retained E-cadherin expression and were phenotypically similar to mice with both wild-type Cdh1 alleles. Lung metastases were identified in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice, but not in the other genotypes. Nuclear beta-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of beta-catenin signaling by E-cadherin or Smad4 downregulates signaling pathways involved in metastases in Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) mice. Knockdown of beta-catenin significantly inhibited the migratory activity of Pdx-1-Cre; Smad4(F/F); Trp53(F/F); Cdh1(F/+) cell lines. Thus, loss of E-cadherin and Smad4 cooperates with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma. C1 [Park, Jun Won; Jang, Seok Hoon; Park, Dong Min; Lim, Na Jung; Kim, Hark Kyun] Natl Canc Ctr, Biomol Funct Res Branch, Goyang 410769, Gyeonggi, South Korea. [Park, Jun Won; Kim, Dae Yong] Seoul Natl Univ, Coll Vet Med, Seoul, South Korea. [Deng, Chuxia] NIDDK, Bethesda, MD USA. [Green, Jeffrey E.] NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kim, HK (reprint author), Natl Canc Ctr, Res Inst, Biomol Funct Res Branch, 323 Ilsanro, Goyang 410769, Gyeonggi, South Korea. EM daeyong@snu.ac.kr; jegreen@nih.gov; hkim@ncc.re.kr RI deng, chuxia/N-6713-2016 FU National Research Foundation of Korea; Converging Research Center Program - Korean Ministry of Education, Science and Technology [2013K000429]; National Cancer Center Grant [1210051]; NIH intramural program, Center for Cancer Research, National Cancer Institute, Bethesda, MD FX This work was supported by the Proteogenomic Research Program through the National Research Foundation of Korea and the Converging Research Center Program (2013K000429) funded by the Korean Ministry of Education, Science and Technology; by National Cancer Center Grant 1210051; and by the NIH intramural program, Center for Cancer Research, National Cancer Institute, Bethesda, MD. NR 41 TC 9 Z9 10 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD AUG PY 2014 VL 12 IS 8 BP 1088 EP 1099 DI 10.1158/1541-7786.MCR-14-0192-T PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AO2FG UT WOS:000341131000003 PM 24784840 ER PT J AU Horton, JK Stefanick, DF Prasad, R Gassman, NR Kedar, PS Wilson, SH AF Horton, Julie K. Stefanick, Donna F. Prasad, Rajendra Gassman, Natalie R. Kedar, Padmini S. Wilson, Samuel H. TI Base Excision Repair Defects Invoke Hypersensitivity to PARP Inhibition SO MOLECULAR CANCER RESEARCH LA English DT Article ID DNA-POLYMERASE-BETA; SINGLE-STRAND BREAKS; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; MUTANT-CELLS; XRCC1; CANCER; DAMAGE; REQUIREMENT; SENSITIVITY AB PARP-1 is important for the recognition of both endogenous and exogenous DNA damage, and binds to DNA strand breaks including intermediates of base excision repair (BER). Once DNA-bound, PARP-1 becomes catalytically activated synthesizing PAR polymers onto itself and other repair factors (PARylation). As a result, BER repair proteins such as XRCC1 and DNA polymerase beta (pol beta) are more efficiently and rapidly recruited to sites of DNA damage. In the presence of an inhibitor of PARP activity (PARPi), PARP-1 binds to sites of DNA damage, but PARylation is prevented. BER enzyme recruitment is hindered, but binding of PARP-1 to DNA is stabilized, impeding DNA repair and leading to double-strand DNA breaks (DSB). Deficiencies in pol beta(-/-) and Xrcc1(-/-) cells resulted in hypersensitivity to the PARP inhibitor 4-AN and reexpression of pol b or XRCC1, in these contexts, reversed the 4-AN hypersensitivity phenotype. BER deficiencies also showed evidence of replication defects that lead to DSB-induced apoptosis upon PARPi treatment. Finally, the clinically relevant PARP inhibitors olaparib and veliparib also exhibited hypersensitivity in both pol beta(-/-) and Xrcc1(-/-) BER-deficient cells. These results reveal heightened sensitivity to PARPi as a function of BER deficiency. (C) 2014 AACR. C1 [Horton, Julie K.; Stefanick, Donna F.; Prasad, Rajendra; Gassman, Natalie R.; Kedar, Padmini S.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov OI Gassman, Natalie/0000-0002-8488-2332 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES050159] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project number Z01 ES050159 to S.H. Wilson). NR 48 TC 16 Z9 16 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD AUG PY 2014 VL 12 IS 8 BP 1128 EP 1139 DI 10.1158/1541-7786.MCR-13-0502 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AO2FG UT WOS:000341131000006 PM 24770870 ER PT J AU Gorman, J Dave, K Norris, E Headlam, M Singh, T Chappel, K Bukreyev, A Buchholz, U Collins, P AF Gorman, Jeffrey Dave, Keyur Norris, Emma Headlam, Madeleine Singh, Toshna Chappel, Keith Bukreyev, Alexander Buchholz, Ursula Collins, Peter TI Comprehensive Proteomic Dissection of the Battle Between Human Respiratory Syncytial Virus and Host Cells SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Gorman, Jeffrey; Dave, Keyur; Norris, Emma; Headlam, Madeleine; Singh, Toshna] QIMR Berghofer Med Res Inst, Herston, Qld, Australia. [Chappel, Keith] Univ Queensland, Brisbane, Qld 4072, Australia. [Bukreyev, Alexander; Buchholz, Ursula; Collins, Peter] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2014 VL 13 IS 8 SU 1 MA C.3 BP S45 EP S45 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AN6QH UT WOS:000340720100067 ER PT J AU Mertins, P Clauser, KR Mani, DR Gillette, M Fenyo, D Wang, P Paulovich, A Ellis, M Carr, SA AF Mertins, Philipp Clauser, Karl R. Mani, D. R. Gillette, Michael Fenyo, David Wang, Pei Paulovich, Amanda Ellis, Matthew Carr, Steven A. CA CPTAC TI Proteogenomic Analysis of Human Breast Cancer Connects Genetic Alterations to Phosphorylation Networks SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Mertins, Philipp; Clauser, Karl R.; Mani, D. R.; Gillette, Michael; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Fenyo, David] NYU Langone Med Ctr, New York, NY USA. [Wang, Pei] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Paulovich, Amanda] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Ellis, Matthew] Washington Univ, St Louis, MO USA. [Carr, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2014 VL 13 IS 8 SU 1 MA 2.2 BP S18 EP S18 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AN6QH UT WOS:000340720100016 ER PT J AU Kraja, AT Chasman, DI North, KE Reiner, AP Yanek, LR Kilpelainen, TO Smith, JA Dehghan, A Dupuis, J Johnson, AD Feitosa, MF Tekola-Ayele, F Chu, AY Nolte, IM Dastani, Z Morris, A Pendergrass, SA Sun, YV Ritchie, MD Vaez, A Lin, HH Ligthart, S Marullo, L Rohde, R Shao, Y Ziegler, MA Im, HK Schnabel, RB Jorgensen, T Jorgensen, ME Hansen, T Pedersen, O Stolk, RP Snieder, H Hofman, A Uitterlinden, AG Franco, OH Ikram, MA Richards, JB Rotimi, C Wilson, JG Lange, L Ganesh, SK Nalls, M Rasmussen-Torvik, LJ Pankow, JS Coresh, J Tang, W Kao, WHL Boerwinkle, E Morrison, AC Ridker, PM Becker, DM Rotter, JI Kardia, SLR Loos, RJF Larson, MG Hsu, YH Province, MA Tracy, R Voight, BF Vaidya, D O'Donnell, CJ Benjamin, EJ Alizadeh, BZ Prokopenko, I Meigs, JB Borecki, IB AF Kraja, Aldi T. Chasman, Daniel I. North, Kari E. Reiner, Alexander P. Yanek, Lisa R. Kilpelainen, Tuomas O. Smith, Jennifer A. Dehghan, Abbas Dupuis, Josee Johnson, Andrew D. Feitosa, Mary F. Tekola-Ayele, Fasil Chu, Audrey Y. Nolte, Ilja M. Dastani, Zari Morris, Andrew Pendergrass, Sarah A. Sun, Yan V. Ritchie, Marylyn D. Vaez, Ahmad Lin, Honghuang Ligthart, Symen Marullo, Letizia Rohde, Rebecca Shao, Yarning Ziegler, Mark A. Im, Hae Kyung Schnabel, Renate B. Jorgensen, Torben Jorgensen, Marit E. Hansen, Torben Pedersen, Oluf Stolk, Ronald P. Snieder, Harold Hofman, Albert Uitterlinden, Andre G. Franco, Oscar H. Ikram, M. Arfan Richards, J. Brent Rotimi, Charles Wilson, James G. Lange, Leslie Ganesh, Santhi K. Nalls, Mike Rasmussen-Torvik, Laura J. Pankow, James S. Coresh, Josef Tang, Weihong Kao, W. H. Linda Boerwinkle, Eric Morrison, Alanna C. Ridker, Paul M. Becker, Diane M. Rotter, Jerome I. Kardia, Sharon L. R. Loos, Ruth J. F. Larson, Martin G. Hsu, Yi-Hsiang Province, Michael A. Tracy, Russell Voight, Benjamin F. Vaidya, Dhananjay O'Donnell, Christopher J. Benjamin, Emelia J. Alizadeh, Behrooz Z. Prokopenko, Inga Meigs, James B. Borecki, Ingrid B. CA Cross Consortia Pleiotropy CHARGE Genetic Invest Anthropomet GLGC MAGIC GBPG ADIPOGen Consortium WGHS HUFS TI Pleiotropic genes for metabolic syndrome and inflammation SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Metabolic syndrome; Inflammatory markers; Pleiotropic associations; Meta-analysis; Regulome ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-ARTERY-DISEASE; DIABETES SUSCEPTIBILITY LOCI; C-REACTIVE PROTEIN; NF-KAPPA-B; INSULIN-RESISTANCE; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; CIRCULATING ADIPONECTIN AB Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kraja, Aldi T.; Feitosa, Mary F.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Kraja, Aldi T.; Feitosa, Mary F.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA. [Chasman, Daniel I.; Chu, Audrey Y.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [North, Kari E.; Rohde, Rebecca; Shao, Yarning] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.; Rohde, Rebecca; Shao, Yarning] Univ N Carolina, Gillings Sch Global Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Yanek, Lisa R.; Becker, Diane M.; Vaidya, Dhananjay] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD USA. [Kilpelainen, Tuomas O.; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Smith, Jennifer A.; Kardia, Sharon L. R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Dehghan, Abbas; Ligthart, Symen; Hofman, Albert; Franco, Oscar H.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Tekola-Ayele, Fasil; Rotimi, Charles] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Dupuis, Josee; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Tekola-Ayele, Fasil; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Nolte, Ilja M.; Vaez, Ahmad; Stolk, Ronald P.; Snieder, Harold; Alizadeh, Behrooz Z.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Dastani, Zari; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Morris, Andrew; Marullo, Letizia] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England. [Pendergrass, Sarah A.] Penn State Univ, Eberly Coll Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Pendergrass, Sarah A.] Penn State Univ, Eberly Coll Sci, Huck Inst Life Sci, University Pk, PA 16802 USA. [Sun, Yan V.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Sun, Yan V.] Emory Univ, Sch Med, Dept Biomed Informat, Atlanta, GA 30322 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Marullo, Letizia] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy. [Ziegler, Mark A.] Washington Univ, Sch Med, MSIBS Program, Div Biostat, St Louis, MO USA. [Im, Hae Kyung] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Jorgensen, Torben] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Jorgensen, Marit E.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Richards, J. Brent] McGill Univ, Dept Med Human Genet Epidemiol & Biostat, Montreal, PQ H3A 2T5, Canada. [Richards, J. Brent] Kings Coll London, Dept Twin Res, London, England. [Wilson, James G.] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Lange, Leslie] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Nalls, Mike] Natl Inst Aging, Neurogenet Lab, Mol Genet Sect, NIH, Bethesda, MD USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL USA. [Boerwinkle, Eric; Morrison, Alanna C.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Coresh, Josef] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA. [Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Boerwinkle, Eric; Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Charles Bronfrnan Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Publ Hlth, Hebrew Senior Life Inst Aging Res, Harvard Med Sch & Mol & Integrat Physiol Sci, Boston, MA 02115 USA. [Tracy, Russell] Univ Vermont, Coll Med, Burlington, VT 05401 USA. [Voight, Benjamin F.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. [Voight, Benjamin F.] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol & Prevent Med Sect, Boston, MA 02118 USA. [Prokopenko, Inga] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Chasman, Daniel I.; Chu, Audrey Y.; Ridker, Paul M.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. RP Kraja, AT (reprint author), Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. EM aldi@wustl.edu; dchasman@research.bwh.harvard.edu; kari_north@unc.edu; apreiner@u.washington.edu; lryanek@jhmi.edu; tuomas.kilpelainen@sund.ku.dk; smjenn@umich.edu; a.dehghan@erasmusmc.nl; dupuis@bu.edu; johnsonad2@nhIbi.nih.gov; mfeitosa@wustl.edu; fasiLayele2@nih.gov; aychu@parmers.org; i.m.nolte@umcg.nl; zari.dastani@mail.mcgill.ca; andrew.morris@well.ox.ac.uk; sap29@psu.edu; yan.v.sun@emory.edu; marylyn.ritchie@psu.edu; a.vaez@umcg.nl; hhlin@bu.edu; sligthart@erasmusmc.nl; lety@well.ox.ac.uk; rohde@email.unc.edu; yaming_shao@unc.edu; MZiegler23@WUSTL.EDU; haky@uchicago.edu; schnabelr@gmx.de; tojo@glo.regionh.dk; maej@steno.dk; torben.hansen@sund.ku.dk; oluf@sund.ku.dk; r.p.stolk@umcg.nl; h.snieder@umcg.nl; a.hofman@erasmusmc.nl; a.g.uitterlinden@erasmusmc.nl; ofranco@erasmusmc.nl; m.a.ikram@erasmusmc.nl; brent.richards@mcgill.ca; rotimic@mail.nih.gov; jgwilson2@umc.edu; leslie_lange@med.unc.edu; sganesh@med.umich.edu; nallsm@mail.nih.gov; ljrtorvik@northwestem.edu; panko001@umn.edu; coresh@jhu.edu; tang0097@umn.edu; wkao@jhsph.edu; Eric.Boerwinkle@uth.tmc.edu; Alanna.CMorrison@uth.tmc.edu; pridker@partners.org; DBecker@6078aol.com; jrotter@labiomed.org; skardia@umich.edu; ruth.loos@mssm.edu; mlarson@bu.edu; YiHsiangHsu@hsl.harvard.edu; mprovince@wustl.edu; russell.tracy@med.uvm.edu; bvoight@upenn.edu; dvaidyal@jhmi.edu; odonnellc@nhIbinih.gov; emelia@bu.edu; b.z.alizadeh@umcg.nl; Lprokopenko@imperiaLac.uk; jmeigs@partners.org; iborecki@wustl.edu RI Prokopenko, Inga/H-3241-2014; Johnson, Andrew/G-6520-2013; Feitosa, Mary/K-8044-2012; OI Dehghan, Abbas/0000-0001-6403-016X; Tekola-Ayele, Fasil/0000-0003-4194-9370; Ikram, Mohammad Arfan/0000-0003-0372-8585; Lin, Honghuang/0000-0003-3043-3942; Benjamin, Emelia/0000-0003-4076-2336; Jorgensen, Torben/0000-0001-9453-2830; Vaidya, Dhananjay/0000-0002-7164-1601; Smith, Jennifer/0000-0002-3575-5468; Pankow, James/0000-0001-7076-483X; Prokopenko, Inga/0000-0003-1624-7457; Feitosa, Mary/0000-0002-0933-2410; Ziad Alizadeh, Behrooz/0000-0002-1415-8007 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100 012C, HL043851, HL080467]; University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]; University of Minnesota [N01-HC-48048]; Northwestern University [N01-HC-48049]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC-45204]; Wake Forest University [N01-HC-45205]; Harbor-UCLA Research and Education Institute [N01-HC-05187]; University of California, Irvine [N01-HC-45134, N01-HC-95100]; National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI [U01 HL72518]; NIH/National Institute of Nursing Research [NR0224103]; NIH/National Center for Research Resources [M01-RR000052]; National Heart, Lung and Blood Institute of the National Institutes of Health [HL054464, HL054457, HL054481, HL081331, HL087660]; NIDDK [1R01DK8925601]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine; National Institute for Diabetes and Digestive and Kidney Diseases [RO1 DK078616, K24 DK080140, 1RO1 HL64753, RO1 HL076784, 1RO1 G028321, 1RO1HL092577]; Danish Medical Research Council; Danish Centre for Health Technology Assessment; Novo Nordisk; Copenhagen County; Danish Heart Foundation; Danish Pharmaceutical Association; Augustinus Foundation; Ib Henriksen Foundation; Becket Foundation; Lundbeck Foundation; Novo Nordisk Foundation; Danish Ministry of Science, Technology and Innovation; Netherlands Organization of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organisation of Scientific Research NWO Investments [175.010, 2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; NWO [916.12.154]; EUR Fellowship; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; U01 HL108630; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN26 8201100001C, HHSN268201100002C, HHSN268201100003C, HHSN26 8201100004C, HHSN271201100004C]; Intramural Research Program of the NIH, National Institute on Aging [Z01-AG000932-06]; [R01DK075681]; [HL58625-01A1]; [HL59684]; [HL071025-01A1] FX The authors express their gratitude to large meta-GWAS Consortia and studies for contributing results in the XC-Pleiotropy. They are recognized as contributing studies in the coauthorship. In addition we acknowledge the followings studies for contributing correlation analyses:; ARIC:; The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100 012C). This work is also funded in part by R01DK075681 (K.E.N.).; The authors thank the staff and participants of the ARIC study for their important contributions.; CARDIA:; Coronary Artery Risk in Young Adults was supported by University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100).; GeneSTAR:; GeneSTAR was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) consortium as well as grants HL58625-01A1, HL59684, and HL071025-01A1, and a grant from the NIH/National Institute of Nursing Research (NR0224103). Additional support was provided by a grant from the NIH/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center.; GENOA:; Support for the Genetic Epidemiology Network of Arteriopathy was provided by the National Heart, Lung and Blood Institute of the National Institutes of Health (HL054464, HL054457, HL054481, HL081331, and HL087660). We would also like to thank the families that participated in the GENOA study.; FamHS:; This work was supported in part by NIDDK grant 1R01DK8925601 (I.B.B.).; FHS:; This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also supported by National Institute for Diabetes and Digestive and Kidney Diseases RO1 DK078616 and K24 DK080140 (J.B.M.), and 1RO1 HL64753, RO1 HL076784, 1RO1 AG028321, 1RO1HL092577 (E.J.B.).; INTER99:; The Inter99 Study was initiated by Torben Jorgensen, Knut Borch-Johnsen, Hans Ibsen and Troels F. Thomsen. The steering committee comprises Torben Jorgensen, Knut Borch-Johnsen and Charlotta Pisinger. The phenotyping was financially supported by grants from the Danish Medical Research Council, The Danish Centre for Health Technology Assessment, Novo Nordisk, Copenhagen County, The Danish Heart Foundation, The Danish Pharmaceutical Association, The Augustinus Foundation, The Ib Henriksen Foundation, and the Becket Foundation. The genetic research was supported by grants from the Lundbeck Foundation (www.lucamp.org) and the Novo Nordisk Foundation (metabol.ku.dk). This work is carried out as a part of the research program of the UNIK: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk). The UNIK project is supported by the Danish Ministry of Science, Technology and Innovation.; LifeLines:; The LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. The authors wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centers delivering data to LifeLines, and all the study participants.; RS:; The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam.; Support for genotyping was provided by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010. 2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. This work is supported also by NWO grant (veni, 916.12.154) and the EUR Fellowship (A.D.).; WGHS:; The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, and the Donald W. Reynolds Foundation, with collaborative scientific support and funding for genotyping provided by Amgen. This research was partially supported by U01 HL108630.; WHI:; The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN26 8201100001C, HHSN268201100002C, HHSN268201100003C, HHSN26 8201100004C, and HHSN271201100004C. A listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents% 20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf; Other:; This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, Z01-AG000932-06, (M.N.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster (http://biowultnih.gov) at the National Institutes of Health, Bethesda, MD (M.N.).; Guarantor's statement: Drs. Aldi T. Kraja and Ingrid B. Borecki are the guarantors of this work and, as such, had full access to all results produced for this study and take responsibility for the integrity of the results and of the accuracy of the analyses. Drs. Daniel I. Chasman, Kari E. North, Alexander P. Reiner, Lisa R. Yanek, Tuomas O. Kilpelainen, Jennifer A. Smith, Abbas Dehghan, Martin G. Larson, and Behrooz Z. Alizadeh are the guarantors of the individual studies, as such, had full access to all results produced by their corresponding study and take responsibility for the integrity of the results and of the accuracy of their results' analyses. NR 134 TC 32 Z9 32 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2014 VL 112 IS 4 BP 317 EP 338 DI 10.1016/j.ymgme.2014.04.007 PG 22 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AN1OU UT WOS:000340354000009 PM 24981077 ER PT J AU Houdayer, E Walthall, J Belluscio, BA Vorbach, S Singer, HS Hallett, M AF Houdayer, Elise Walthall, Jessica Belluscio, Beth A. Vorbach, Sherry Singer, Harvey S. Hallett, Mark TI Absent Movement-Related Cortical Potentials in Children With Primary Motor Stereotypies SO MOVEMENT DISORDERS LA English DT Article DE motor stereotypies; movement-related cortical potentials; EEG; motor control ID CONTINGENT NEGATIVE-VARIATION; COMPLEX STEREOTYPIES; PARKINSONS-DISEASE; HAND MOVEMENTS; L-DOPA; AMPHETAMINE; BEHAVIOR; RATS; STIMULATION; ACTIVATION AB The underlying pathophysiologic mechanism for complex motor stereotypies in children is unknown, with hypotheses ranging from an arousal to a motor control disorder. Movement-related cortical potentials (MRCPs), representing the activation of cerebral areas involved in the generation of movements, precede and accompany self-initiated voluntary movements. The goal of this study was to compare cerebral activity associated with stereotypies to that seen with voluntary movements in children with primary complex motor stereotypies. Electroencephalographic (EEG) activity synchronized with video recording was recorded in 10 children diagnosed with primary motor stereotypies and 7 controls. EEG activity related to stereotypies and self-paced arm movements were analyzed for presence or absence of early or late MRCP, a steep negativity beginning about 1 second before the onset of a voluntary movement. Early MRCPs preceded self-paced arm movements in 8 of 10 children with motor stereotypies and in 6 of 7 controls. Observed MRCPs did not differ between groups. No MRCP was identified before the appearance of a complex motor stereotypy. Unlike voluntary movements, stereotypies are not preceded by MRCPs. This indicates that premotor areas are likely not involved in the preparation of these complex movements and suggests that stereotypies are initiated by mechanisms different from voluntary movements. Further studies are required to determine the site of the motor control abnormality within cortico-striatal-thalamo-cortical pathways and to identify whether similar findings would be found in children with secondary stereotypies. (C) 2013 International Parkinson and Movement Disorder Society C1 [Houdayer, Elise; Walthall, Jessica; Belluscio, Beth A.; Vorbach, Sherry; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Houdayer, Elise] Ist Sci San Raffaele, Inst Expt Neurol INSPE, Expt Neurophysiol Unit, I-20132 Milan, Italy. [Belluscio, Beth A.] Meridian Med Technol Inc, Dept Res & Dev, Columbia, MD USA. [Singer, Harvey S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Singer, Harvey S.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 7D37,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU NINDS FX NINDS Intramural Research Program NR 50 TC 4 Z9 4 U1 0 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 AUG PY 2014 VL 29 IS 9 BP 1134 EP 1140 DI 10.1002/mds.25753 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AN4BJ UT WOS:000340532300010 PM 24259275 ER PT J AU Goldman, SM Kamel, F Ross, GW Jewell, SA Marras, C Hoppin, JA Umbach, DM Bhudhikanok, GS Meng, C Korell, M Comyns, K Hauser, RA Jankovic, J Factor, SA Bressman, S Lyons, KE Sandler, DP Langston, JW Tanner, CM AF Goldman, Samuel M. Kamel, Freya Ross, G. Webster Jewell, Sarah A. Marras, Connie Hoppin, Jane A. Umbach, David M. Bhudhikanok, Grace S. Meng, Cheryl Korell, Monica Comyns, Kathleen Hauser, Robert A. Jankovic, Joseph Factor, Stewart A. Bressman, Susan Lyons, Kelly E. Sandler, Dale P. Langston, J. William Tanner, Caroline M. TI Peptidoglycan Recognition Protein Genes and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; peptidoglycan; PGLYRP; microbiome; gut ID ALPHA-SYNUCLEIN; IMMUNE-RESPONSES; GUT MICROBIOTA; ASSOCIATION; INFLAMMATION; PATHOLOGY; SYSTEM; BRAIN; NEUROINFLAMMATION; NEURODEGENERATION AB Increased gut permeability, inflammation, and colonic alpha-synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case-control studies were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5' untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95% CI 0.4-0.9], CC OR 0.15 [95% CI 0.04-0.6]; log-additive P-trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD. (C) 2014 International Parkinson and Movement Disorder Society C1 [Goldman, Samuel M.; Tanner, Caroline M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Goldman, Samuel M.; Tanner, Caroline M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goldman, Samuel M.; Bhudhikanok, Grace S.; Meng, Cheryl; Korell, Monica; Comyns, Kathleen; Langston, J. William] Parkinsons Inst, Sunnyvale, CA USA. [Kamel, Freya; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Jewell, Sarah A.] German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany. [Marras, Connie] Univ Toronto, Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Hoppin, Jane A.] N Carolina State Univ, Raleigh, NC 27695 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Hauser, Robert A.] Univ S Florida, Tampa, FL USA. [Jankovic, Joseph] Baylor Coll Med, Houston, TX 77030 USA. [Factor, Stewart A.] Emory Univ, Sch Med, Atlanta, GA USA. [Bressman, Susan] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Lyons, Kelly E.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Goldman, SM (reprint author), San Francisco VA Med Ctr, 4150 Clement St,PADRECC 127P, San Francisco, CA 94121 USA. EM samuel.goldman@ucsf.edu OI Jewell, Sarah/0000-0002-9877-2599; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU NIH; National Institute of Environmental Health Sciences; NIEHS [Z01-ES044007, Z01-ES049030, R01-ES10803, U54 ES012077]; NCI [Z01-CP010119]; Michael J. Fox Foundation; Parkinson's Unity Walk FX This study was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, NIEHS (grants Z01-ES044007 and Z01-ES049030), NCI (grant Z01-CP010119), NIEHS grants R01-ES10803 and U54 ES012077, the Michael J. Fox Foundation, Parkinson's Unity Walk, and James and Sharron Clark. SEARCH was supported by an unrestricted grant from a group of current and former manufacturers of welding consumables awarded to The Parkinson's Institute. NR 59 TC 8 Z9 9 U1 6 U2 12 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 AUG PY 2014 VL 29 IS 9 BP 1171 EP 1180 DI 10.1002/mds.25895 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AN4BJ UT WOS:000340532300015 PM 24838182 ER PT J AU Eguether, T Ermolaeva, MA Zhao, Y Bonnet, MC Jain, A Pasparakis, M Courtois, G Tassin, AM AF Eguether, Thibaut Ermolaeva, Maria A. Zhao, Yongge Bonnet, Marion C. Jain, Ashish Pasparakis, Manolis Courtois, Gilles Tassin, Anne-Marie TI The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells SO NATURE COMMUNICATIONS LA English DT Article ID NF-KAPPA-B; PRIMARY CILIUM; CENTROSOMAL PROTEINS; MOTHER CENTRIOLE; SIGNALING CENTER; GOLGI-COMPLEX; MOTILE CILIA; CILIOGENESIS; DOMAIN; EB1 AB CYLD is a tumour suppressor gene mutated in familial cylindromatosis, a genetic disorder leading to the development of skin appendage tumours. It encodes a deubiquitinating enzyme that removes Lys63-or linear-linked ubiquitin chains. CYLD was shown to regulate cell proliferation, cell survival and inflammatory responses, through various signalling pathways. Here we show that CYLD localizes at centrosomes and basal bodies via interaction with the centrosomal protein CAP350 and demonstrate that CYLD must be both at the centrosome and catalytically active to promote ciliogenesis independently of NF-kB. In transgenic mice engineered to mimic the smallest truncation found in cylindromatosis patients, CYLD interaction with CAP350 is lost disrupting CYLD centrosome localization, which results in cilia formation defects due to impairment of basal body migration and docking. These results point to an undiscovered regulation of ciliogenesis by Lys63 ubiquitination and provide new perspectives regarding CYLD function that should be considered in the context of cylindromatosis. C1 [Eguether, Thibaut; Tassin, Anne-Marie] Inst Curie INSERM U759, F-91405 Orsay, France. [Eguether, Thibaut] Univ Paris 06, F-75005 Paris, France. [Ermolaeva, Maria A.; Bonnet, Marion C.; Pasparakis, Manolis] Univ Cologne, Inst Genet, Ctr Mol Med CMMC, D-50931 Cologne, Germany. [Ermolaeva, Maria A.; Bonnet, Marion C.; Pasparakis, Manolis] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. [Zhao, Yongge; Jain, Ashish] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Bonnet, Marion C.] Univ Rennes 1, Fac Pharm, IRSET INSERM UMR1085, Univ Europeenne Bretagne,Excellence Res Chair, F-35000 Rennes, France. [Courtois, Gilles] Univ Grenoble Alpes, F-38000 Grenoble, France. [Courtois, Gilles] CEA Grenoble, INSERM BGE Inst Rech Technol & Sci Vivant U1038, F-38054 Grenoble, France. [Tassin, Anne-Marie] CNRS, Ctr Genet Mol, UPR3404, F-91198 Gif Sur Yvette, France. RP Tassin, AM (reprint author), Inst Curie INSERM U759, Campus Univ,Bat 112, F-91405 Orsay, France. EM anne-marie.tassin@cgm.cnrs-gif.fr RI Bonnet, Marion/C-5612-2014; OI Pasparakis, Manolis/0000-0002-9870-0966 FU INSERM [U759]; Institut Curie [ARC3865]; French Ministry for Research; ARC [DOC20110603070] FX We thank A. Hoppeler-Lebel for performing the CAP350 immunoprecipitations. We thank W. Faigle for mass spectrometry analysis and J.L. Guerquin-Kern for performing the sectioning for transmission electron microscopy. We thank Y. Bourgeois, A. Thadal, V. Dangles-Marie, I. Grandjean for general mouse care. We also thank the Institut Pasteur PFMU for providing access to the scanning electron microscope. We thank Charlene Lasgi for performing the FACS analysis experiment and J.L. Ferrat for his advice. We thank M. Bornens, C. Janke, A. Fry, E. Nigg and G. Pereira for providing antibodies. We also thank S. Marco and I. Urbain for their preliminary observations of tracheas in transmission electron microscopy. Finally, we thank M. Bornens, R. Basto, C. Janke, H. Hehnly, A. Fleury-Aubusson, J. Beisson and P. Guichard for critical reading of the manuscript. This work was supported by the INSERM (U759) and Institut Curie, by grant ARC3865 to A.-M.T and T. E. was funded by the French Ministry for Research and ARC (DOC20110603070). NR 70 TC 8 Z9 10 U1 0 U2 8 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 PY 2014 VL 5 AR 4585 DI 10.1038/ncomms5585 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1DS UT WOS:000341052900012 PM 25134987 ER PT J AU Horikawa, I Fujita, K Jenkins, LMM Hiyoshi, Y Mondal, AM Vojtesek, B Lane, DP Appella, E Harris, CC AF Horikawa, Izumi Fujita, Kaori Jenkins, Lisa M. Miller Hiyoshi, Yukiharu Mondal, Abdul M. Vojtesek, Borivoj Lane, David P. Appella, Ettore Harris, Curtis C. TI Autophagic degradation of the inhibitory p53 isoform Delta 133p53 alpha as a regulatory mechanism for p53-mediated senescence SO NATURE COMMUNICATIONS LA English DT Article ID CHAPERONE-MEDIATED AUTOPHAGY; UBIQUITIN LIGASE CHIP; CELLULAR SENESCENCE; SELECTIVE AUTOPHAGY; DOWN-REGULATION; HUMAN-CELLS; DNA-DAMAGE; MUTANT P53; CANCER; TUMORIGENESIS AB Delta 133p53 alpha, a p53 isoform that can inhibit full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. Here we demonstrate that, unlike full-length p53, Delta 133p53 alpha is degraded by autophagy during replicative senescence. Pharmacological inhibition of autophagy restores Delta 133p53 alpha expression levels in replicatively senescent fibroblasts, without affecting full-length p53. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also restores Delta 133p53 alpha expression. The chaperone-associated E3 ubiquitin ligase STUB1, which is known to regulate autophagy, interacts with Delta 133p53 alpha and is downregulated at replicative senescence. The siRNA knockdown of STUB1 in proliferating, early-passage fibroblasts induces the autophagic degradation of Delta 133p53 alpha and thereby induces senescence. Upon replicative senescence or STUB1 knockdown, Delta 133p53 alpha is recruited to autophagosomes, consistent with its autophagic degradation. This study reveals that STUB1 is an endogenous regulator of Delta 133p53 alpha degradation and senescence, and identifies a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence. C1 [Horikawa, Izumi; Fujita, Kaori; Hiyoshi, Yukiharu; Mondal, Abdul M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jenkins, Lisa M. Miller; Appella, Ettore] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vojtesek, Borivoj] Masaryk Mem Canc Inst, Reg Ctr Appl & Mol Oncol, Brno 65653, Czech Republic. [Lane, David P.] Inst Mol & Cell Biol, Singapore 138673, Singapore. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI ASTAR, IMCB/E-2320-2012 FU Intramural Research Program of the NIH, NCI; European Regional Development Fund; State Budget of the Czech Republic [CZ.1.05/2.1.00/03.0101, P206/12/G151] FX We thank Dr Michael Tainsky for cells, Drs Noboru Mizushima and Ken-ichi Fujita for valuable advice, Dr Ana Robles for bioinformatics search and Dr Natalia von Muhlinen for critical reading of the manuscript. This research was supported in part by the Intramural Research Program of the NIH, NCI. B.V. was supported by the European Regional Development Fund and the State Budget of the Czech Republic RECAMO CZ.1.05/2.1.00/03.0101 and GACR P206/12/G151. NR 65 TC 11 Z9 11 U1 3 U2 12 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 PY 2014 VL 5 AR 4706 DI 10.1038/ncomms5706 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1NH UT WOS:000341078900004 PM 25144556 ER PT J AU Tsuzuki, S Matsumoto, H Furihata, S Ryuda, M Tanaka, H Sung, EJ Bird, GS Zhou, YX Shears, SB Hayakawa, Y AF Tsuzuki, Seiji Matsumoto, Hitoshi Furihata, Shunsuke Ryuda, Masasuke Tanaka, Hirotoshi Sung, Eui Jae Bird, Gary S. Zhou, Yixing Shears, Stephen B. Hayakawa, Yoichi TI Switching between humoral and cellular immune responses in Drosophila is guided by the cytokine GBP SO NATURE COMMUNICATIONS LA English DT Article ID GROWTH-BLOCKING PEPTIDE; PLASMATOCYTE-SPREADING PEPTIDE; INSECT CYTOKINE; PSEUDOPLUSIA-INCLUDENS; CELLS; MELANOGASTER; ACTIVATION; HEMOCYTES; RECEPTOR; DEFENSE AB Insects combat infection through carefully measured cellular (for example, phagocytosis) and humoral (for example, secretion of antimicrobial peptides (AMPs)) innate immune responses. Little is known concerning how these different defense mechanisms are coordinated. Here, we use insect plasmatocytes and hemocyte-like Drosophila S2 cells to characterize mechanisms of immunity that operate in the haemocoel. We demonstrate that a Drosophila cytokine, growth-blocking peptides (GBP), acts through the phospholipase C (PLC)/Ca2+ signalling cascade to mediate the secretion of Pvf, a ligand for platelet-derived growth factor-and vascular endothelial growth factor-receptor (Pvr) homologue. Activated Pvr recruits extracellular signal-regulated protein kinase to inhibit humoral immune responses, while stimulating cell 'spreading', an initiating event in cellular immunity. The double-stranded RNA (dsRNA)-targeted knockdown of either Pvf2 or Pvr inhibits GBP-mediated cell spreading and activates AMP expression. Conversely, Pvf2 overexpression enhances cell spreading but inhibits AMP expression. Thus, we describe mechanisms to initiate immune programs that are either humoral or cellular in nature, but not both; such immunophysiological polarization may minimize homeostatic imbalance during infection. C1 [Tsuzuki, Seiji; Matsumoto, Hitoshi; Furihata, Shunsuke; Ryuda, Masasuke; Tanaka, Hirotoshi; Hayakawa, Yoichi] Saga Univ, Dept Appl Biol Sci, Saga 8408502, Japan. [Sung, Eui Jae; Bird, Gary S.; Zhou, Yixing; Shears, Stephen B.] NIEHS, Inositol Signaling Sect, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Bird, Gary S.] NIEHS, Calcium Regulat Sect, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Hayakawa, Y (reprint author), Saga Univ, Dept Appl Biol Sci, Saga 8408502, Japan. EM hayakayo@cc.saga-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Intramural Research Program of the NIH/National Institute of Environmental Health Sciences FX We thank the Bloomington Indiana Stock Center for supplying some of the basic stocks for this study. We thank John Patrenka for assistance with the calcium assays. This work was supported by a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and also by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences. NR 43 TC 10 Z9 11 U1 0 U2 20 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 PY 2014 VL 5 AR 4628 DI 10.1038/ncomms5628 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1FE UT WOS:000341057000019 PM 25130174 ER PT J AU Wang, HS Burnett, T Kono, S Haiman, CA Iwasaki, M Wilkens, LR Loo, LWM Van den Berg, D Kolonel, LN Henderson, BE Keku, TO Sandler, RS Signorello, LB Blot, WJ Newcomb, PA Pande, M Amos, CI West, DW Bezieau, S Berndt, SI Zanke, BW Hsu, L Lindor, NM Haile, RW Hopper, JL Jenkins, MA Gallinger, S Casey, G Stenzel, SL Schumacher, FR Peters, U Gruber, SB Tsugane, S Stram, DO Le Marchand, L AF Wang, Hansong Burnett, Terrilea Kono, Suminori Haiman, Christopher A. Iwasaki, Motoki Wilkens, Lynne R. Loo, Lenora W. M. Van den Berg, David Kolonel, Laurence N. Henderson, Brian E. Keku, Temitope O. Sandler, Robert S. Signorello, Lisa B. Blot, William J. Newcomb, Polly A. Pande, Mala Amos, Christopher I. West, Dee W. Bezieau, Stephane Berndt, Sonja I. Zanke, Brent W. Hsu, Li Lindor, Noralane M. Haile, Robert W. Hopper, John L. Jenkins, Mark A. Gallinger, Steven Casey, Graham Stenzel, Stephanie L. Schumacher, Fredrick R. Peters, Ulrike Gruber, Stephen B. Tsugane, Shoichiro Stram, Daniel O. Le Marchand, Loic CA Genetics Epidemiology Colorectal C Colon Canc Family Registry CCFR Colorectal Transdisciplinary Study TI Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A SO NATURE COMMUNICATIONS LA English DT Article ID PANCREATIC-CANCER; PROSTATE-CANCER; METAANALYSIS; RISK; 8Q24 AB The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 x 10(-8)) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P = 1.4 x 10(-9)), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations. C1 [Wang, Hansong; Burnett, Terrilea; Wilkens, Lynne R.; Loo, Lenora W. M.; Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Kono, Suminori] Kyushu Univ, Grad Sch Med Sci, Dept Prevent Med, Fukuoka 8128581, Japan. [Haiman, Christopher A.; Van den Berg, David; Henderson, Brian E.; Casey, Graham; Stenzel, Stephanie L.; Schumacher, Fredrick R.; Gruber, Stephen B.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Van den Berg, David; Henderson, Brian E.; Casey, Graham; Stenzel, Stephanie L.; Schumacher, Fredrick R.; Gruber, Stephen B.; Stram, Daniel O.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Iwasaki, Motoki; Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Tokyo 1040045, Japan. [Keku, Temitope O.; Sandler, Robert S.] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27599 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Signorello, Lisa B.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Signorello, Lisa B.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Blot, William J.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol, Nashville, TN 37235 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Newcomb, Polly A.; Hsu, Li; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98124 USA. [Pande, Mala] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Res, Houston, TX 77030 USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Lebanon, NH 03755 USA. [West, Dee W.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Bezieau, Stephane] CHU Nantes, Serv Genet Med, F-44093 Nantes, France. [Berndt, Sonja I.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zanke, Brent W.] Univ Ottawa, Fac Med, Div Hematol, Ottawa, ON K1J 8M5, Canada. [Zanke, Brent W.] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON K1J 8M5, Canada. [Lindor, Noralane M.] Mayo Clin Arizona, Dept Hlth Sci Res, Scottsdale, AZ 85054 USA. [Haile, Robert W.] Stanford Canc Inst, Stanford, CA 94305 USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Gallinger, Steven] Canc Care Ontario, Toronto, ON M5G 2L3, Canada. RP Le Marchand, L (reprint author), Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. EM loic@cc.hawaii.edu RI Gallinger, Steven/E-4575-2013; Tsugane, Shocichiro/A-2424-2015; Hoffmeister, Michael/B-5745-2012; KURY, Sebastien/G-5971-2015; Bezieau, stephane/G-5621-2015; Jenkins, Mark/P-7803-2015; U-ID, Kyushu/C-5291-2016; Brenner, Hermann/B-4627-2017 OI Hoffmeister, Michael/0000-0002-8307-3197; KURY, Sebastien/0000-0001-5497-0465; Bezieau, stephane/0000-0003-0095-1319; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572 FU US National Institutes of Health (NIH) [1R01-CA126895, 1R01-CA126895-S1, 1R01-CA104132, 2U24-CA074806]; NIH [R01-CA132839, RC2-CA148085, R01-CA1326792, U01-HG004726, R37 CA54281, P01 CA033619, R01 CA63464, R01CA092447]; Department of Defense Breast Cancer Research Program, Era of Hope Scholar Award [W81XWH-08-1-0383]; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); MD Anderson University Cancer Fund; MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment; Center for Clinical and Translational Sciences of the University of Texas Health Science Center at Houston, NCI Cancer Center Support Grant [CA16672]; NCI [K07CA160753, R01 CA81488, P30 CA014089]; National Cancer Center Research and Development Fund; Ministry of Health, Labor and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology, Japan; National Cancer Institute as part of the GAME-ON consortium [U19 CA148107]; National Human Genome Research Institute at the NIH [T32 HG000040]; National Institute of Environmental Health Sciences at the NIH [T32 ES013678]; National Cancer Institute, NIH under RFA [CA-95-011]; National Cancer Institute [P30 CA014089, U01CA122839]; Australasian Colorectal Cancer Family Registry [U01 CA097735]; Seattle Colorectal Cancer Family Registry [U01 CA074794]; Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NHS by the NIH [R01 CA137178, P01 CA 087969, P50 CA 127003]; PHS by the NIH [R01 CA042182]; GL2 grant from the Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research from the Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH; NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH GEI [U01 HG 004438]; NIH. [U01 CA137088, R01 CA059045, R01 CA60987]; The NIH [U01 CA074783, P50 CA 127003, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, U01 HG004446, R01 CA076366, CA 087969, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; [U01 CA 093326]; [P50 CA 106991]; [R01 CA 66635] FX We thank Dr Daniel Mirel, who supervised the genotyping of samples while working at the Broad Institute, Boston, MA, and Xin Sheng, Loreall Pooler, Dr Gary K. Chen and Alex H. Stram at the University of Southern California (USC), and Lucy Shen and Mike Loomis at the University of Hawai'i Cancer Center for their technical assistance. The colorectal cancer GWAS among Japanese and African Americans was funded through US National Institutes of Health (NIH) grants 1R01-CA126895, 1R01-CA126895-S1, 1R01-CA104132 and 2U24-CA074806. Genotyping of the additional MEC controls was funded through NIH grants R01-CA132839, RC2-CA148085, R01-CA1326792 and U01-HG004726, as well as a Department of Defense Breast Cancer Research Program, Era of Hope Scholar Award to CAH (W81XWH-08-1-0383). MEC was funded through NIH grants R37 CA54281, P01 CA033619, and R01 CA63464. The SCCS was funded by NIH grant R01CA092447. Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry, which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. The UNC studies were supported by grants U01 CA 093326, P50 CA 106991 and R01 CA 66635. The MD Anderson data collection was supported in part by the MD Anderson University Cancer Fund, the MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment, the Center for Clinical and Translational Sciences of the University of Texas Health Science Center at Houston, NCI Cancer Center Support Grant (CA16672) and NCI grant (K07CA160753). JPHC was supported by the National Cancer Center Research and Development Fund (since 2011) and a Grant-in-Aid for Cancer Research (from 1989 to 2010) from the Ministry of Health, Labor and Welfare of Japan. The Fukuoka Colorectal Cancer Study was funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan. The CORECT Study is supported by the National Cancer Institute as part of the GAME-ON consortium (U19 CA148107) with additional support from NCI grants (R01 CA81488, P30 CA014089), the National Human Genome Research Institute at the NIH (T32 HG000040) and the National Institute of Environmental Health Sciences at the NIH (T32 ES013678). CCFR (http://www.coloncfr.; org/) is supported by the National Cancer Institute, NIH under RFA # CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and PIs of the Australasian Colorectal Cancer Family Registry (U01 CA097735), Familial Colorectal Neoplasia Collaborative Group (U01 CA074799) [USC], Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794) and the University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). The Colon CFR GWAS work was supported by a National Cancer Institute grant (U01CA122839 and P30 CA014089), Australasian Colorectal Cancer Family Registry (U01 CA097735), Seattle Colorectal Cancer Family Registry (U01 CA074794) and Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute, NIH or any of the collaborating centres in the CCFRs, nor does it mention trade names, commercial products or organizations imply endorsement by the US Government or the CCFR. GECCO was funded by NIH grants U01 CA137088 and R01 CA059045. ASTERISK was supported by a Hospital Clinical Research Program (PHRC) and by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). CR2&3 was funded by NIH grant R01 CA60987. DACHS was funded by the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1) and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS was funded by the NIH (R01 CA48998 to M. L. S.). HPFS is supported by the NIH (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), NHS by the NIH (R01 CA137178, P01 CA 087969 and P50 CA 127003) and PHS by the NIH (R01 CA042182). OFCCR was supported by the NIH through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see the CCFR section above. As a subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. Thomas J. Hudson and Brent W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO (http://dcp.cancer.gov/plco) was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS22, CGEMS pancreatic cancer scan (PanScan)23,24 and the Lung Cancer and Smoking study25. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2.; Funding for the Lung Cancer and Smoking study was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH was funded by the NIH grant R01 CA076366 to P. A. Newcomb. NHS was supported by NIH grants CA 087969, R01 137178, and P50 CA 127003. VITAL was funded by NIH grant K05 CA154337. The WHI program is funded by the National Heart, Lung, and Blood Institute, and NIH through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. The ASTERISK study are very grateful to Dr Bruno Buecher, without whom this project would not have existed and also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. The DACHS study thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik and Ursula Eilber at DACHS for excellent technical assistance. GECCO would like to thank all those at the Coordinating Center for helping to bring together the data and people that made this project possible. HPFS, NHS and PHS would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS and HPFS, and Haiyan Zhang who assisted in programming for the PHS. We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. The PLCO thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the PLCO Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and Drs Bill Kopp, Wen Shao, and staff, SAIC-Frederick, and most importantly the study participants for their contributions to making this study possible. The PMH study would like to thank the study participants and staff of the Hormones and Colon Cancer study. The WHI study thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20 Investigator%20Short%20List.pdf. NR 26 TC 22 Z9 22 U1 1 U2 10 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 PY 2014 VL 5 AR 4613 DI 10.1038/ncomms5613 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1FE UT WOS:000341057000004 PM 25105248 ER PT J AU Kauffman, EC Ricketts, CJ Rais-Bahrami, S Yang, YF Merino, MJ Bottaro, DP Srinivasan, R Linehan, WM AF Kauffman, Eric C. Ricketts, Christopher J. Rais-Bahrami, Soroush Yang, Youfeng Merino, Maria J. Bottaro, Donald P. Srinivasan, Ramaprasad Linehan, W. Marston TI Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers SO NATURE REVIEWS UROLOGY LA English DT Review ID MICROPHTHALMIA TRANSCRIPTION FACTOR; ACTIVATOR INHIBITOR-1 GENE; BETA-INDUCED TRANSCRIPTION; LOOP-HELIX PROTEIN; GROWTH-FACTOR-BETA; RENAL-CARCINOMA; SMAD PROTEINS; FACTOR FAMILY; CLINICOPATHOLOGICAL FEATURES; LYSOSOMAL BIOGENESIS AB Despite Ready two decades passing since the discovery of gene fusions involving TFE3 or TFEB in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis of these genes remain largely unclear. The recently published findings of The Cancer Genome Atlas Network reported that five of the 416 surveyed clear cell RCC tumours (1.2%) harboured SFPQ-TFE3 fusions, providing further evidence for the importance of gene fusions. A total of five TFE3 gene fusions (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3, and CLTC-TFE3) and one TFEB gene fusion (MALAT1-TFEB) have been identified in RCC tumours and characterized at the mRNA transcript level. A multitude of molecular pathways well-described in carcinogenesis are regulated in part by TFE3 or TFEB proteins, including activation of TGF beta and ETS transcription factors, E-cadherin expression, CD4OL-dependent lymphocyte activation, mTORC1 signalling, insulin-dependent metabolism regulation, folliculin signalling, and retinoblastoma-dependent cell cycle arrest. Determining which pathways are most important to RCC oncogenesis will be critical in discovering the most promising therapeutic targets for this disease. C1 [Kauffman, Eric C.; Ricketts, Christopher J.; Rais-Bahrami, Soroush; Yang, Youfeng; Bottaro, Donald P.; Srinivasan, Ramaprasad; Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10,CRC Room 1-5940, Bethesda, MD 20892 USA. EM wml@nih.gov RI di Ronza, Alberto/H-7674-2016; OI di Ronza, Alberto/0000-0002-9813-5143; Bottaro, Donald/0000-0002-5057-5334; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Intramural NIH HHS [Z01 BC011023-01]; NCI NIH HHS [Z01 BC011028-01, Z01 BC011038-01, Z01 BC011043-01] NR 114 TC 22 Z9 23 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD AUG PY 2014 VL 11 IS 8 BP 465 EP 475 DI 10.1038/nrurol.2014.162 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA AN4RR UT WOS:000340576700008 PM 25048860 ER PT J AU Laughlin, MR AF Laughlin, Maren R. TI Normal Roles for Dietary Fructose in Carbohydrate Metabolism SO NUTRIENTS LA English DT Article DE fructose; carbohydrate; metabolism; liver ID ORAL GLUCOSE-TOLERANCE; INSULIN-SECRETION; CONSCIOUS DOG; MUSCLE; RATS; INGESTION; EXERCISE; SUCROSE; HUMANS; CELLS AB Although there are many well-documented metabolic effects linked to the fructose component of a very high sugar diet, a healthy diet is also likely to contain appreciable fructose, even if confined to that found in fruits and vegetables. These normal levels of fructose are metabolized in specialized pathways that synergize with glucose at several metabolic steps. Glucose potentiates fructose absorption from the gut, while fructose catalyzes glucose uptake and storage in the liver. Fructose accelerates carbohydrate oxidation after a meal. In addition, emerging evidence suggests that fructose may also play a role in the secretion of insulin and GLP-1, and in the maturation of preadipocytes to increase fat storage capacity. Therefore, fructose undergoing its normal metabolism has the interesting property of potentiating the disposal of a dietary carbohydrate load through several routes. C1 NIDDK, Div Diabet Endocrine & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Laughlin, MR (reprint author), NIDDK, Div Diabet Endocrine & Metab Dis, NIH, 6707 Democracy Blvd,Room 787,MSC 5460, Bethesda, MD 20892 USA. EM maren.laughlin@nih.gov NR 53 TC 15 Z9 16 U1 7 U2 39 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD AUG PY 2014 VL 6 IS 8 BP 3117 EP 3129 DI 10.3390/nu6083117 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AO3AB UT WOS:000341199100009 PM 25100436 ER PT J AU Cook, GA Sullivan, P Holmes, C Goldstein, DS AF Cook, G. A. Sullivan, P. Holmes, C. Goldstein, D. S. TI Cardiac sympathetic denervation without Lewy bodies in a case of multiple system atrophy SO PARKINSONISM & RELATED DISORDERS LA English DT Letter DE MSA; Multiple system atrophy; Parkinson disease; Alpha-synuclein; DOPAL; Catecholaldehyde ID PARKINSONS-DISEASE C1 [Cook, G. A.; Sullivan, P.; Holmes, C.; Goldstein, D. S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Cook, GA (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM glen.cook@nih.gov FU Intramural NIH HHS [ZIA NS003034-09, ZIA NS003033-09, Z99 NS999999] NR 5 TC 2 Z9 2 U1 0 U2 1 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 AUG PY 2014 VL 20 IS 8 BP 926 EP 928 DI 10.1016/j.parkreldis.2014.04.003 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA AO0DF UT WOS:000340978600026 PM 24794098 ER PT J AU Zong, N Ping, PP Lau, E Choi, HJH Ng, DCM Meyer, D Fang, CY Li, HM Wang, D Zelaya, IM Yates, JR Lam, MPY AF Zong, Nobel Ping, Peipei Lau, Edward Choi, Howard J. H. Ng, Dominic C. M. Meyer, David Fang, Caiyun Li, Haomin Wang, Ding Zelaya, Ivette M. Yates, John R., III Lam, Maggie P. Y. TI Lysine ubiquitination and acetylation of human cardiac 20S proteasomes SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Acetylation; 20S proteasome; PTM; Spectral library; Ubiquitination ID MITOCHONDRIAL PROTEIN-PHOSPHORYLATION; MASS-SPECTROMETRY; QUANTITATIVE-ANALYSIS; PROTEOMICS; SUBSTRATE; REVEALS; MURINE AB Purpose: Altered proteasome functions are associated with multiple cardiomyopathies. While the proteasome targets polyubiquitinated proteins for destruction, it itself is modifiable by ubiquitination. We aim to identify the exact ubiquitination sites on cardiac proteasomes and examine whether they are also subject to acetylations. Experimental design: Assembled cardiac 20S proteasome complexes were purified from five human hearts with ischemic cardiomyopathy, then analyzed by high-resolution MS to identify ubiquitination and acetylation sites. We developed a library search strategy that may be used to complement database search in identifying PTM in different samples. Results: We identified 63 ubiquitinated lysines from intact human cardiac 20S proteasomes. In parallel, 65 acetylated residues were also discovered, 39 of which shared with ubiquitination sites. Conclusion and clinical relevance: This is the most comprehensive characterization of cardiac proteasome ubiquitination to date. There are significant overlaps between the discovered ubiquitination and acetylation sites, permitting potential crosstalk in regulating proteasome functions. The information presented here will aid future therapeutic strategies aimed at regulating the functions of cardiac proteasomes. C1 [Zong, Nobel; Ping, Peipei; Lau, Edward; Choi, Howard J. H.; Ng, Dominic C. M.; Meyer, David; Fang, Caiyun; Li, Haomin; Wang, Ding; Zelaya, Ivette M.; Lam, Maggie P. Y.] Univ Calif Los Angeles, NHLBI Prote Ctr, Los Angeles, CA 90095 USA. [Zong, Nobel; Ping, Peipei; Lau, Edward; Wang, Ding; Lam, Maggie P. Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Zong, Nobel; Ping, Peipei; Lau, Edward; Wang, Ding; Lam, Maggie P. Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Cardiol, Los Angeles, CA 90095 USA. [Yates, John R., III] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, 675 Charles E Young Dr,MRL Bldg 1-619, Los Angeles, CA 90095 USA. EM pping@mednet.ucla.edu OI Lau, Edward/0000-0001-9083-5922; Ping, Peipei/0000-0003-3583-3881 FU NIH [HL-R37-63901, HHSN268201000035C]; Laubisch endowment; AHA [13POST14700031, 12PRE11610024] FX This work was supported by the NIH awards HL-R37-63901 and HHSN268201000035C, and the Laubisch endowment to P. Ping; AHA fellowships 13POST14700031 to M. P. Lam; 12PRE11610024 to E. Lau. NR 22 TC 7 Z9 7 U1 0 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD AUG PY 2014 VL 8 IS 7-8 SI SI BP 590 EP 594 DI 10.1002/prca.201400029 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4YJ UT WOS:000340595600013 PM 24957502 ER PT J AU Wang, D Liem, DA Lau, E Ng, DCM Bleakley, BJ Cadeiras, M Deng, MC Lam, MPY Ping, PP AF Wang, Ding Liem, David A. Lau, Edward Ng, Dominic C. M. Bleakley, Brian J. Cadeiras, Martin Deng, Mario C. Lam, Maggie P. Y. Ping, Peipei TI Characterization of human plasma proteome dynamics using deuterium oxide SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Deuterium oxide; Heavy water; Plasma proteome; Protein dynamics; Protein turnover ID LIQUID-CHROMATOGRAPHY; STABLE-ISOTOPES; METABOLISM; TURNOVER; KINETICS; PHASE; CELLS AB Purpose: High-throughput quantification of human protein turnover via in vivo administration of deuterium oxide ((H2O)-H-2) is a powerful new approach to examine potential disease mechanisms. Its immediate clinical translation is contingent upon characterizations of the safety and hemodynamic effects of in vivo administration of (H2O)-H-2 to human subjects. Experimental design: We recruited ten healthy human subjects with a broad demographic variety to evaluate the safety, feasibility, efficacy, and reproducibility of (H2O)-H-2 intake for studying protein dynamics. We designed a protocol where each subject orally consumed weight-adjusted doses of 70% (H2O)-H-2 daily for 14 days to enrich body water and proteins with deuterium. Plasma proteome dynamics was measured using a high-resolution MS method we recently developed. Results: This protocol was successfully applied in ten human subjects to characterize the endogenous turnover rates of 542 human plasma proteins, the largest such human dataset to-date. Throughout the study, we did not detect physiological effects or signs of discomfort from (H2O)-H-2 consumption. Conclusions and clinical relevance: Our investigation supports the utility of a (H2O)-H-2 intake protocol that is safe, accessible, and effective for clinical investigations of large-scale human protein turnover dynamics. This workflow shows promising clinical translational value for examining plasma protein dynamics in human diseases. C1 [Wang, Ding; Liem, David A.; Lau, Edward; Ng, Dominic C. M.; Cadeiras, Martin; Deng, Mario C.; Lam, Maggie P. Y.; Ping, Peipei] Univ Calif Los Angeles, NHLBI Prote Ctr, Los Angeles, CA 90095 USA. [Wang, Ding; Liem, David A.; Lau, Edward; Ng, Dominic C. M.; Bleakley, Brian J.; Lam, Maggie P. Y.; Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Liem, David A.; Cadeiras, Martin; Deng, Mario C.; Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, 675 Charles E Young Dr,MRL Bldg 1-619, Los Angeles, CA 90095 USA. EM pping@mednet.ucla.edu OI Lau, Edward/0000-0001-9083-5922; Ping, Peipei/0000-0003-3583-3881; Bleakley, Brian/0000-0002-9930-2169 FU NIH [HL-R37-63901, HHSN268201000035C]; Laubisch endowment; AHA [13POST14700031, 12PRE11610024] FX This work was supported by the NIH awards HL-R37-63901 and HHSN268201000035C, and the Laubisch endowment to P. Ping; AHA fellowships 13POST14700031 to M. P. Lam and 12PRE11610024 to E. Lau. NR 33 TC 9 Z9 9 U1 1 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD AUG PY 2014 VL 8 IS 7-8 SI SI BP 610 EP 619 DI 10.1002/prca.201400038 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4YJ UT WOS:000340595600016 PM 24946186 ER PT J AU Ferguson, SA Law, CD Kissling, GE AF Ferguson, Sherry A. Law, Charles Delbert Kissling, Grace E. TI Developmental Treatment with Ethinyl Estradiol, but Not Bisphenol A, Causes Alterations in Sexually Dimorphic Behaviors in Male and Female Sprague Dawley Rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE bisphenol A; ethinyl estradiol; developmental; behavior; estrous cycle; puberty ID LORDOSIS REFLEX INTENSITY; ESTROGEN-RECEPTOR-ALPHA; SOCIAL PLAY-BEHAVIOR; LACTATIONAL EXPOSURE; IN-UTERO; CIRCADIAN-RHYTHMS; REPRODUCTIVE DEVELOPMENT; INDIVIDUAL-DIFFERENCES; ENDOCRINE DISRUPTION; OVARIECTOMIZED RATS AB The developing central nervous system may be particularly sensitive to bisphenol A (BPA)-induced alterations. Here, pregnant Sprague Dawley rats (n = 11-12/group) were gavaged daily with vehicle, 2.5 or 25.0 mu g/kg BPA, or 5.0 or 10.0 mu g/kg ethinyl estradiol (EE2) on gestational days 6-21. The BPA doses were selected to be below the no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day. On postnatal days 1-21, all offspring/litter were orally treated with the same dose. A naive control group was not gavaged. Body weight, pubertal age, estrous cyclicity, and adult serum hormone levels were measured. Adolescent play, running wheel activity, flavored solution intake, female sex behavior, and manually elicited lordosis were assessed. No significant differences existed between the vehicle and naive control groups. Vehicle controls exhibited significant sexual dimorphism for most behaviors, indicating these evaluations were sensitive to sex differences. However, only EE2 treatment caused significant effects. Relative to female controls, EE2-treated females were heavier, exhibited delayed vaginal opening, aberrant estrous cyclicity, increased play behavior, decreased running wheel activity, and increased aggression toward the stimulus male during sexual behavior assessments. Relative to male controls, EE2-treatedmales were older at testes descent and preputial separation and had lower testosterone levels. These results suggest EE2-induced masculinization/defeminization of females and are consistent with increased volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) at weaning in female siblings of these subjects (He, Z., Paule, M. G. and Ferguson, S. A. (2012) Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. Neurotoxicol. Teratol. 34, 331-337). Although EE2 treatment caused pubertal delays and decreased testosterone levels in males, their behaviors were within the range of controlmales. Conversely, BPA treatment did not alter anymeasured endpoint. Similar to our previous reports (Ferguson, S. A., Law, C. D. Jr and Abshire, J. S. (2011) Developmental treatment with bisphenolAor ethinyl estradiol causes few alterations on early preweaning measures. Toxicol. Sci. 124, 149-160; Ferguson, S. A., Law, C. D. and Abshire, J. S. (2012) Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. Neurotoxicol. Teratol. 34, 598-606), the BPA doses and design used here produced few alterations. C1 [Ferguson, Sherry A.; Law, Charles Delbert] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Ferguson, SA (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, HFT 132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM sherry.ferguson@fda.hhs.gov FU National Center for Toxicological Research/Food and Drug Administration [P00706]; National Institutes of Health [Z01ES45003] FX National Center for Toxicological Research/Food and Drug Administration (Protocol no. P00706 to S.A.F.); National Institutes of Health (Project no. Z01ES45003 to G.E.K., in part). NR 94 TC 13 Z9 14 U1 5 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2014 VL 140 IS 2 BP 374 EP 392 DI 10.1093/toxsci/kfu077 PG 19 WC Toxicology SC Toxicology GA AN6DL UT WOS:000340684100012 PM 24798382 ER PT J AU Furr, JR Lambright, CS Wilson, VS Foster, PM Gray, LE AF Furr, Johnathan R. Lambright, Christy S. Wilson, Vickie S. Foster, Paul M. Gray, Leon E., Jr. TI A Short-term In Vivo Screen Using Fetal Testosterone Production, a Key Event in the Phthalate Adverse Outcome Pathway, to Predict Disruption of Sexual Differentiation SO TOXICOLOGICAL SCIENCES LA English DT Article DE Phthalate Syndrome; Fetal endocrine biomarkers; Phthalate adverse outcome pathway; testosterone production; fetal rat testis ID N-BUTYL PHTHALATE; SPRAGUE-DAWLEY RAT; ANDROGEN-RECEPTOR ANTAGONIST; INDUCED TESTICULAR ATROPHY; REPRODUCTIVE DEVELOPMENT; DEVELOPMENTAL TOXICITY; DIISOBUTYL PHTHALATE; GENE-EXPRESSION; DIETHYLHEXYL PHTHALATE; DI(N-BUTYL) PHTHALATE AB This study was designed to develop and validate a short-term in vivo protocol termed the Fetal Phthalate Screen (FPS) to detect phthalate esters (PEs) and other chemicals that disrupt fetal testosterone synthesis and testis gene expression in rats. We propose that the FPS can be used to screen chemicals that produce adverse developmental outcomes via disruption of the androgen synthesis pathway more rapidly and efficiently, and with fewer animals than a postnatal one-generation study. Pregnant rats were dosed from gestational day (GD) 14 to 18 at one dose level with one of 27 chemicals including PEs, PE alternatives, pesticides known to inhibit steroidogenesis, an estrogen and a potent PPAR alpha agonist and ex vivo testis testosterone production (T Prod) was measured on GD 18. We also included some chemicals with "unknown" activity including DMEP, DHeP, DHEH, DPHCH, DAP, TOTM, tetrabromodiethyl hexyl phthalate (BrDEHP), and a relatively potent environmental estrogen BPAF. Dose-response studies also were conducted with this protocol with 11 of the above chemicals to determine their relative potencies. CD-1 mice also were exposed to varying dose levels of DPeP from GD 13 to 17 to determine if DPeP reduced T Prod in this species since there is a discrepancy among the results of in utero studies of PEs in mice. Compared to the known male reproductive effects of the PEs in rats the FPS correctly identified all known "positives" and "negatives" tested. Seven of eight "unknowns" tested were "negatives", they did not reduce T Prod, whereas DAP produced an "equivocal" response. Finally, a dose-response study with DPeP in CD-1 mice revealed that fetal T Prod can be inhibited by exposure to a PE in utero in this species, but at a higher dose level than required in rats. Key words. Phthalate Syndrome, Fetal endocrine biomarkers, Phthalate adverse outcome pathway, testosterone production, fetal rat testis. C1 [Furr, Johnathan R.; Lambright, Christy S.; Wilson, Vickie S.; Gray, Leon E., Jr.] US EPA, Reprod Toxicol Branch, TAD, NHEERL,ORD, Res Triangle Pk, NC 27711 USA. [Foster, Paul M.] NIEHS, Natl Toxicol Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Gray, LE (reprint author), Mail Code B105-04,109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM gray.ear@epa.gov OI Wilson, Vickie/0000-0003-1661-8481 FU National Institute of Environmental Health Sciences, National Institutes of Health; National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); NTP/NIEHS IA [RW7592285501-1] FX Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (in part); National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); NTP/NIEHS IA (RW7592285501-1). NR 81 TC 16 Z9 16 U1 2 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2014 VL 140 IS 2 BP 403 EP 424 DI 10.1093/toxsci/kfu081 PG 22 WC Toxicology SC Toxicology GA AN6DL UT WOS:000340684100014 PM 24798384 ER PT J AU Glass, RI Razak, MH Said, M AF Glass, Roger I. Razak, Myat Htoo Said, Maria TI The Importance of Research in the MEPI Program: Perspectives From the National Institutes of Health SO ACADEMIC MEDICINE LA English DT Editorial Material AB The Medical Education Partnership Initiative (MEPI), which aims to strengthen and transform education in medicine and the health sciences in Africa, has placed special emphasis on including research as part of new curricula. The great progress achieved against HIV/AIDS globally has been based in part on major research conducted by African investigators working in African institutions at African field sites in collaboration with international partners. This experience demonstrates the key role of academic institutions in generating knowledge while training the next generation of health professionals. Research is a key driver of innovation in the health sciences, and it can spur global collaborations, build substantial financial support, empower scientific leadership, and promote economic development. Through MEPI, young investigators are becoming engaged in research training early in their careers with projects that develop research skills to help them better understand how to evaluate and integrate new evidence into policy and practice, advance the science of health within their countries, and strengthen the academic institutions in which they work. Research training is an essential component of MEPI and should endure long after the program ends. It may help build a critical mass of researchers as well as a cadre of health professionals, teachers, and leaders who will be better equipped to embrace the continually changing panorama of advances in the health sciences. C1 [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Glass, Roger I.] NIH, Bethesda, MD 20892 USA. [Razak, Myat Htoo; Said, Maria] NIH, Div Int Training & Res, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. EM Glassr@mail.nih.gov FU National Institutes of Health (NIH); Common Fund; Office of AIDS Research; Office of Research on Women's Health; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute; National Cancer Institute; National Human Genome Research Institute FX National Institutes of Health (NIH) support for the Medical Education Partnership Initiative comes from NIH Director Dr. Francis Collins and his offices (Common Fund, Office of AIDS Research, and Office of Research on Women's Health) and five NIH Institutes (National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute; National Cancer Institute; and National Human Genome Research Institute). NR 2 TC 5 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2014 VL 89 IS 8 SU S BP S9 EP S10 DI 10.1097/ACM.0000000000000351 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AN0QX UT WOS:000340290200005 PM 25072589 ER PT J AU Wang, LQ Wang, XY Bhirde, A Cao, JB Zeng, Y Huang, XL Sun, YP Liu, G Chen, XY AF Wang, Liqin Wang, Xiaoyong Bhirde, Ashwinkumar Cao, Jianbo Zeng, Yun Huang, Xinglu Sun, Yaping Liu, Gang Chen, Xiaoyuan TI Carbon-Dot-Based Two-Photon Visible Nanocarriers for Safe and Highly Efficient Delivery of siRNA and DNA SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID NONVIRAL GENE DELIVERY; COATED QUANTUM DOTS; IN-VIVO; INTRACELLULAR TRAFFICKING; NANOPARTICLES; TRANSFECTION; NANOTUBES; CELLS; NANOTECHNOLOGY; NANOCLUSTERS C1 [Wang, Liqin; Wang, Xiaoyong; Cao, Jianbo; Zeng, Yun; Liu, Gang] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Xiamen 361102, Peoples R China. [Wang, Liqin; Wang, Xiaoyong; Cao, Jianbo; Zeng, Yun; Liu, Gang] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361102, Peoples R China. [Bhirde, Ashwinkumar; Huang, Xinglu; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Sun, Yaping] Clemson Univ, Dept Chem, Clemson, SC 29634 USA. [Sun, Yaping] Clemson Univ, Lab Emerging Mat & Technol, Clemson, SC 29634 USA. RP Liu, G (reprint author), Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Xiamen 361102, Peoples R China. EM gangliu.cmitm@xmu.edu.cn; shawn.chen@nih.gov FU Major State Basic Research Development Program of China (973 Program) [2013CB733802, 2014CB744503]; National Natural Science Foundation of China (NSFC) [81101101, 81371596, 51273165]; Chinese Ministry of Education [212149]; Fundamental Research Funds for the Central Universities, China [2013121039]; Program for New Century Excellent Talents in University [NCET-13-0502]; National Institute of Biomedical Imaging and Bioengineering FX L.W. and X.W. contributed equally to this work. This work was supported by the Major State Basic Research Development Program of China (973 Program) (Grant Nos. 2013CB733802 and 2014CB744503), the National Natural Science Foundation of China (NSFC) (Grant Nos. 81101101, 81371596, and 51273165), the Key Project of Chinese Ministry of Education (Grant No. 212149), the Fundamental Research Funds for the Central Universities, China (Grant No. 2013121039), the Program for New Century Excellent Talents in University (NCET-13-0502), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering. NR 46 TC 22 Z9 22 U1 9 U2 115 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD AUG PY 2014 VL 3 IS 8 SI SI BP 1203 EP 1209 DI 10.1002/adhm.201300611 PG 7 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA AN4IG UT WOS:000340550500008 PM 24692418 ER PT J AU Wang, Z Yue, XY Wang, Y Qian, CQ Huang, P Lizak, M Niu, G Wang, F Rong, PF Kiesewetter, DO Ma, Y Chen, XY AF Wang, Zhe Yue, Xuyi Wang, Yu Qian, Chunqi Huang, Peng Lizak, Marty Niu, Gang Wang, Fu Rong, Pengfei Kiesewetter, Dale O. Ma, Ying Chen, Xiaoyuan TI A Symmetrical Fluorous Dendron-Cyanine Dye-Conjugated Bimodal Nanoprobe for Quantitative F-19 MRI and NIR Fluorescence Bioimaging SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID MAGNETIC NANOPARTICLES; CELLS; TRACKING; DESIGN; BIODISTRIBUTION; CONTRAST; SURVIVAL AB F-19 MRI and optical imaging are two powerful noninvasive molecular imaging modalities in biomedical applications. F-19 MRI has great potential for high resolution in vivo imaging, while fluorescent probes enable ultracontrast cellular/tissue imaging with high accuracy and sensitivity. A bimodal nanoprobe is developed, integrating the merits of F-19 MRI and fluorescence imaging into a single synthetic molecule, which is further engineered into nanoprobe, by addressing shortcomings of conventional contrast agents to explore the quantitative F-19 MRI and fluorescence imaging and cell tracking. Results show that this bimodal imaging nanoprobe presents high correlation of F-19 MR signal and NIR fluorescence intensity in vitro and in vivo. Additionally, this nanoprobe enables quantitative F-19 MR analysis, confirmed by a complementary fluorescence analysis. This unique feature can hardly be obtained by traditional F-19 MRI contrast agents. It is envisioned that this nanoprobe can hold great potential for quantitative and sensitive multi-modal molecular imaging. C1 [Wang, Zhe; Yue, Xuyi; Wang, Yu; Huang, Peng; Niu, Gang; Wang, Fu; Rong, Pengfei; Kiesewetter, Dale O.; Ma, Ying; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Yue, Xuyi] Xiamen Univ, Ctr Mol Imaging & Translat Med, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Xiamen 361005, Peoples R China. [Wang, Yu] Southeast Univ, Jiangsu Key Lab Mol & Funct Imaging, Dept Radiol, Zhongda Hosp,Med Sch, Nanjing 210009, Jiangsu, Peoples R China. [Qian, Chunqi] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Lizak, Marty] NIH, MIF, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Huang, Peng/H-9985-2013; Huang, Peng/R-2480-2016; OI Huang, Peng/0000-0003-3651-7813; Wang, Fu/0000-0001-9222-0833 FU National Basic Research Program of China (973 program) [2013CB733802, 2014CB744503]; Center for Neuroscience and Regenerative Medicine (CNRM) program at Henry M. Jackson Foundation; Intramural Research Program (IRP) at NIBIB/NIH FX Z. W. Wang and X. Y. Yue contributed equally to this work. This work was supported, in part, by the National Basic Research Program of China (973 program, 2013CB733802, 2014CB744503), Center for Neuroscience and Regenerative Medicine (CNRM) program at Henry M. Jackson Foundation, and the Intramural Research Program (IRP) at NIBIB/NIH. NR 27 TC 8 Z9 8 U1 5 U2 85 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD AUG PY 2014 VL 3 IS 8 SI SI BP 1326 EP 1333 DI 10.1002/adhm.201400088 PG 8 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA AN4IG UT WOS:000340550500021 PM 24789108 ER PT J AU Gandhi, M Fernandez, A Stoff, DM Narahari, S Blank, M Fuchs, J Evans, CH Kahn, JS Johnson, MO AF Gandhi, Monica Fernandez, Alicia Stoff, David M. Narahari, Swathi Blank, Michael Fuchs, Jonathan Evans, Clyde H. Kahn, James S. Johnson, Mallory O. TI Development and Implementation of a Workshop to Enhance the Effectiveness of Mentors Working with Diverse Mentees in HIV Research SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID UNDERREPRESENTED MINORITY FACULTY; HIGHER-EDUCATION; MENTAL-HEALTH; AIDS-RESEARCH; CENTERS; SUCCESS; PROGRAM; SKILLS; WOMEN; EXPECTATIONS AB A growing body of evidence highlights the importance of competent mentoring in academic research in the field of HIV, particularly for early stage investigators from diverse, underrepresented backgrounds. We describe the development and implementation of a 2-day intensive workshop to train mid-level and senior-level investigators conducting HIV-related clinical and translational research across multiple academic institutions on more effective mentoring, with an emphasis on techniques to foster mentees of diversity. The workshop was focused on training mentors in techniques designed to improve the effectiveness of the mentor-mentee relationship, and included didactic presentations, interactive discussions, and small-group problem-based learning activities. Mid-level or senior-level faculty involved or planning to be involved in significant mentorship activities related to HIV research were eligible. Surveys and formal actions plans allowed for workshop evaluation and laid the groundwork for subsequent workshops. Twenty-six faculty from 16 U. S.-based institutions participated, with good representation across discipline, gender, and race/ethnicity. The sessions were highly rated and discussions and evaluations revealed important barriers and facilitators to mentoring, challenges and solutions related to mentoring mentees from diverse backgrounds, and specific tools to enhance mentoring effectiveness. The Mentoring the Mentors training program for HIV researchers focusing on early career investigators of diversity was the first of its kind and was well attended, was rated highly, and provided guidance for improving the program in the future. This training program fills an important gap in the HIV researcher community and offers guidance for training mentors interested in diversity issues in settings outside of HIV. C1 [Gandhi, Monica; Fernandez, Alicia; Fuchs, Jonathan; Johnson, Mallory O.] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Stoff, David M.] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. [Narahari, Swathi] Scripps Coll, Claremont, CA 91711 USA. [Blank, Michael] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Fuchs, Jonathan] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Evans, Clyde H.] Acad Acad Leadership, Boston, MA USA. [Kahn, James S.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. RP Gandhi, M (reprint author), San Francisco Gen Hosp, Dept Med, 995 Potrero Ave,4th Floor, San Francisco, CA 94110 USA. EM monica.gandhi@ucsf.edu FU National Institute of Mental Health of the National Institutes of Health [R24MH094274, K24MH087220] FX This project was supported by grants R24MH094274 (P.I. M. Gandhi) and K24MH087220 (P.I. M.O. Johnson) from the National Institute of Mental Health of the National Institutes of Health The opinions expressed herein are those of the authors and do not necessarily reflect the official positions of the National Institute of Mental Health or any other part of the U.S. Department of Health and Human Services. The authors would like to acknowledge the contribution of Dr. Ruth Greenblatt, former co-director of the Center for AIDS Research (CFAR) Mentoring Program at UCSF, as well as Drs. Paul Volberding and Warner Greene, co-directors of the UCSF CFAR, for their unflagging support of mentoring across the HIV community at UCSF. NR 31 TC 7 Z9 7 U1 3 U2 19 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2014 VL 30 IS 8 BP 730 EP 737 DI 10.1089/aid.2014.0018 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AN4DX UT WOS:000340538900002 PM 24735004 ER PT J AU Odigie, M Osinusi, A Barrett, L Townsend, K Wang, HH Suffredini, AF Masur, H Polis, MA Kottilil, S AF Odigie, Madeline Osinusi, Anu Barrett, Lisa Townsend, Kerry Wang, Honghui Suffredini, Anthony F. Masur, Henry Polis, Michael A. Kottilil, Shyam TI Inteleukin-23 Promotes Interferon-alpha Responsiveness in Hepatitis C Virus/HIV-Coinfected Patients SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTION; THERAPY; CELLS; HCV; PROGRESSION; PREVALENCE; IL-23 AB Patients coinfected with HIV and hepatitis C virus (HCV) have poor to modest rates of response with interferon-based therapies, which remain a backbone of the treatment in HIV/HCV-coinfected patients. The mechanisms responsible for poor responsiveness to interferon are not well described. In this study a targeted proteomic analysis of plasma from 42 patients infected with both HIV and HCV and undergoing therapy for HCV with peginterferon and ribavirin was performed. Higher baseline plasma levels of interleukin (IL)-23 were associated with sustained virologic response. Further investigation of how IL-23 facilitates interferon (IFN) responsiveness, as evidenced by a > 2-fold increase in most interferon-stimulated genes (ISGs), revealed that IL-23 indirectly enhances IFN signaling in peripheral blood mononuclear cells and HCV continuous culture system by preventing the down-regulation of the IFNAR2 receptor after exposure to IFN-alpha. These findings suggest a unique role of the IL-23 pathway in enhancing host response to type I interferons, thereby facilitating eradication of HCV. Low levels of IL-23 present in plasma of nonresponders may reflect an impaired immune state that in the case of HIV/HCV-coinfected subjects could potentially lead to disruption of TH17 CD4(+) T cells. This study suggests a major role for HIV-associated immune dysregulation present in HIV-infected subjects that subsequently determines the overall responsiveness to exogenous interferon-a-based HCV therapy. C1 [Odigie, Madeline; Osinusi, Anu; Barrett, Lisa; Townsend, Kerry; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, Bethesda, MD USA. [Osinusi, Anu] Univ Maryland, Sch Med, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA. [Wang, Honghui; Suffredini, Anthony F.; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Osinusi, A (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A-33A, Bethesda, MD 20892 USA. EM osinusia@niaid.nih.gov FU NIH (National Institute of Allergy and Infectious Diseases); NIH (Critical Care Medicine Department, Clinical Center) FX This research was supported in whole by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases and the Critical Care Medicine Department, Clinical Center). We acknowledge Apath LLC for providing us with J6/JFH-1 HCV clone and Huh7.5 cells. NR 22 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2014 VL 30 IS 8 BP 775 EP 782 DI 10.1089/aid.2014.0003 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AN4DX UT WOS:000340538900008 PM 24856902 ER PT J AU Shaffer, A Hubbard, JJ Townsend, K Kottilil, S Polis, MA Masur, H Kohli, A AF Shaffer, Ashton Hubbard, Jon J. Townsend, Kerry Kottilil, Shyam Polis, Michael A. Masur, Henry Kohli, Anita TI Short Communication: Serum-Based Assay Accurately Detects Single Nucleotide Polymorphisms of IL28B and SOCS3 in HIV/Hepatitis C Virus-Coinfected Subjects SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CHRONIC HEPATITIS-C; INFECTED PATIENTS; ANTIVIRAL THERAPY; VIRAL KINETICS; PLUS RIBAVIRIN; HCV GENOTYPE; EXPRESSION; SUPPRESSOR; STEATOSIS; EFFICACY AB Single nucleotide polymorphisms (SNPs) have become important in predicting treatment response to interferon containing anti-hepatitis C virus (HCV) therapy in HCV and HIV/HCV-infected patients. A reliable method for extracting host DNA from serum for genotyping assays would present a practical alternative for clinicians and investigators seeking to perform SNP analyses in HCV-infected patients, particularly in resource-limited settings. Human genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) and serum of 51 HIV/HCV coinfected patients using the QIAamp DNA Blood Mini Kit and QIAamp Min Elute Virus Spin Kit, respectively. Genotyping assays for the IL28B SNP (rs12979860) and SOCS3 SNP (rs4969170) were performed using the commercially available ABI Taqman allelic discrimination kit and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using 50 cycles. Results of the genotyping assays using DNA from both PBMCs and cell-free serum were determined separately and then analyzed for concurrence. Genotype analyses performed using DNA isolated from PBMCs or cell-free serum showed a 100% agreement between the IL28B genotyping results from the serum and PBMC isolates and 98% agreement for SOCS3 SNP. This novel serum-based assay to isolate DNA fragments from the serum of HIV/HCV-coinfected subjects can accurately determine a subject's genotype for IL28B (rs12979860) and SOCS3 (rs4969170). This assay could be immediately valuable for detecting clinically relevant SNPs from serum in cases in which PBMCs are not available. C1 [Shaffer, Ashton; Kohli, Anita] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20814 USA. [Hubbard, Jon J.; Townsend, Kerry; Kottilil, Shyam; Polis, Michael A.; Masur, Henry] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Kohli, Anita] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kohli, A (reprint author), NIH, CCMD, CC, 10 Ctr Dr,Bldg 10 Room 11C442, Bethesda, MD 20814 USA. EM kohlia@niaid.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH [National Institute of Allergy and Infectious Diseases]; Intramural Research Program of the NIH [NIH Clinical Center] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH [National Institute of Allergy and Infectious Diseases and NIH Clinical Center]. NR 14 TC 2 Z9 2 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2014 VL 30 IS 8 BP 792 EP 795 DI 10.1089/aid.2014.0028 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AN4DX UT WOS:000340538900010 PM 24946792 ER PT J AU Flegal, KM Kit, BK Graubard, BI AF Flegal, Katherine M. Kit, Brian K. Graubard, Barry I. TI Body Mass Index Categories in Observational Studies of Weight and Risk of Death SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; body weight; epidemiologic methods; mortality; obesity; overweight ID ALL-CAUSE MORTALITY; PROSPECTIVE COHORT; OBESITY; OVERWEIGHT; ADIPOSITY; ADULTS; WOMEN; MEN; US; ASSOCIATION AB The World Health Organization (Geneva, Switzerland) and the National Heart, Lung, and Blood Institute (Bethesda, Maryland) have developed standard categories of body mass index (BMI) (calculated as weight (kg)/height (m) 2) of less than 18.5 (underweight), 18.5-24.9 (normal weight), 25.0-29.9 (overweight), and 30.0 or more (obesity). Nevertheless, studies of BMI and the risk of death sometimes use nonstandard BMI categories that vary across studies. In a meta-analysis of 8 large studies that used nonstandard BMI categories and were published between 1999 and 2014 and included 5.8 million participants, hazard ratios tended to be small throughout the range of overweight and normal weight. Risks were similar between subjects of high-normal weight (BMI of approximately 23.0-24.9) and those of low overweight (BMI of approximately 25.0-27.4). In an example using national survey data, minor variations in the reference category affected hazard ratios. For example, choosing high-normal weight (BMI of 23.0-24.9) instead of standard normal weight (BMI of 18.5-24.9) as the reference category produced higher nonsignificant hazard ratios (1.05 vs. 0.97 for men and 1.06 vs. 1.02 for women) for the standard overweight category (BMI of 25.0-29.9). Use of the standard BMI groupings avoids problems of ad hoc and post hoc category selection and facilitates between-study comparisons. The ways in which BMI data are categorized and reported may shape inferences about the degree of risk for various BMI categories. C1 [Flegal, Katherine M.; Kit, Brian K.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4336, Hyattsville, MD 20782 USA. EM kmf2@cdc.gov OI Flegal, Katherine/0000-0002-0838-469X FU Intramural CDC HHS [CC999999] NR 45 TC 21 Z9 22 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2014 VL 180 IS 3 BP 288 EP 296 DI 10.1093/aje/kwu111 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AN2RK UT WOS:000340432800009 PM 24893710 ER PT J AU Catalano, PM Mele, L Landon, MB Ramin, SM Reddy, UM Casey, B Wapner, RJ Varner, MW Rouse, DJ Thorp, JM Saade, G Sorokin, Y Peaceman, AM Tolosa, JE AF Catalano, Patrick M. Mele, Lisa Landon, Mark B. Ramin, Susan M. Reddy, Uma M. Casey, Brian Wapner, Ronald J. Varner, Michael W. Rouse, Dwight J. Thorp, John M., Jr. Saade, George Sorokin, Yoram Peaceman, Alan M. Tolosa, Jorge E. CA Eunice Kennedy Shriver Natl Inst C TI Inadequate weight gain in overweight and obese pregnant women: what is the effect on fetal growth? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE fetal anthropometry; gestational diabetes; gestational weight loss ID BODY-COMPOSITION; MATERNAL OBESITY; UNITED-STATES; OUTCOMES; TRENDS; RISK; MASS; METAANALYSIS; HEALTH; BIRTHS AB OBJECTIVE: We sought to evaluate inadequate gestational weight gain and fetal growth among overweight and obese women. STUDY DESIGN: We conducted an analysis of prospective singleton term pregnancies in which 1053 overweight and obese women gained >5 kg (14.4 +/- 6.2 kg) or 188 who either lost or gained <= 5 kg (1.1 +/- 4.4 kg). Birthweight, fat mass, and lean mass were assessed using anthropometry. Small for gestational age (SGA) was defined as <= 10th percentile of a standard US population. Univariable and multivariable analysis evaluated the association between weight change and neonatal morphometry. RESULTS: There was no significant difference in age, race, smoking, parity, or gestational age between groups. Weight loss or gain <= 5 kg was associated with SGA, 18/188 (9.6%) vs 51/1053 (4.9%); (adjusted odds ratio, 2.6; 95% confidence interval, 1.4-4.7; P = .003). Neonates of women who lost or gained <= 5 kg had lower birthweight (3258 +/- 443 vs 3467 +/- 492 g, P < .0001), fat mass (403 +/- 175 vs 471 +/- 193 g, P < .0001), and lean mass (2855 +/- 321 vs 2995 +/- 347 g, P < .0001), and smaller length, percent fat mass, and head circumference. Adjusting for diabetic status, pre-pregnancy body mass index, smoking, parity, study site, gestational age, and sex, neonates of women who gained <= 5 kg had significantly lower birthweight, lean body mass, fat mass, percent fat mass, head circumference, and length. There were no significant differences in neonatal outcomes between those who lost weight and those who gained <= 5 kg. CONCLUSION: In overweight and obese women weight loss or gain <= 5 kg is associated with increased risk of SGA and decreased neonatal fat mass, lean mass, and head circumference. C1 [Catalano, Patrick M.] Case Western Reserve Univ, Dept Reprod Biol, Ctr Reprod Hlth, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Mele, Lisa] George Washington Univ, Ctr Biostat, Washington, DC USA. [Landon, Mark B.] Ohio State Univ, Dept Obstet, Columbus, OH 43210 USA. [Landon, Mark B.] Ohio State Univ, Dept Gynecol, Columbus, OH 43210 USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Casey, Brian] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Varner, Michael W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Thorp, John M., Jr.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Detroit, MI USA. [Peaceman, Alan M.] Northwestern Univ, Sch Med, Chicago, IL USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Catalano, PM (reprint author), Case Western Reserve Univ, Dept Reprod Biol, Ctr Reprod Hlth, MetroHlth Med Ctr, Cleveland, OH 44106 USA. RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801]; General Clinical Research Centers [M01-RR00034]; National Center for Research Resources [UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research [UL1TR000439]; [HD 22965-19] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801); General Clinical Research Centers Grant (M01-RR00034) and the National Center for Research Resources (UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234); Clinical and Translational Science Collaborative of Cleveland; grant number UL1TR000439 from the National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research; and HD 22965-19 (P.M.C.). NR 31 TC 9 Z9 9 U1 1 U2 11 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 AUG PY 2014 VL 211 IS 2 AR 137.e1 DI 10.1016/j.ajog.2014.02.004 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN0FM UT WOS:000340259300012 PM 24530820 ER PT J AU Grobman, WA Bailit, JL Rice, MM Wapner, RJ Varner, MW Thorp, JM Leveno, KJ Caritis, SN Iams, JD Tita, AT Saade, G Sorokin, Y Rouse, DJ Tolosa, JE Van Dorsten, JP AF Grobman, William A. Bailit, Jennifer L. Rice, Madeline Murguia Wapner, Ronald J. Varner, Michael W. Thorp, John M., Jr. Leveno, Kenneth J. Caritis, Steve N. Iams, Jay D. Tita, Alan T. Saade, George Sorokin, Yoram Rouse, Dwight J. Tolosa, Jorge E. Van Dorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst C TI Can differences in obstetric outcomes be explained by differences in the care provided? The MFMU Network APEX study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE obstetrics; quality care; quality measures ID SAMPLE-SIZE; PERFORMANCE; SAFETY AB OBJECTIVE: The purpose of this study was to determine whether hospital differences in the frequency of adverse obstetric outcomes are related to differences in care. STUDY DESIGN: The Assessment of Perinatal EXcellence cohort comprises 115,502 women and their neonates who were born in 25 hospitals in the United States between March 2008 and February 2011. Hierarchical logistic regression was used to quantify the amount of variation in postpartum hemorrhage, peripartum infection, severe perineal laceration, and a composite adverse neonatal outcome among hospitals that is explained by differences in patient characteristics, hospital characteristics, and obstetric care provided. RESULTS: The study included 115,502 women. For most outcomes, 20-40% of hospital differences in outcomes were related to differences in patient populations. After adjusting for patient-, provider-, and hospital-level factors, multiple care processes were associated with the predefined adverse outcomes; however, these care processes did not explain significant variation in the frequency of adverse outcomes among hospitals. Ultimately, 50-100% of the interhospital variation in outcomes was unexplained. CONCLUSION: Hospital differences in the frequency of adverse obstetric outcomes could not be explained by differences in frequency of types of care provided. C1 [Grobman, William A.] Northwestern Univ, Dept Obstet, Chicago, IL 60611 USA. [Grobman, William A.] Northwestern Univ, Dept Gynecol, Chicago, IL 60611 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Thorp, John M., Jr.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Caritis, Steve N.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Iams, Jay D.] Ohio State Univ, Sch Med, Columbus, OH 43210 USA. [Tita, Alan T.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Detroit, MI USA. [Rouse, Dwight J.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Van Dorsten, J. Peter] Med Univ S Carolina, Charleston, SC 29425 USA. [Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Grobman, WA (reprint author), 250 East Super St,Suite 05-2175, Chicago, IL 60611 USA. EM w-grobman@northwestern.edu RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources [UL1 RR024989, 5UL1 RR025764] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118] and the National Center for Research Resources [UL1 RR024989; 5UL1 RR025764] and its contents do not necessarily represent the official views of the NICHD, NCRR, or NIH. NR 11 TC 0 Z9 0 U1 0 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 AUG PY 2014 VL 211 IS 2 AR 147.e1 DI 10.1016/j.ajog.2014.03.017 PG 16 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN0FM UT WOS:000340259300016 PM 24631441 ER PT J AU Subak, LL Goode, PS Brubaker, L Kusek, JW Schembri, M Lukacz, ES Kraus, SR Chai, TC Norton, P Tennstedt, SL AF Subak, Leslee L. Goode, Patricia S. Brubaker, Linda Kusek, John W. Schembri, Michael Lukacz, Emily S. Kraus, Stephen R. Chai, Toby C. Norton, Peggy Tennstedt, Sharon L. CA Urinary Incontinence Treatment Net TI Urinary incontinence management costs are reduced following Burch or sling surgery for stress incontinence SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE costs; cost analysis; urinary incontinence; urinary incontinence costs ID QUALITY-OF-LIFE; WOMEN; TRIAL AB OBJECTIVE: The objective of the study was to estimate the effect of Burch and fascial sling surgery on out-of-pocket urinary incontinence (UI) management costs at 24 months postoperatively and identify predictors of change in cost among women enrolled in a randomized trial comparing these procedures. STUDY DESIGN: Resources used for UI management (supplies, laundry, dry cleaning) were self-reported by 491 women at baseline and 24 months after surgery, and total out-of-pocket costs for UI management (in 2012 US dollars) were estimated. Data from the 2 surgical groups were combined to examine the change in cost for UI management over 24 months. Univariate and bivariate changes in cost were analyzed using the Wilcoxon signed rank test. Predictors of change in cost were examined using multivariate mixed models. RESULTS: At baseline mean (+/- SD) age of participants was 53 +/- 10 years, and the frequency of weekly UI episodes was 23 +/- 21. Weekly UI episodes decreased by 86% at 24 months (P < .001). The mean weekly cost was $16.60 +/- $27.00 (median $9.39) at baseline and $4.57 +/- $15.00 (median $0.10) at 24 months (P < .001), a decrease of 72%. In multivariate analyses, cost decreased by $3.38 +/- $0.77 per week for each decrease of 1 UI episode per day (P < .001) and was strongly associated with greater improvement in Urogenital Distress Inventory and Incontinence Impact Questionnaire scores (P < .001) and decreased 24-hour pad weight (P < .02). CONCLUSION: Following Burch or fascial sling surgery, the UI management cost at 24 months decreased by 72% ($625 per woman per year) and was strongly associated with decreasing UI frequency. Reduced out-of-pocket expenses may be a benefit of these established urinary incontinence procedures. C1 [Subak, Leslee L.; Schembri, Michael] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94115 USA. [Subak, Leslee L.; Schembri, Michael] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94115 USA. [Subak, Leslee L.; Schembri, Michael] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94115 USA. [Subak, Leslee L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Lukacz, Emily S.] Univ Calif San Diego, Sch Med, Dept Reprod Med, San Diego, CA 92103 USA. [Goode, Patricia S.] Birmingham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Goode, Patricia S.] Univ Alabama Birmingham, Birmingham, AL USA. [Brubaker, Linda] Loyola Univ, Chicago Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Chicago Sch Med, Dept Urol, Chicago, IL 60611 USA. [Kusek, John W.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Chai, Toby C.] Univ Maryland, Sch Med, Dept Urol, Baltimore, MD 21201 USA. [Kraus, Stephen R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Norton, Peggy] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Tennstedt, Sharon L.] New England Res Inst, Watertown, MA 02172 USA. RP Subak, LL (reprint author), Univ Calif San Francisco, Mt Zion Womens Hlth Clin Res Ctr, 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM subakl@obgyn.ucsf.edu OI Wadie, Bassem/0000-0002-6977-6849 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Research in Women's Health, National Institutes of Health FX This study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, and U01 DK60401) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Research in Women's Health, National Institutes of Health. NR 21 TC 3 Z9 3 U1 0 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 AUG PY 2014 VL 211 IS 2 AR 171.e1 DI 10.1016/j.ajog.2014.03.012 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN0FM UT WOS:000340259300025 PM 24631433 ER PT J AU Yoshinaga, K AF Yoshinaga, Koji TI Progesterone and Its Downstream Molecules as Blastocyst Implantation Essential Factors SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Review DE Blastocyst implantation essential factors; downstream molecules; immunomodulaton; implantation; progesterone ID HUMAN EMBRYO IMPLANTATION; MATERNAL-FETAL INTERFACE; ENDOMETRIAL EPITHELIAL-CELLS; DECIDUAL STROMAL CELLS; T-CELL; INDOLEAMINE 2,3-DIOXYGENASE; MOUSE UTERUS; RAT UTERUS; TRYPTOPHAN 2,3-DIOXYGENASE; PERIIMPLANTATION PERIOD AB This review is to update the previous review (Am J Reprod Immunol, 63, 2010 and 413) on the research on blastocyst implantation essential factors (BIEFs). Focus of the current review is on progesterone and its downstream molecules in the process of blastocyst implantation. To understand the process of implantation, we need to know where and when the BIEFs are expressed and what they do. Progress in this research area is rapid, and its update is indeed necessary. The basic concept of BIEFs is that they have dual functions, one physiological and the other immunological (J Reprod Dev, 58, 2012 and 196). As we are still exploring the mechanism of implantation, available data are incomplete and human data are few. Thus, I will use information obtained through research on animal models, in vitro studies, cell lines, and some human studies where available. The ultimate goal of the review is to understand human blastocyst implantation. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Div Extramural Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Yoshinaga, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Div Extramural Res, NIH,DHHS, Bethesda, MD 20892 USA. EM ky6a@nih.gov NR 91 TC 3 Z9 3 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD AUG PY 2014 VL 72 IS 2 BP 117 EP 128 DI 10.1111/aji.12253 PG 12 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA AN4AJ UT WOS:000340529700002 PM 24754263 ER PT J AU Clemens, JQ Mullins, C Kusek, JW Kirkali, Z Mayer, EA Rodriguez, LV Klumpp, DJ Schaeffer, AJ Kreder, KJ Buchwald, D Andriole, GL Lucia, MS Landis, JR Clauw, DJ AF Clemens, J. Quentin Mullins, Chris Kusek, John W. Kirkali, Ziya Mayer, Emeran A. Rodriguez, Larissa V. Klumpp, David J. Schaeffer, Anthony J. Kreder, Karl J. Buchwald, Dedra Andriole, Gerald L. Lucia, M. Scott Landis, J. Richard Clauw, Daniel J. CA MAPP Res Network Study Grp TI The MAPP research network: a novel study of urologic chronic pelvic pain syndromes SO BMC UROLOGY LA English DT Article DE Urological chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Translational research; Multi-disciplinary ID CYSTITIS/PAINFUL BLADDER SYNDROME; BACILLUS-CALMETTE-GUERIN; MYOFASCIAL PHYSICAL-THERAPY; RANDOMIZED-CONTROLLED-TRIAL; INTERSTITIAL CYSTITIS; CLINICAL-TRIAL; NONBLADDER SYNDROMES; CHRONIC PROSTATITIS; RISK-FACTORS; FOLLOW-UP AB Urologic chronic pelvic pain syndrome (UCPPS) may be defined to include interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The hallmark symptom of UCPPS is chronic pain in the pelvis, urogenital floor, or external genitalia often accompanied by lower urinary tract symptoms. Despite numerous past basic and clinical research studies there is no broadly identifiable organ-specific pathology or understanding of etiology or risk factors for UCPPS, and diagnosis relies primarily on patient reported symptoms. In addition, there are no generally effective therapies. Recent findings have, however, revealed associations between UCPPS and "centralized" chronic pain disorders, suggesting UCPPS may represent a local manifestation of more widespread pathology in some patients. Here, we describe a new and novel effort initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U. S. National Institutes of Health (NIH) to address the many long standing questions regarding UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The MAPP Network approaches UCPPS in a systemic manner, in which the interplay between the genitourinary system and other physiological systems is emphasized. The network's study design expands beyond previous research, which has primarily focused on urologic organs and tissues, to utilize integrated approaches to define patient phenotypes, identify clinically-relevant subgroups, and better understand treated natural history and pathophysiology. Thus, the MAPP Network provides an unprecedented, multi-layered characterization of UCPPS. Knowledge gained is expected to provide important insights into underlying pathophysiology, a foundation for better segmenting patients for future clinical trials, and ultimately translation into improved clinical management. In addition, the MAPP Network's integrated multi-disciplinary research approach may serve as a model for studies of urologic and non-urologic disorders that have proven refractory to past basic and clinical study. C1 [Clemens, J. Quentin] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Mullins, Chris; Kusek, John W.; Kirkali, Ziya] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Mayer, Emeran A.; Rodriguez, Larissa V.] Univ Calif Los Angeles, Div Digest Dis, Los Angeles, CA USA. [Klumpp, David J.; Schaeffer, Anthony J.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Kreder, Karl J.] Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. [Buchwald, Dedra] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Buchwald, Dedra] Univ Washington, Dept Med, Seattle, WA USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Dept Surg, Div Urol Surg, St Louis, MO 63110 USA. [Lucia, M. Scott] Univ Colorado, Dept Pathol, Aurora, CO USA. [Landis, J. Richard] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Clauw, Daniel J.] Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA. [Clauw, Daniel J.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. RP Clemens, JQ (reprint author), Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. EM qclemens@med.umich.edu OI Ness, Timothy/0000-0002-7908-4459 FU NIH [U01 DK82315, U01 DK82316, U01 DK82325, U01 DK82333, U01 DK82342, U01 DK82344, U01 DK82345, U01 DK82370] FX The MAPP Research Network acknowledges support through NIH grants: U01 DK82315, U01 DK82316, U01 DK82325, U01 DK82333, U01 DK82342, U01 DK82344, U01 DK82345, and U01 DK82370. The NIDDK and MAPP Network investigators wish to thank the Interstitial Cystitis Association (ICA) and the Prostatitis Foundation (PF) for their assistance in study participant recruitment and other network efforts. NR 36 TC 29 Z9 29 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2490 J9 BMC UROL JI BMC Urol. PD AUG 1 PY 2014 VL 14 AR 57 DI 10.1186/1471-2490-14-57 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AN5PL UT WOS:000340643700001 PM 25085007 ER PT J AU Keevan, J Figg, WD AF Keevan, Jacob Figg, William D. TI New mechanism of lenalidomide activity SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE lenalidomide; immunomodulatory agent; IKZF1; IKZF3; CRBN; IKZF1/3; IMiD AB Lenalidomide is an immunomodulatory agent (IMiD) that has activity in hematologic cancer (e. g., multiple myeloma). The immunomodulatory and apoptotic properties are readily apparent in therapy. However, the exact mechanism of action has been difficult to quantify until recently when it was shown that another IMiD, thalidomide, binds to an E3 ubiquitin ligase complex constituent, CRBN.(1) The article by Kronke et al. demonstrates that, by binding to CRBN and altering its selectivity, lenalidomide potentiates the ubiquitination and proteolysis of 2 specific proteins, IKZF1 and IKZF3. An article in the same issue, by Lu et al., supports these observations.(2,3) IKZF1 and IKZF3 are transcription factors that are necessary for multiple myeloma, and repression of these transcription factors is a likely mechanism for lenalidomide activity in this disease. C1 [Keevan, Jacob; Figg, William D.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 3 TC 0 Z9 0 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2014 VL 15 IS 8 BP 968 EP 969 DI 10.4161/cbt.29189 PG 2 WC Oncology SC Oncology GA AN4IJ UT WOS:000340550800002 PM 24840055 ER PT J AU Mittal, K Koon, H Elson, P Triozzi, P Dowlati, A Chen, HL Borden, EC Rini, BI AF Mittal, Kriti Koon, Henry Elson, Paul Triozzi, Pierre Dowlati, Afshin Chen, Helen Borden, Ernest C. Rini, Brian I. TI Dual VEGF/VEGFR inhibition in advanced solid malignancies Clinical effects and pharmacodynamic biomarkers SO CANCER BIOLOGY & THERAPY LA English DT Article DE angiogenesis; VEGF; VEGFR; sunitinib; bevacizumab ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; RENAL-CELL CARCINOMA; TUMOR ANGIOGENESIS; MELANOMA PATIENTS; METASTATIC MELANOMA; THROMBOTIC MICROANGIOPATHY; CUTANEOUS MELANOMA; FACTOR EXPRESSION; MULTIPLE-MYELOMA AB Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients. Patients with metastatic solid tumors received sunitinib (37.5 mg/d, 4 wk on/2 wk off) and bevacizumab (5 mg/kg intravenously every 2 wk). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays. Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 wk of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold. Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development. C1 [Mittal, Kriti; Elson, Paul; Triozzi, Pierre; Borden, Ernest C.; Rini, Brian I.] Cleveland Clin Taussig Canc Inst, Cleveland, OH 44195 USA. [Koon, Henry; Dowlati, Afshin] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Chen, Helen] NCI, Rockville, MD USA. RP Rini, BI (reprint author), Cleveland Clin Taussig Canc Inst, Cleveland, OH 44195 USA. EM rinib2@ccf.org FU CTEP [U01-CA062502] FX CTEP Grant U01-CA062502 and a philanthropic gift to Taussig Cancer Institute from Maria and Carlos Tejada. NR 58 TC 4 Z9 5 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2014 VL 15 IS 8 BP 975 EP 981 DI 10.4161/cbt.29187 PG 7 WC Oncology SC Oncology GA AN4IJ UT WOS:000340550800004 PM 24842548 ER PT J AU Dohle, W Leese, MP Jourdan, FL Chapman, CJ Hamel, E Ferrandis, E Potter, BVL AF Dohle, Wolfgang Leese, Mathew P. Jourdan, Fabrice L. Chapman, Christopher J. Hamel, Ernest Ferrandis, Eric Potter, Barry V. L. TI Optimisation of Tetrahydroisoquinoline-Based Chimeric Microtubule Disruptors SO CHEMMEDCHEM LA English DT Article DE chimeras; colchicine binding; microtubule disruptors; tetrahydroisoquinolines; tubulin assembly ID ANTICANCER AGENTS; PHILADELPHIA-CHROMOSOME; ANTIPROLIFERATIVE SAR; ACTIVE-SITE; IN-VITRO; TUBULIN; ANALOGS; ANTITUBULIN; INHIBITION; COLCHICINE AB Tetrahydroisoquinoline (THIQ)-based "chimeric" microtubule disruptors were optimised through modification of the N-benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro anti-proliferative activities (e. g. 15: GI(50) 20 nm in DU-145). The broad anticancer activity of these novel structures was confirmed in the NCI 60-cell line assay, with 12e,f displaying MGM values in the 40 nm region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8 mu m, close to that of the clinical drug combretastatin A-4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50=1.6 mu m). Compound 12 f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development. C1 [Dohle, Wolfgang; Leese, Mathew P.; Jourdan, Fabrice L.; Chapman, Christopher J.; Potter, Barry V. L.] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. [Hamel, Ernest] NCI, Sceening Technol Branch, Frederick, MD 21702 USA. [Ferrandis, Eric] Inst Rech Henri Beaufour, F-91966 Les Ulis, France. RP Potter, BVL (reprint author), Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. EM B.V.L.Potter@bath.ac.uk FU Sterix Ltd. of the IPSEN Group. FX This work was supported by Sterix Ltd., a member of the IPSEN Group. We thank Ms Alison Smith (University of Bath) for technical support and the NCI DTP for providing in vitro and in vivo screening resources. NR 35 TC 3 Z9 3 U1 0 U2 13 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD AUG PY 2014 VL 9 IS 8 BP 1783 EP 1793 DI 10.1002/cmdc.201402025 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AN1RE UT WOS:000340360500016 PM 24819406 ER PT J AU Pandey, D Bhunia, A Oh, YJ Chang, FM Bergman, Y Kim, JH Serbo, J Boronina, TN Cole, RN Van Eyk, J Remaley, AT Berkowitz, DE Romer, LH AF Pandey, Deepesh Bhunia, Anil Oh, Young Jun Chang, Fumin Bergman, Yehudit Kim, Jae Hyung Serbo, Janna Boronina, Tatiana N. Cole, Robert N. Van Eyk, Jennifer Remaley, Alan T. Berkowitz, Dan E. Romer, Lewis H. TI OxLDL Triggers Retrograde Translocation of Arginase2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase SO CIRCULATION RESEARCH LA English DT Article DE arginase; atherosclerosis; mitochondria; mitochondrial processing peptidase; nitric oxide synthase type III; oxidized low density lipoprotein ID LOW-DENSITY-LIPOPROTEIN; NITRIC-OXIDE SYNTHASE; ISCHEMIA-REPERFUSION; CORONARY ARTERIOLES; MEDIATED DILATION; INHIBITION; ATHEROSCLEROSIS; MACROPHAGES; DYSFUNCTION; EXPRESSION AB Rationale: Increased arginase activity contributes to endothelial dysfunction by competition for L-arginine substrate and reciprocal regulation of nitric oxide synthase (NOS). The rapid increase in arginase activity in human aortic endothelial cells exposed to oxidized low-density lipoprotein (OxLDL) is consistent with post-translational modification or subcellular trafficking. Objective: To test the hypotheses that OxLDL triggers reverse translocation of mitochondrial arginase 2 (Arg2) to cytosol and Arg2 activation, and that this process is dependent on mitochondrial processing peptidase, lectin-like OxLDL receptor-1 receptor, and rho kinase. Methods and Results: OxLDL-triggered translocation of Arg2 from mitochondria to cytosol in human aortic endothelial cells and in murine aortic intima with a concomitant rise in arginase activity. All of these changes were abolished by inhibition of mitochondrial processing peptidase or by its siRNA-mediated knockdown. Rho kinase inhibition and the absence of the lectin-like OxLDL receptor-1 in knockout mice also ablated translocation. Aminoterminal sequencing of Arg2 revealed 2 candidate mitochondrial targeting sequences, and deletion of either of these confined Arg2 to the cytoplasm. Inhibitors of mitochondrial processing peptidase or lectin-like OxLDL receptor-1 knockout attenuated OxLDL-mediated decrements in endothelial-specific NO production and increases in superoxide generation. Finally, Arg2(-/-) mice bred on an ApoE(-/-) background showed reduced plaque load, reduced reactive oxygen species production, enhanced NO, and improved endothelial function when compared with ApoE(-/-) controls. Conclusions: These data demonstrate dual distribution of Arg2, a protein with an unambiguous mitochondrial targeting sequence, in mammalian cells, and its reverse translocation to cytoplasm by alterations in the extracellular milieu. This novel molecular mechanism drives OxLDL-mediated arginase activation, endothelial NOS uncoupling, endothelial dysfunction, and atherogenesis. C1 [Pandey, Deepesh; Bhunia, Anil; Oh, Young Jun; Chang, Fumin; Bergman, Yehudit; Kim, Jae Hyung; Serbo, Janna; Berkowitz, Dan E.; Romer, Lewis H.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. [Serbo, Janna; Berkowitz, Dan E.; Romer, Lewis H.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Romer, Lewis H.] Johns Hopkins Univ, Sch Med, Ctr Cell Dynam, Baltimore, MD 21287 USA. [Boronina, Tatiana N.; Cole, Robert N.] Johns Hopkins Univ, Sch Med, Mass Spectrometry & Prote Facil, Baltimore, MD 21287 USA. [Van Eyk, Jennifer] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Van Eyk, Jennifer] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21287 USA. [Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Romer, LH (reprint author), Johns Hopkins Univ, Sch Med, Charlotte R Bloomberg Childrens Ctr, Suite 6318-C Pediat ACCM,1800 Orleans St, Baltimore, MD 21287 USA. EM LRomer@jhmi.edu FU American Heart Association [13POST16810011]; National Heart, Lung, and Blood Institute [HL089668]; NSF [MCB-0923661]; Clinical Translational Science Award at Johns Hopkins University; National Institutes of Health [S10RR024550] FX This work was supported by American Heart Association Postdoctoral Fellowship to D. Pandey (13POST16810011) and HL089668 from National Heart, Lung, and Blood Institute to D. E. Berkowitz and L. H. Romer, by NSF MCB-0923661 to L. H. Romer, and by a Clinical Translational Science Award at Johns Hopkins University (J. Van Eyk) and National Institutes of Health S10RR024550. NR 48 TC 18 Z9 18 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG 1 PY 2014 VL 115 IS 4 BP 450 EP 459 DI 10.1161/CIRCRESAHA.115.304262 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AN1SU UT WOS:000340364700010 PM 24903103 ER PT J AU Pastoor, TP Bachman, AN Bell, DR Cohen, SM Dellarco, M Dewhurst, IC Doe, JE Doerrer, NG Embry, MR Hines, RN Moretto, A Phillips, RD Rowlands, JC Tanir, JY Wolf, DC Boobis, AR AF Pastoor, Timothy P. Bachman, Ammie N. Bell, David R. Cohen, Samuel M. Dellarco, Michael Dewhurst, Ian C. Doe, John E. Doerrer, Nancy G. Embry, Michelle R. Hines, Ronald N. Moretto, Angelo Phillips, Richard D. Rowlands, J. Craig Tanir, Jennifer Y. Wolf, Douglas C. Boobis, Alan R. TI A 21st century roadmap for human health risk assessment SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE exposure; framework; hazard; problem formulation; risk; risk assessment; risk policy; tiered ID TOXICOLOGICAL CONCERN; SUBSTANCES PRESENT; DOSE-RESPONSE; FRAMEWORK; THRESHOLDS; DIET AB The Health and Environmental Sciences Institute (HESI)-coordinated Risk Assessment in the 21st Century (RISK21) project was initiated to develop a scientific, transparent, and efficient approach to the evolving world of human health risk assessment, and involved over 120 participants from 12 countries, 15 government institutions, 20 universities, 2 non-governmental organizations, and 12 corporations. This paper provides a brief overview of the tiered RISK21 framework called the roadmap and risk visualization matrix, and articulates the core principles derived by RISK21 participants that guided its development. Subsequent papers describe the roadmap and matrix in greater detail. RISK21 principles include focusing on problem formulation, utilizing existing information, starting with exposure assessment (rather than toxicity), and using a tiered process for data development. Bringing estimates of exposure and toxicity together on a two-dimensional matrix provides a clear rendition of human safety and risk. The value of the roadmap is its capacity to chronicle the stepwise acquisition of scientific information and display it in a clear and concise fashion. Furthermore, the tiered approach and transparent display of information will contribute to greater efficiencies by calling for data only as needed (enough precision to make a decision), thus conserving animals and other resources. C1 [Pastoor, Timothy P.] Syngenta Ltd, Greensboro, NC USA. [Bachman, Ammie N.; Phillips, Richard D.] ExxonMobil Biomed Sci Inc, Annandale, NJ USA. [Bell, David R.] European Chem Agcy, Helsinki, Finland. [Cohen, Samuel M.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Dellarco, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Dewhurst, Ian C.] UK Chem Regulat Directorate, York, N Yorkshire, England. [Doe, John E.] Parker Doe Partnership LLP, Frodsham, Cheshire, England. [Doerrer, Nancy G.; Embry, Michelle R.; Tanir, Jennifer Y.] ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Hines, Ronald N.; Wolf, Douglas C.] US EPA, ORD, NHEERL, Res Triangle Pk, NC 27711 USA. [Moretto, Angelo] Univ Milan, Dept Biomed & Clin Sci, Milan, Italy. [Rowlands, J. Craig] Dow Chem Co USA, Midland, MI 48674 USA. [Boobis, Alan R.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Embry, MR (reprint author), ILSI Hlth & Environm Sci Inst, 1156 15th St NW, Washington, DC 20005 USA. EM membry@hesiglobal.org RI Doe, Jane/B-8500-2015; OI Moretto, Angelo/0000-0003-4386-5736 FU International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI); NGOs FX This manuscript was prepared under the auspices of the International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI), a non-profit organization aimed at engaging scientists from academia, government, industry, research institutes, and NGOs to identify and resolve global health and environmental issues. ILSI HESI collects funding from member companies to support projects. The authors' affiliations are as shown on the cover page. The authors had sole responsibility for the writing and content of the paper. The views and opinions expressed in the paper are those of the authors, and do not necessarily reflect the views of the authors' employers or the opinions or policies of the US EPA or NIH. Mention of trade names does not constitute endorsement. None of the authors has recently or is currently involved as an expert witness in litigation or formal government rule-making on the subject of this paper. The authors employed by ILSI HESI participated as part of their normal employment. No other authors received financial support or an honorarium in the preparation of this paper. The authors declare that there are no conflicts of interest. NR 16 TC 26 Z9 27 U1 2 U2 23 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD AUG PY 2014 VL 44 SU 3 BP 1 EP 5 DI 10.3109/10408444.2014.931923 PG 5 WC Toxicology SC Toxicology GA AN1RB UT WOS:000340360200001 PM 25070413 ER PT J AU Embry, MR Bachman, AN Bell, DR Boobis, AR Cohen, SM Dellarco, M Dewhurst, IC Doerrer, NG Hines, RN Moretto, A Pastoor, TP Phillips, RD Rowlands, JC Tanir, JY Wolf, DC Doe, JE AF Embry, Michelle R. Bachman, Ammie N. Bell, David R. Boobis, Alan R. Cohen, Samuel M. Dellarco, Michael Dewhurst, Ian C. Doerrer, Nancy G. Hines, Ronald N. Moretto, Angelo Pastoor, Timothy P. Phillips, Richard D. Rowlands, J. Craig Tanir, Jennifer Y. Wolf, Douglas C. Doe, John E. TI Risk assessment in the 21st century: Roadmap and matrix SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE exposure; framework; hazard; problem formulation; risk; risk assessment; risk policy; tiered ID CHEMICALS; EXPOSURE AB The RISK21 integrated evaluation strategy is a problem formulation-based exposure-driven risk assessment roadmap that takes advantage of existing information to graphically represent the intersection of exposure and toxicity data on a highly visual matrix. This paper describes in detail the process for using the roadmap and matrix. The purpose of this methodology is to optimize the use of prior information and testing resources (animals, time, facilities, and personnel) to efficiently and transparently reach a risk and/or safety determination. Based on the particular problem, exposure and toxicity data should have sufficient precision to make such a decision. Estimates of exposure and toxicity, bounded by variability and/or uncertainty, are plotted on the X- and Y-axes of the RISK21 matrix, respectively. The resulting intersection is a highly visual representation of estimated risk. Decisions can then be made to increase precision in the exposure or toxicity estimates or declare that the available information is sufficient. RISK21 represents a step forward in the goal to introduce new methodologies into 21st century risk assessment. Indeed, because of its transparent and visual process, RISK21 has the potential to widen the scope of risk communication beyond those with technical expertise. C1 [Embry, Michelle R.; Doerrer, Nancy G.; Tanir, Jennifer Y.] ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Bachman, Ammie N.; Phillips, Richard D.] ExxonMobil Biomed Sci Inc, Annandale, NJ USA. [Bell, David R.] European Chem Agcy, Helsinki, Finland. [Boobis, Alan R.] Univ London Imperial Coll Sci Technol & Med, London, England. [Cohen, Samuel M.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Dellarco, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Dewhurst, Ian C.] UK Chem Regulat Directorate, York, N Yorkshire, England. [Hines, Ronald N.; Wolf, Douglas C.] US EPA, Res Triangle Pk, NC USA. [Moretto, Angelo] Univ Milan, Dept Biomed & Clin Sci, Milan, Italy. [Pastoor, Timothy P.] Syngenta Ltd, Greensboro, NC USA. [Rowlands, J. Craig] Dow Chem Co USA, Midland, MI 48674 USA. [Doe, John E.] Parker Doe Partnership LLP, Stockport, Cheshire, England. RP Embry, MR (reprint author), ILSI Hlth & Environm Sci Inst, 1156 15th St NW,Second Floor, Washington, DC 20005 USA. EM membry@hesiglobal.org RI Doe, Jane/B-8500-2015; OI Moretto, Angelo/0000-0003-4386-5736 FU International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI); NGOs FX This manuscript was prepared under the auspices of the International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI), a non-profit organization aimed at engaging scientists from academia, government, industry, research institutes, and NGOs to identify and resolve global health and environmental issues. ILSI HESI collects funding from member companies to support projects. The authors' affiliations are as shown on the cover page. The authors had sole responsibility for the writing and content of the paper. The views and opinions expressed in the paper are those of the authors, and do not necessarily reflect the views of the authors' employers or the opinions or policies of the US EPA or NIH. Mention of trade names does not constitute endorsement. None of the authors has recently or is currently involved as an expert witness in litigation or formal government rule-making on the subject of this paper. The authors employed by ILSI HESI participated as part of their normal employment. No other authors received financial support or an honorarium in the preparation of this paper. The authors declare that there are no conflicts of interest. NR 24 TC 26 Z9 27 U1 2 U2 16 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD AUG PY 2014 VL 44 SU 3 BP 6 EP 16 DI 10.3109/10408444.2014.931924 PG 11 WC Toxicology SC Toxicology GA AN1RB UT WOS:000340360200002 PM 25070414 ER PT J AU Simon, TW Simons, SS Preston, RJ Boobis, AR Cohen, SM Doerrer, NG Fenner-Crisp, PA McMullin, TS McQueen, CA Rowlands, JC AF Simon, Ted W. Simons, S. Stoney, Jr. Preston, R. Julian Boobis, Alan R. Cohen, Samuel M. Doerrer, Nancy G. Fenner-Crisp, Penelope A. McMullin, Tami S. McQueen, Charlene A. Rowlands, J. Craig CA RISK21 Dose-Response Subteam TI The use of mode of action information in risk assessment: Quantitative key events/dose-response framework for modeling the dose-response for key events SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE associative event; key event; mode of action; modulating factor; Q-KEDRF; risk assessment ID ESTROGEN-RECEPTOR-ALPHA; PHARMACODYNAMIC PBPK/PD MODEL; HUMAN PROGESTERONE-RECEPTOR; HUMAN RELEVANCE ANALYSIS; RAT UTEROTROPHIC ASSAY; CONTINUOUS END-POINTS; REPORTER GENE ASSAY; TO-OUTCOME MODEL; BISPHENOL-A; IN-VIVO AB The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs. C1 [Simon, Ted W.] Ted Simon LLC, Winston, GA USA. [Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, LERB, NIH, Bethesda, MD USA. [Preston, R. Julian; McQueen, Charlene A.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Boobis, Alan R.] Univ London Imperial Coll Sci Technol & Med, London, England. [Cohen, Samuel M.] Univ Nebraska Med Ctr, Omaha, NE USA. [Doerrer, Nancy G.; RISK21 Dose-Response Subteam] ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. [McMullin, Tami S.] Dow Corning Corp, Midland, MI USA. [Rowlands, J. Craig] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. RP Doerrer, NG (reprint author), ILSI Hlth & Environm Sci Inst, 1156 15th St NW, Washington, DC 20005 USA. EM ndoerrer@hesiglobal.org OI Teeguarden, Justin/0000-0003-3817-4391 FU International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI); NGOs FX This manuscript was prepared under the auspices of the International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI), a non-profit organization aimed at engaging scientists from academia, government, industry, research institutes, and NGOs to identify and resolve global health and environmental issues. ILSI HESI collects funding from member companies to support projects. The authors' affiliations are as shown on the cover page. The authors had sole responsibility for the writing and content of the paper. The views and opinions expressed in the paper are those of the authors, and do not necessarily reflect the views of the authors' employers or the opinions or policies of the US EPA or NIH. Mention of trade names does not constitute endorsement. None of the authors has recently or is currently involved as an expert witness in litigation or formal government rule-making on the subject of this paper. The authors employed by ILSI HESI participated as part of their normal employment. No other authors received financial support or an honorarium in the preparation of this paper. The authors declare that there are no conflicts of interest. NR 197 TC 24 Z9 24 U1 0 U2 30 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD AUG PY 2014 VL 44 SU 3 BP 17 EP 43 DI 10.3109/10408444.2014.931925 PG 27 WC Toxicology SC Toxicology GA AN1RB UT WOS:000340360200003 PM 25070415 ER PT J AU Lehmann, GM Verner, MA Luukinen, B Henning, C Assimon, SA LaKind, JS McLanahan, ED Phillips, LJ Davis, MH Powers, CM Hines, EP Haddad, S Longnecker, MP Poulsen, MT Farrer, DG Marchitti, SA Tan, YM Swartout, JC Sagiv, SK Welsh, C Campbell, JL Foster, WG Yang, RSH Fenton, SE Tornero-Velez, R Francis, BM Barnett, JB El-Masri, HA Simmons, JE AF Lehmann, Geniece M. Verner, Marc-Andre Luukinen, Bryan Henning, Cara Assimon, Sue Anne LaKind, Judy S. McLanahan, Eva D. Phillips, Linda J. Davis, Matthew H. Powers, Christina M. Hines, Erin P. Haddad, Sami Longnecker, Matthew P. Poulsen, Michael T. Farrer, David G. Marchitti, Satori A. Tan, Yu-Mei Swartout, Jeffrey C. Sagiv, Sharon K. Welsh, Clement Campbell, Jerry L., Jr. Foster, Warren G. Yang, Raymond S. H. Fenton, Suzanne E. Tornero-Velez, Rogelio Francis, Bettina M. Barnett, John B. El-Masri, Hisham A. Simmons, Jane Ellen TI Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE children; exposure; PBT chemicals; persistent organic pollutants; POPs; research needs; risk assessment; uncertainty ID CHILDRENS HEALTH; POLYCHLORINATED-BIPHENYLS; PARTITION-COEFFICIENTS; LACTATIONAL TRANSFER; UNITED-STATES; PHARMACOKINETIC MODELS; TECHNICAL WORKSHOP; CRITICAL WINDOWS; INFANT EXPOSURE; EXPERT PANEL AB Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals. C1 [Lehmann, Geniece M.; McLanahan, Eva D.; Powers, Christina M.; Hines, Erin P.; Tan, Yu-Mei; Tornero-Velez, Rogelio; El-Masri, Hisham A.; Simmons, Jane Ellen] US EPA, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Verner, Marc-Andre] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Luukinen, Bryan; Henning, Cara] ICF Int, Res Triangle Pk, NC USA. [Assimon, Sue Anne] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [LaKind, Judy S.] LaKind Associates LLC, Catonsville, MD USA. [LaKind, Judy S.] Univ Maryland Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD USA. [LaKind, Judy S.] Penn State Univ Coll Med, Dept Pediat, Hershey, PA USA. [Phillips, Linda J.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Davis, Matthew H.] US EPA, Off Childrens Hlth Protect, Washington, DC 20460 USA. [Haddad, Sami] Univ Quebec, Dept Environm Hlth & Occupat Hlth, IRSPUM Univ Montreal Publ Hlth Res Inst, Montreal, PQ H3C 3P8, Canada. [Longnecker, Matthew P.; Fenton, Suzanne E.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Poulsen, Michael T.] Oregon Dept Environm Qual, Portland, OR USA. [Farrer, David G.] Oregon Hlth Author, Portland, OR USA. [Marchitti, Satori A.] US EPA, Off Res & Dev, Athens, GA USA. [Swartout, Jeffrey C.] US EPA, Off Res & Dev, Cincinnati, OH 45268 USA. [Sagiv, Sharon K.] Boston Univ Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Welsh, Clement] Agcy Tox Subst & Dis Registry, Div Toxicol & Human Hlth Sci, Atlanta, GA USA. [Campbell, Jerry L., Jr.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Foster, Warren G.] McMaster Univ, Dept Obstet & Gynecol, Hamilton, ON, Canada. [Yang, Raymond S. H.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Francis, Bettina M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Barnett, John B.] West Virginia Univ Sch Med, Dept Microbiol Immunol & Cell Biol, Morgantown, WV USA. RP Lehmann, GM (reprint author), US EPA, MD B243-01,4930 Old Page Rd, Durham, NC 27703 USA. EM lehmann.geniece@epa.gov RI Haddad, Sami/F-4537-2012; OI Haddad, Sami/0000-0001-8906-9693; Hines, Erin Pias/0000-0002-2458-6267; Verner, Marc-Andre/0000-0002-1935-8913; Longnecker, Matthew/0000-0001-6073-5322 FU U.S. EPA [EP-C-09-009, 2-62, 3-62, 4-62]; Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS); NIH FX The employment affiliation of the authors is shown on the cover page. The following authors were participants in a multidisciplinary workshop that served as the basis for this review paper: MAV, SAA, JSL, MHD, SH, MPL, MTP, DGF, YMT, SKS, CW, JCS, JLC, WGF, BMF, RSHY, JBB, HAE, SEF, JES, and RT. Some workshop participants chose not to participate as authors in the development of this review. Those individuals are acknowledged in the preceding section. The workshop was co-chaired by GML and EDM. ICF International organized the workshop under contract from the U.S. EPA (Contract No. EP-C-09-009, Work Assignments 2-62, 3-62, and 4-62). Workshop organization functions performed by ICF International included the independent identification and selection of workshop participants. ICF International is a for-profit firm providing professional services and technology solutions to clients in the following markets: energy, environment, and infrastructure; health, social programs, and consumer/financial; and public safety and defense. ICF International provides these services to both government and private sector clients. This research was also supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). The following workshop participants received support for travel and/or lodging: MAV, SAA, JSL, MHD, SH, MTP, DGF, SKS, WGF, BMF, RSHY, and JBB. MAV, SH, SKS, JLC, WGF, BMF, RSHY, JBB, and JSL received an honorarium for their participation in the workshop. LaKind Associates is a private consulting firm specializing in strategic risk management, assessment of human exposures and health risks, biomonitoring, state-of-the-science reviews, and environmental regulatory review; LaKind Associates consults to governmental and private sectors. The Hamner Institutes for Health Sciences is a nonprofit research institute with a primary focus on drug and chemical safety, including the development of methods to improve human health risk assessment. This paper has been reviewed in accordance with the peer and administrative review policies of the U. S. EPA, Food and Drug Administration (FDA), NIEHS, and Agency for Toxic Substances and Disease Registry (ATSDR) and approved for publication. The views expressed in this report are those of the authors and do not necessarily reflect the opinions and/or policies of the U. S. EPA, FDA, NIEHS or ATSDR. The remaining authors are all employees of either state governments or various academic institutions. Many of the academic scientists participating in the workshop and authoring this paper have received financial support for their research programs from the U.S. EPA and/or the NIH. All authors have sole responsibility as individual scientists for the writing and content of this review. The views, conclusions and recommendations are not necessarily those of their employers. NR 80 TC 7 Z9 7 U1 1 U2 24 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD AUG PY 2014 VL 44 IS 7 BP 600 EP 617 DI 10.3109/10408444.2014.926306 PG 18 WC Toxicology SC Toxicology GA AN1QZ UT WOS:000340360000005 PM 25068490 ER PT J AU Kaplan, RM Chambers, DA Glasgow, RE AF Kaplan, Robert M. Chambers, David A. Glasgow, Russell E. TI Big Data and Large Sample Size: A Cautionary Note on the Potential for Bias SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE big data; research methods; bias; sampling ID CARDIOVASCULAR-DISEASE; NURSES HEALTH; THERAPY AB A number of commentaries have suggested that large studies are more reliable than smaller studies and there is a growing interest in the analysis of "big data" that integrates information from many thousands of persons and/or different data sources. We consider a variety of biases that are likely in the era of big data, including sampling error, measurement error, multiple comparisons errors, aggregation error, and errors associated with the systematic exclusion of information. Using examples from epidemiology, health services research, studies on determinants of health, and clinical trials, we conclude that it is necessary to exercise greater caution to be sure that big sample size does not lead to big inferential errors. Despite the advantages of big studies, large sample size can magnify the bias associated with error resulting from sampling or study design. C1 [Kaplan, Robert M.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Kaplan, Robert M.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Chambers, David A.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Glasgow, Russell E.] Univ Colorado, Colorado Hlth Outcomes Program, Anschutz, CO USA. RP Kaplan, RM (reprint author), NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. EM robert.kaplan@ahrq.hhs.gov NR 25 TC 14 Z9 14 U1 4 U2 34 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD AUG PY 2014 VL 7 IS 4 BP 342 EP 346 DI 10.1111/cts.12178 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN4HM UT WOS:000340548300017 PM 25043853 ER PT J AU Kiriakis, J Gaich, N Johnston, SC Kitterman, D Rosenblum, D Salberg, L Rifkind, A AF Kiriakis, James Gaich, Nicholas Johnston, S. Claiborne Kitterman, Darlene Rosenblum, Daniel Salberg, Libby Rifkind, Adam TI Observational Study of Contracts Processing at 29 CTSA Sites (vol 6, pg 279, 2013) SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Correction C1 [Kiriakis, James] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gaich, Nicholas] Stanford Univ, Stanford, CA 94305 USA. [Johnston, S. Claiborne] Univ Calif San Francisco, Clin & Translat Sci Inst, San Francisco, CA 94143 USA. [Kitterman, Darlene] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97201 USA. [Rosenblum, Daniel] NIH, Div Clin Innovat, NCATS, Bethesda, MD 20892 USA. [Salberg, Libby] Vanderbilt Univ, Off Contracts Management, Nashville, TN 37235 USA. [Rifkind, Adam] Univ Penn, Off Res Serv, Philadelphia, PA 19104 USA. RP Rosenblum, D (reprint author), NIH, Div Clin Innovat, NCATS, Bldg 10, Bethesda, MD 20892 USA. EM rosenblumd@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD AUG PY 2014 VL 7 IS 4 BP 348 EP 348 DI 10.1111/cts.12201 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN4HM UT WOS:000340548300019 ER PT J AU Halter, JB Musi, N Horne, FM Crandall, JP Goldberg, A Harkless, L Hazzard, WR Huang, ES Kirkman, MS Plutzky, J Schmader, KE Zieman, S High, KP AF Halter, Jeffrey B. Musi, Nicolas Horne, Frances McFarland Crandall, Jill P. Goldberg, Andrew Harkless, Lawrence Hazzard, William R. Huang, Elbert S. Kirkman, M. Sue Plutzky, Jorge Schmader, Kenneth E. Zieman, Susan High, Kevin P. TI Diabetes and Cardiovascular Disease in Older Adults: Current Status and Future Directions SO DIABETES LA English DT Article ID 10-YEAR FOLLOW-UP; A-BETA OLIGOMERS; WEIGHT-LOSS; INSULIN-RESISTANCE; RISK-FACTORS; SEVERE HYPOGLYCEMIA; ALZHEIMER-DISEASE; KIDNEY-DISEASE; HEART-FAILURE; UNITED-STATES AB The prevalence of diabetes increases with age, driven in part by an absolute increase in incidence among adults aged 65 years and older. Individuals with diabetes are at higher risk for cardiovascular disease, and age strongly predicts cardiovascular complications. Inflammation and oxidative stress appear to play some role in the mechanisms underlying aging, diabetes, cardiovascular disease, and other complications of diabetes. However, the mechanisms underlying the age-associated increase in risk for diabetes and diabetes-related cardiovascular disease remain poorly understood. Moreover, because of the heterogeneity of the older population, a lack of understanding of the biology of aging, and inadequate study of the effects of treatments on traditional complications and geriatric conditions associated with diabetes, no consensus exists on the optimal interventions for older diabetic adults. The Association of Specialty Professors, along with the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the American Diabetes Association, held a workshop, summarized in this Perspective, to discuss current knowledge regarding diabetes and cardiovascular disease in older adults, identify gaps, and propose questions to guide future research. C1 [Halter, Jeffrey B.] Univ Michigan, Sch Med, Dept Internal Med, Div Geriatr & Palliat Med, Ann Arbor, MI 48109 USA. [Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Musi, Nicolas] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Horne, Frances McFarland] Assoc Specialty Prof, Alexandria, VA USA. [Crandall, Jill P.] Albert Einstein Coll Med, Div Endocrinol, Dept Med, Bronx, NY 10467 USA. [Goldberg, Andrew] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Goldberg, Andrew] Baltimore VA Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. [Harkless, Lawrence] Western Univ Hlth Sci, Pomona, CA USA. [Hazzard, William R.] Univ Washington, Dept Med, Puget Sound VA Hlth Care Syst, Seattle, WA USA. [Huang, Elbert S.] Univ Chicago, Dept Med, Div Gen Internal Med, Chicago, IL 60637 USA. [Kirkman, M. Sue] Univ N Carolina, Dept Med, Div Endocrinol & Metab, Chapel Hill, NC USA. [Plutzky, Jorge] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Schmader, Kenneth E.] Duke Univ, Sch Med, Geriatr Res Educ & Clin Ctr, Durham, NC USA. [Schmader, Kenneth E.] Durham VA Med Ctr, Durham, NC USA. [Zieman, Susan] NIA, Bethesda, MD 20892 USA. [High, Kevin P.] Wake Forest Sch Med, Dept Internal Med, Infect Dis Sect, Winston Salem, NC USA. RP Halter, JB (reprint author), Univ Michigan, Sch Med, Dept Internal Med, Div Geriatr & Palliat Med, Ann Arbor, MI 48109 USA. EM jhalter@umich.edu; musi@uthscsa.edu FU National Institute on Aging [1-U13-AG-040938 01]; John A. Hartford Foundation; National Institutes of Health's National Institute on Aging; Alliance for Academic Internal Medicine; American Diabetes Association FX Funding. This workshop was supported by generous grants to Association of Specialty Professors from the National Institute on Aging (1-U13-AG-040938 01) and the John A. Hartford Foundation (J.B.H., K.E.S., K.P.H.). J.B.H. reports grants from the John A. Hartford Foundation, National Institutes of Health's National Institute on Aging, and Alliance for Academic Internal Medicine during the conduct of the project, and from the American Diabetes Association outside the submitted work. F.M.H. reports grants from the John A. Hartford Foundation during the conduct of the project. NR 54 TC 27 Z9 27 U1 2 U2 12 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 AUG PY 2014 VL 63 IS 8 BP 2578 EP 2589 DI 10.2337/db14-0020 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN0GK UT WOS:000340262100004 PM 25060886 ER PT J AU Pawlyk, AC Giacomini, KM McKeon, C Shuldiner, AR Florez, JC AF Pawlyk, Aaron C. Giacomini, Kathleen M. McKeon, Catherine Shuldiner, Alan R. Florez, Jose C. TI Metformin Pharmacogenomics: Current Status and Future Directions SO DIABETES LA English DT Article ID DIABETES PREVENTION PROGRAM; POLYCYSTIC-OVARY-SYNDROME; LIFE-STYLE INTERVENTION; CATION TRANSPORTER 1; GENETIC-VARIATION; IMPLEMENTATION CONSORTIUM; RESEARCH NETWORK; GLYCEMIC CONTROL; WEIGHT-LOSS; TYPE-2 AB The incidence of type 2 diabetes (T2D) and its costs to the health care system continue to rise. Despite the availability of at least 10 drug classes for the treatment of T2D, metformin remains the most widely used first-line pharmacotherapy for its treatment; however, marked interindividual variability in response and few clinical or biomarker predictors of response reduce its optimal use. As clinical care moves toward precision medicine, a variety of broad discovery-based "omics" approaches will be required. Technical innovation, decreasing sequencing cost, and routine sample storage and processing has made pharmacogenomics the most widely applied discovery-based approach to date. This opens up the opportunity to understand the genetics underlying the interindividual variation in metformin responses in order for clinicians to prescribe specific treatments to given individuals for better efficacy and safety: metformin for those predicted to respond and alternative therapies for those predicted to be nonresponders or who are at increased risk for adverse side effects. Furthermore, understanding of the genetic determinants of metformin response may lead to the identification of novel targets and development of more effective agents for diabetes treatment. The goals of this workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases were to review the state of research on metformin pharmacogenomics, discuss the scientific and clinical hurdles to furthering our knowledge of the variability in patient responses to metformin, and consider how to effectively use this increased understanding to improve patient outcomes. C1 [Pawlyk, Aaron C.; McKeon, Catherine] NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. [Giacomini, Kathleen M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Giacomini, Kathleen M.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Diabet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. EM jcflorez@partners.org FU NIDDK FX Funding. The workshop was sponsored by NIDDK. NR 58 TC 31 Z9 32 U1 1 U2 14 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 AUG PY 2014 VL 63 IS 8 BP 2590 EP 2599 DI 10.2337/db13-1367 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN0GK UT WOS:000340262100005 PM 25060887 ER PT J AU Holt, RIG de Groot, M Lucki, I Hunter, CM Sartorius, N Golden, SH AF Holt, Richard I. G. de Groot, Mary Lucki, Irwin Hunter, Christine M. Sartorius, Norman Golden, Sherita H. TI NIDDK International Conference Report on Diabetes and Depression: Current Understanding and Future Directions SO DIABETES CARE LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; ANTIDEPRESSANT MEDICINE USE; QUALITY-OF-LIFE; COST-EFFECTIVENESS; PHYSICAL-ACTIVITY; NEIGHBORHOOD RESOURCES; CARDIOVASCULAR HEALTH; COLLABORATIVE CARE; PREVENTION PROGRAM; INSULIN-RESISTANCE AB Comorbid diabetes and depression are a major clinical challenge as the outcomes of each condition are worsened by the other. This article is based on the presentations and discussions during an international meeting on diabetes and depression convened by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the National Institute of Mental Health and the Dialogue on Diabetes and Depression. While the psychological burden of diabetes may contribute to depression in some cases, this explanation does not sufficiently explain the relationship between these two conditions. Shared biological and behavioral mechanisms, such as hypothalamic-pituitary-adrenal axis activation, inflammation, autonomic dysfunction, sleep disturbance, inactive lifestyle, poor dietary habits, and environmental and cultural risk factors, are important to consider in understanding the link between depression and diabetes. Both individual psychological and pharmacological depression treatments are effective in people with diabetes, but the current range of treatment options is limited and has shown mixed effects on glycemic outcomes. More research is needed to understand what factors contribute to individual differences in vulnerability, treatment response, and resilience to depression and metabolic disorders across the life course and how best to provide care for people with comorbid diabetes and depression in different health care settings. Training programs are needed to create a cross-disciplinary workforce that can work in different models of care for comorbid conditions. C1 [Holt, Richard I. G.] Univ Southampton, Fac Med, Human Dev & Hlth Acad Unit, Southampton SO9 5NH, Hants, England. [de Groot, Mary] Indiana Univ Sch Med, Diabet Translat Res Ctr, Indianapolis, IN 46202 USA. [Lucki, Irwin] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Hunter, Christine M.] NIDDK, NIH, Bethesda, MD USA. [Sartorius, Norman] Assoc Improvement Mental Hlth Programmes & Dialog, Geneva, Switzerland. [Golden, Sherita H.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Golden, Sherita H.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Golden, Sherita H.] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. RP Holt, RIG (reprint author), Univ Southampton, Fac Med, Human Dev & Hlth Acad Unit, Southampton SO9 5NH, Hants, England. EM r.i.g.holt@soton.ac.uk FU National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]); National Institutes of Health (National Institute of Mental Health [NIMH]); Dialogue on Diabetes and Depression FX The authors acknowledge the support of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] and National Institute of Mental Health [NIMH]) and of the Dialogue on Diabetes and Depression, which was established in 2008 as an international collaboration with the aim of addressing the challenges of comorbid diabetes and depression. The goals of the Dialogue on Diabetes and Depression include the coordination of research, the development of training materials, the organization of symposia and training courses, the production of reviews of knowledge, and the facilitation of collaboration among countries, organizations, and clinical and scientific experts to prevent or reduce the sequelae of these comorbid conditions. NR 72 TC 38 Z9 38 U1 7 U2 20 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2014 VL 37 IS 8 BP 2067 EP 2077 DI 10.2337/dc13-2134 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN3MI UT WOS:000340491800016 PM 25061135 ER PT J AU Schneiderman, N Llabre, M Cowie, CC Barnhart, J Carnethon, M Gallo, LC Giachello, AL Heiss, G Kaplan, RC LaVange, LM Teng, YP Villa-Caballero, L Aviles-Santa, ML AF Schneiderman, Neil Llabre, Maria Cowie, Catherine C. Barnhart, Janice Carnethon, Mercedes Gallo, Linda C. Giachello, Aida L. Heiss, Gerardo Kaplan, Robert C. LaVange, Lisa M. Teng, Yanping Villa-Caballero, Leonel Aviles-Santa, M. Larissa TI Prevalence of Diabetes Among Hispanics/Latinos From Diverse Backgrounds: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) SO DIABETES CARE LA English DT Article ID UNITED-STATES; CARDIOVASCULAR RISK; METAANALYSIS; DISPARITIES; POPULATION; IMMIGRANTS; DESIGN; A1C AB OBJECTIVE We examine differences in prevalence of diabetes and rates of awareness and control among adults from diverse Hispanic/Latino backgrounds in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). RESEARCH DESIGN AND METHODS The HCHS/SOL, a prospective, multicenter, population-based study, enrolled from four U. S. metropolitan areas from 2008 to 2011 16,415 18-74-year-old people of Hispanic/Latino descent. Diabetes was defined by either fasting plasma glucose, impaired glucose tolerance 2 h after a glucose load, glycosylated hemoglobin (A1C), or documented use of hypoglycemic agents (scanned medications). RESULTS Diabetes prevalence varied from 10.2% in South Americans and 13.4% in Cubans to 17.7% in Central Americans, 18.0% in Dominicans and Puerto Ricans, and 18.3% in Mexicans (P < 0.0001). Prevalence related positively to age (P < 0.0001), BMI (P < 0.0001), and years living in the U. S. (P = 0.0010) but was negatively related to education (P = 0.0005) and household income (P = 0.0043). Rate of diabetes awareness was 58.7%, adequate glycemic control (A1C <7%, 53 mmol/mol) was 48.0%, and having health insurance among those with diabetes was 52.4%. CONCLUSIONS Present findings indicate a high prevalence of diabetes but considerable diversity as a function of Hispanic background. The low rates of diabetes awareness, diabetes control, and health insurance in conjunction with the negative associations between diabetes prevalence and both household income and education among Hispanics/ Latinos in the U. S. have important implications for public health policies. C1 [Schneiderman, Neil; Llabre, Maria] Univ Miami, Res Ctr, Dept Psychol & Behav Med, Miami, FL 33124 USA. [Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD 20892 USA. [Barnhart, Janice; Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Carnethon, Mercedes; Giachello, Aida L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gallo, Linda C.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [LaVange, Lisa M.; Teng, Yanping] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Villa-Caballero, Leonel] Univ Calif San Diego, Certificate Program Clin Trials Adm Latin Amer, La Jolla, CA 92093 USA. [Aviles-Santa, M. Larissa] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Schneiderman, N (reprint author), Univ Miami, Res Ctr, Dept Psychol & Behav Med, Miami, FL 33124 USA. EM nschneid@miami.edu FU NHLBI [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237] FX The HCHS/SOL was carried out as a collaborative study supported by contracts from the NHLBI to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes/centers/offices contributed to the baseline HCHS/SOL funding period through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and National Institutes of Health Office of Dietary Supplements. NR 21 TC 45 Z9 45 U1 3 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2014 VL 37 IS 8 BP 2233 EP 2239 DI 10.2337/dc13-2939 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN3MI UT WOS:000340491800037 PM 25061138 ER PT J AU Heiss, G Snyder, ML Teng, YP Schneiderman, N Llabre, MM Cowie, C Carnethon, M Kaplan, R Giachello, A Gallo, L Loehr, L Aviles-Santa, L AF Heiss, Gerardo Snyder, Michelle L. Teng, Yanping Schneiderman, Neil Llabre, Maria M. Cowie, Catherine Carnethon, Mercedes Kaplan, Robert Giachello, Aida Gallo, Linda Loehr, Laura Aviles-Santa, Larissa TI Prevalence of Metabolic Syndrome Among Hispanics/Latinos of Diverse Background: The Hispanic Community Health Study/Study of Latinos SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR-DISEASE; WAIST CIRCUMFERENCE; INSULIN-RESISTANCE; ABDOMINAL OBESITY; NATIONAL-HEALTH; GUT MICROBIOTA; UNITED-STATES; RISK-FACTORS; US ADULTS; MEN AB OBJECTIVE Approximately one-third of the adult U. S. population has the metabolic syndrome. Its prevalence is the highest among Hispanic adults, but variation by Hispanic/Latino background is unknown. Our objective was to quantify the prevalence of the metabolic syndrome among men and women 18-74 years of age of diverse Hispanic/Latino background. RESEARCH DESIGN AND METHODS Two-stage area probability sample of households in four U. S. locales, yielding 16,319 adults (52% women) who self-identified as Cuban, Dominican, Mexican, Puerto Rican, Central American, or South American. The metabolic syndrome was defined according to the American Heart Association/National Heart, Lung, and Blood Institute 2009 Joint Scientific Statement. The main outcome measures were age-standardized prevalence of the metabolic syndrome per the harmonized American Heart Association/National Heart, Lung, and Blood Institute definition and its component abnormalities. RESULTS The metabolic syndrome was present in 36% of women and 34% of men. Differences in the age-standardized prevalence were seen by age, sex, and Hispanic/Latino background. The prevalence of the metabolic syndrome among those 1844, 45-64, and 65-74 years of age was 23%, 50%, and 62%, respectively, among women; and 25%, 43%, and 55%, respectively, among men. Among women, the metabolic syndrome prevalence ranged from 27% in South Americans to 41% in Puerto Ricans. Among men, prevalences ranged from 27% in South Americans to 35% in Cubans. In those with the metabolic syndrome, abdominal obesity was present in 96% of the women compared with 73% of the men; more men (73%) than women (62%) had hyperglycemia. CONCLUSIONS The burden of cardiometabolic abnormalities is high in Hispanic/Latinos but varies by age, sex, and Hispanic/Latino background. Hispanics/Latinos are thus at increased, but modifiable, predicted lifetime risk of diabetes and its cardiovascular sequelae. C1 [Heiss, Gerardo; Snyder, Michelle L.; Loehr, Laura] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Teng, Yanping] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Schneiderman, Neil; Llabre, Maria M.] Univ Miami, Res Ctr, Dept Psychol & Behav Med, Miami, FL USA. [Cowie, Catherine] NIDDK, NIH, Bethesda, MD 20892 USA. [Carnethon, Mercedes; Giachello, Aida] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Kaplan, Robert] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Gallo, Linda] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Aviles-Santa, Larissa] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Heiss, G (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. EM gerardo_heiss@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; National Center on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Office of Dietary Supplements FX The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), the University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes, centers, or offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. NR 40 TC 23 Z9 23 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2014 VL 37 IS 8 BP 2391 EP 2399 DI 10.2337/dc13-2505 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN3MI UT WOS:000340491800058 PM 25061141 ER PT J AU Katz, ML Mehta, S Nansel, T Quinn, H Lipsky, LM Laffel, LMB AF Katz, Michelle L. Mehta, Sanjeev Nansel, Tonja Quinn, Heidi Lipsky, Leah M. Laffel, Lori M. B. TI Associations of Nutrient Intake with Glycemic Control in Youth with Type 1 Diabetes: Differences by Insulin Regimen SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID GLUCOSE CONTROL; DIETARY-INTAKE; ADOLESCENTS; CHILDREN; FAT; FIBER; COMPLICATIONS; MANAGEMENT; EAT AB Background: Type 1 diabetes management has evolved from meal plans towards flexible eating with carbohydrate counting. With this shift, youth with type 1 diabetes may consume excess fat and insufficient fiber, which may impact glycemic control. Few studies consider whether insulin regimen influences associations between dietary intake and hemoglobin A1c. Patients and Methods: In this cross-sectional study, 252 youth (52% male; age, 13.2 +/- 2.8 years; body mass index z-score [z-BMI], 0.7 +/- 0.8) with type 1 diabetes completed 3-day food records. Dietary intake was compared with published guidelines. Logistic regression predicted the odds of suboptimal glycemic control (an A1c level of >= 8.5%) related to fat and protein intake or fiber intake according to insulin regimen (pump vs. injection) adjusting for age, sex, diabetes duration, z-BMI, insulin dose, glucose monitoring frequency, and total energy intake (TEI). Results: Youth had a mean TEI of 40.9 +/- 15.4 kcal/kg/day and excess fat and insufficient fiber intake compared against published guidelines. Pump-treated youth consuming the highest quartile of fat intake (as percentage TEI) had 3.6 (95% confidence interval, 1.3-9.7) times the odds of a suboptimal A1c than those in the lowest quartile. No such association was found in injection-treated youth. In the total sample, youth with the lowest quartile of fiber intake had 3.6 (95% confidence interval, 1.4-9.0) times the odds of a suboptimal A1c, but this association did not differ by insulin regimen. There was no association between protein intake and A1c. Conclusions: Higher fat intake in pump-treated youth and lower fiber intake in all youth were associated with an A1c level of >= 8.5%. Improving dietary quality may help improve A1c. C1 [Katz, Michelle L.; Mehta, Sanjeev; Quinn, Heidi; Laffel, Lori M. B.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Genet & Epidemiol Sect, Boston, MA 02215 USA. [Nansel, Tonja; Lipsky, Leah M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Laffel, LMB (reprint author), Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Genet & Epidemiol Sect, One Joslin Pl, Boston, MA 02215 USA. EM lori.laffel@joslin.harvard.edu OI Nansel, Tonja/0000-0002-8298-7595; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200703434C]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health grants T32 [5T32DK007260-35, 1K12DK094721-01, P30DK036836]; Katherine Adler Astrove Youth Education Fund; Maria Griffin Drury Fund; Eleanor Chesterman Beatson Care Ambassador Fund FX We thank all the families for their participation in this investigation. We also thank the research staff for their efforts. This research was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract number HHSN267200703434C) and by National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health grants T32 #5T32DK007260-35, 1K12DK094721-01, and grant P30DK036836 to the Joslin Diabetes and Endocrinology Research Center. Additional support came from the Katherine Adler Astrove Youth Education Fund, the Maria Griffin Drury Fund, and the Eleanor Chesterman Beatson Care Ambassador Fund. NR 24 TC 4 Z9 4 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 EI 1557-8593 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD AUG PY 2014 VL 16 IS 8 BP 512 EP 518 DI 10.1089/dia.2013.0389 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN4EL UT WOS:000340540300005 PM 24766666 ER PT J AU Zhang, T Ye, YH AF Zhang, Ting Ye, Yihong TI The Final Moments of Misfolded Proteins en Route to the Proteasome SO DNA AND CELL BIOLOGY LA English DT Article ID RETICULUM-ASSOCIATED DEGRADATION; ER-ASSOCIATED DEGRADATION; UBIQUITIN-LIKE DOMAIN; AAA ATPASE CDC48/P97; ENDOPLASMIC-RETICULUM; RETROTRANSLOCATION COMPLEX; STRUCTURAL INSIGHTS; QUALITY-CONTROL; CENTRAL PORE; U-BOX AB Protein homeostasis in the endoplasmic reticulum (ER) in eukaryotic cells is maintained by a conserved quality control system named ER-associated degradation (ERAD). The ERAD system retains misfolded or unassembled polypeptides in the ER, retrotranslocates them into the cytosol for degradation by the ubiquitin proteasome system. Central to the ERAD process is the AAA+ (ATPase associated with various cellular activities), ATPase p97/VCP (also known as Cdc48p in yeast), and the proteasome. p97/VCP couples ATP hydrolysis to the extraction of misfolded proteins from retrotranslocation sites and subsequently targets them for degradation, but how p97/VCP hands substrate off to the proteasome is unclear. Recent studies suggest that p97/VCP may either directly translocate polypeptides into the proteolytic compartment of the 20S subcomplex, or use a set of shuttling factors to deliver retrotranslocated polypeptides to the proteasome. C1 [Zhang, Ting; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU NIH intramural AIDS Targeted Antiviral Program (IATAP); Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX The authors' research is supported by the NIH intramural AIDS Targeted Antiviral Program (IATAP) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 68 TC 7 Z9 7 U1 2 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5498 EI 1557-7430 J9 DNA CELL BIOL JI DNA Cell Biol. PD AUG PY 2014 VL 33 IS 8 BP 477 EP 483 DI 10.1089/dna.2014.2452 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA AN4BB UT WOS:000340531500001 PM 24833120 ER PT J AU Zhang, W Parniak, MA Mitsuya, H Sarafianos, SG Graebing, PW Rohan, LC AF Zhang, Wei Parniak, Michael A. Mitsuya, Hiroaki Sarafianos, Stefan G. Graebing, Phillip W. Rohan, Lisa C. TI Preformulation studies of EFdA, a novel nucleoside reverse transcriptase inhibitor for HIV prevention SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Caco-2 cells; EFdA; permeability; preformulation; solubility; transport ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VITRO; CACO-2 MONOLAYERS; CANDIDATE MICROBICIDES; POLYSTYRENE SULFONATE; DRUG PERMEABILITY; TRANSPORT; MODEL; CELLS; INFECTION AB 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a novel nucleoside analog of great interest because of its superior activity against wild-type and multidrug-resistant HIV-1 strains, and favorable safety profiles in vitro and in vivo. The aim of this work was to provide preformulation information of EFdA important for delivery system development. A simple, accurate and specific reverse-phase high performance liquid chromatographic (RP-HPLC) method with UV detection was developed for quantification of EFdA. In addition, physicochemical characterizations including pH solubility profile, octanol/water partition coefficient (Log P-o/w), DSC analysis, field emission scanning electron microscopy, and stability studies under various conditions were conducted. EFdA existed in planar or flake shape, with a melting point of similar to 130 degrees C, and had a pH dependent solubility. The log Po/w value of EFdA was -1.19. The compound was stable upon exposure to pH levels from 3 to 9 and showed good stability at elevated temperature (65 degrees C). In vitro cytotoxicity assessments were performed in two different epithelial cell lines. In cell-based studies, the EFdA selectivity index (50% cytotoxic concentration [CC50] values/50% effective concentration [EC50]) was found to be greater than 1 x 10(3). Permeability studies using cell-and tissue-based models showed that EFdA had an apparent permeability coefficient (P-app) < 1 x 10(-6) cm/s and that the paracelluar pathway was the dominant transport route for EFdA. Overall, EFdA possesses favorable characteristics for further formulation development. C1 [Zhang, Wei; Graebing, Phillip W.; Rohan, Lisa C.] Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA 15260 USA. [Zhang, Wei; Rohan, Lisa C.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Parniak, Michael A.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol & Infect Dis, Kumamoto, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Sarafianos, Stefan G.] Univ Missouri, Dept Mol Microbiol & Immunol & Biochem, Columbiaville, MI USA. RP Rohan, LC (reprint author), Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA 15260 USA. EM rohanlc@upmc.edu OI Sarafianos, Stefan G/0000-0002-5840-154X FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [AI 076119, AI 079801] FX Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number AI 076119 and AI 079801. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 2 Z9 2 U1 1 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PD AUG PY 2014 VL 40 IS 8 BP 1101 EP 1111 DI 10.3109/03639045.2013.809535 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AN2ZW UT WOS:000340455600014 PM 23841536 ER PT J AU Postel-Vinay, S Collette, L Paoletti, X Rizzo, E Massard, C Olmos, D Fowst, C Levy, B Mancini, P Lacombe, D Ivy, P Seymour, L Le Tourneau, C Siu, LL Kaye, SB Verweij, J Soria, JC AF Postel-Vinay, Sophie Collette, Laurence Paoletti, Xavier Rizzo, Elisa Massard, Christophe Olmos, David Fowst, Camilla Levy, Bernard Mancini, Pierre Lacombe, Denis Ivy, Percy Seymour, Lesley Le Tourneau, Christophe Siu, Lillian L. Kaye, Stan B. Verweij, Jaap Soria, Jean-Charles TI Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents - Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Phase 1; Targeted agents; Dose limiting toxicity; Maximum tolerated dose; Recommended phase 2 dose; Toxicities; Trial design ID PHASE-I TRIALS; CLINICAL-TRIALS; CYTOSTATIC AGENTS; ESCALATION; ANTIBODY; DESIGNS AB Introduction: Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. Patients and methods: In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT); collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. Results: The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in Cl, but only 9.1% of them presented protocol-defined DLTs. After Cl, 16-19% of patients received <75% of the intended RDI. A similar proportion of G >= 3 toxicities was recorded in Cl and after Cl (936 and 1087 toxicities, respectively), with the first G 3 toxicity occurring after Cl in 18.6% of patients. Conclusion: Although protocol-defined DLT period is traditionally limited to Cl, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Postel-Vinay, Sophie; Massard, Christophe; Soria, Jean-Charles] Gustave Roussy Canc Campus, DITEP, F-94800 Villejuif, France. [Postel-Vinay, Sophie; Massard, Christophe; Soria, Jean-Charles] Univ Paris 11, F-94276 Le Kremlin Bicetre, France. [Collette, Laurence; Rizzo, Elisa; Lacombe, Denis] EORTC Headquarters, B-1200 Brussels, Belgium. [Paoletti, Xavier] Inst Curie, Dept Stat, F-75006 Paris, France. [Paoletti, Xavier; Olmos, David] Inst Curie, INSERM U900, F-75006 Paris, France. [Olmos, David] Inst Curie, Dept Med Oncol, F-75006 Paris, France. [Olmos, David] Inst Curie, Dept Med Oncol, St Cloud, France. [Olmos, David] Inst Curie, INSERM U900, St Cloud, France. [Olmos, David] Spanish Natl Canc Res Ctr CNIO, Prostate Canc Clin Res Unit, Madrid 28029, Spain. [Fowst, Camilla] Hosp Univ Madrid Norte Sanchinarro, Ctr Integral Oncol Clara Campal, Madrid 28050, Spain. [Levy, Bernard] Pfizer Italia SpA, Pfizer Oncol, Clin Dev, I-20152 Milan, Italy. [Mancini, Pierre] Roche TCRC Inc, New York, NY 10016 USA. [Ivy, Percy] Sanofi R&D, F-94403 Vitry Sur Seine, France. [Seymour, Lesley] NCI, Bethesda, MD 20892 USA. [Seymour, Lesley] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Le Tourneau, Christophe] Queens Univ, NCIC Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Siu, Lillian L.] Princess Margaret Canc Ctr, Toronto, ON 5MG 2M9, Canada. [Kaye, Stan B.] Royal Marsden Hosp, Inst Canc Res, Drug Dev Unit, Sutton SM2 5P, Surrey, England. [Verweij, Jaap] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands. RP Postel-Vinay, S (reprint author), Inst Gustave Roussy, DITEP 4e Etage,114 Rue Edouard Vaillant, F-94800 Villejuif, France. EM Sophie.postel-vinay@gustaveroussy.fr; Jean-charles.soria@gustaveroussy.fr FU EORTC Charitable Trust Foundation from Belgium FX This study was supported by the EORTC Charitable Trust Foundation from Belgium. NR 18 TC 30 Z9 30 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD AUG PY 2014 VL 50 IS 12 BP 2040 EP 2049 DI 10.1016/j.ejca.2014.04.031 PG 10 WC Oncology SC Oncology GA AN1GE UT WOS:000340329900005 PM 24880774 ER PT J AU Paoletti, X Le Tourneau, C Verweij, J Siu, LL Seymour, L Postel-Vinay, S Collette, L Rizzo, E Ivy, P Olmos, D Massard, C Lacombe, D Kaye, SB Soria, JC AF Paoletti, Xavier Le Tourneau, Christophe Verweij, Jaap Siu, Lillian L. Seymour, Lesley Postel-Vinay, Sophie Collette, Laurence Rizzo, Elisa Ivy, Percy Olmos, David Massard, Christophe Lacombe, Denis Kaye, Stan B. Soria, Jean-Charles TI Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Dose-limiting toxicity; Assessment period; Experts; Dose intensity; Phase 1; Recommended phase 2 dose ID CANCER CLINICAL-TRIALS; OF-THE-LITERATURE; END-POINTS; I TRIALS; THERAPY; DEFINITIONS; ADHERENCE; DESIGN; TUMORS AB Introduction: It is increasingly clear that definitions of dose-limiting toxicity (DLT) established for phase 1 trials of cytotoxic agents are not suitable for molecularly targeted agents because of specific toxicity profiles. An international survey collected expertise on the definition of DLT, as part of an initiative aimed at presenting new guidelines for phase 1 trials of targeted agents. Methods: A 15-question survey was sent to corresponding authors of phase 1 reports. Questions involved: duration of the DLT assessment period, incorporation of specific grade 1 (G1) or G2 toxicity and their minimum duration to qualify as DLT, exclusion of specific G3 and inclusion of dose modification/delay. Results: Among the 400 investigators contacted, 93 replied of whom 65 completed the questionnaires. A total of 87% opted for an extended DLT assessment period beyond cycle 1, with the proviso not to delay patient accrual. Reanalysis at the end of the study of all safety data was proposed in order to recommend the phase 2 dose. Most respondents (92%) suggested including dose modification in the definition of DLT when dose intensity was decreased to 70%. Whilst moderate toxicity was deemed relevant by 70%, the G1/2 toxicities selected to define DLT however varied. Conclusion: The majority of experts favoured a longer DLT assessment period as well as incorporation of specific G2 toxicities into the DLT definition. However, no clear consensus existed on a re-definition of DLT. Therefore analyses of a large international data warehouse were also used to develop guidelines presented in a companion paper. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Paoletti, Xavier] Inst Curie, Dept Biostat, F-75005 Paris, France. [Paoletti, Xavier; Le Tourneau, Christophe] INSERM U900, Paris, France. [Le Tourneau, Christophe] Inst Curie, Dept Med Oncol, F-75005 Paris, France. [Verweij, Jaap] Erasmus Univ MC, Dept Med Oncol, Rotterdam, Netherlands. [Siu, Lillian L.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Seymour, Lesley] Natl Canc Inst Canada, Clin Trials Grp, Kingston, ON, Canada. [Seymour, Lesley] Queens Univ, Kingston, ON, Canada. [Collette, Laurence; Rizzo, Elisa; Lacombe, Denis] European Org Res & Treatment Canc Headquarter, Brussels, Belgium. [Ivy, Percy] NCI, Rockville, MD USA. [Ivy, Percy] Canc Therapy Evaluat Program, Rockville, MD USA. [Olmos, David] Spanish Natl Canc Res Ctr CNIO, Clin Res Programme, Prostate Canc Clin Res Unit, Madrid, Spain. [Kaye, Stan B.] Royal Marsden Hosp, Inst Canc Res, Drug Dev Unit, Sutton, Surrey, England. [Postel-Vinay, Sophie; Massard, Christophe; Soria, Jean-Charles] Gustave Roussy Canc Campus, DITEP, Villejuif, France. [Postel-Vinay, Sophie; Massard, Christophe; Soria, Jean-Charles] Univ Paris 11, Orsay, France. RP Paoletti, X (reprint author), Inst Curie, Dept Biostat, 26 Rue Ulm, F-75005 Paris, France. EM xavier.paoletti@curie.fr OI Ivy, S. Percy/0000-0001-7747-072X FU EORTC Charitable Trust Foundation from Belgium; Institut National du Cancer (INCa) of France [2010-1-PL SHS-06-IC-1] FX We are indebted to all experts who accepted to spend some time in filling out the survey and who shared their know-how with the community. This study was partially supported by the EORTC Charitable Trust Foundation from Belgium; X.P. and J.C.S. were partially funded by the Institut National du Cancer (INCa) of France (Optidose # 2010-1-PL SHS-06-IC-1). NR 15 TC 19 Z9 20 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD AUG PY 2014 VL 50 IS 12 BP 2050 EP 2056 DI 10.1016/j.ejca.2014.04.030 PG 7 WC Oncology SC Oncology GA AN1GE UT WOS:000340329900006 PM 24928189 ER PT J AU Gourgari, E Nella, AA Lodish, M Stratakis, CA Yanovski, JA AF Gourgari, Evgenia Nella, Aikaterini A. Lodish, Maya Stratakis, Constantine A. Yanovski, Jack A. TI Vitamin B12 deficiency in an adolescent girl with polycystic ovarian syndrome SO EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY LA English DT Letter ID METFORMIN C1 [Gourgari, Evgenia; Nella, Aikaterini A.; Lodish, Maya; Stratakis, Constantine A.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Gourgari, Evgenia] Georgetown Univ, Med Ctr, Div Pediat Endocrinol, Washington, DC 20007 USA. RP Gourgari, E (reprint author), Georgetown Univ Hosp, Div Pediat Endocrinol, 4200 Wisconsin Ave NW,4th Floor, Washington, DC 20016 USA. EM evgenia.gourgari@gunet.georgetown.edu OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z99 HD999999, ZIA HD000641-18, ZIA HD000642-13] NR 4 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-2115 EI 1872-7654 J9 EUR J OBSTET GYN R B JI Eur. J. Obstet. Gynecol. Reprod. Biol. PD AUG PY 2014 VL 179 BP 254 EP 254 DI 10.1016/j.ejogrb.2014.04.036 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AN1BR UT WOS:000340318200050 PM 24933126 ER PT J AU Lin, FC Karwan, M Saleh, B Hodge, D Boelte, K Chan, T Keller, J Young, H AF Lin, Fanching Karwan, Megan Saleh, Bahara Hodge, Debora Boelte, Kimberly Chan, Tim Keller, Jonathan Young, Howard TI IFN-GAMMA CAUSES APLASTIC ANEMIA BY ALTERING HSC COMPOSITION AND INTERRUPTING LINEAGE DIFFERENTIATION SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Lin, Fanching; Saleh, Bahara; Hodge, Debora; Boelte, Kimberly; Chan, Tim; Keller, Jonathan; Young, Howard] NCI, Frederick, MD 21701 USA. [Karwan, Megan] Leidos, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 5 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 AUG PY 2014 VL 42 IS 8 SU 1 MA O1006 BP S14 EP S14 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300036 ER PT J AU Thalheimer, F Wingert, S De Giacomo, P Haetscher, N Brill, B Theis, F Hennighausen, L Schroeder, T Rieger, M AF Thalheimer, Frederic Wingert, Susanne De Giacomo, Pangrazio Haetscher, Nadine Brill, Boris Theis, Fabian Hennighausen, Lothar Schroeder, Timm Rieger, Michael TI CYTOKINE-REGULATED GADD45G INDUCES DIFFERENTIATION AND LINEAGE SELECTION IN HEMATOPOIETIC STEM CELLS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Thalheimer, Frederic; Wingert, Susanne; Haetscher, Nadine; Rieger, Michael] Goethe Univ Frankfurt, LOEWE Ctr Cell & Gene Therapy, D-60054 Frankfurt, Germany. [Schroeder, Timm] Swiss Fed Inst Technol, Basel, Switzerland. [De Giacomo, Pangrazio; Brill, Boris] Georg Speyer Haus, Frankfurt, Germany. [Theis, Fabian] Helmholtz Zentrum Munich, Neuherberg, Germany. [Hennighausen, Lothar] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 AUG PY 2014 VL 42 IS 8 SU 1 MA P1137 BP S57 EP S57 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300202 ER PT J AU Walker, B Izumikawa, K Tsai, HF Bennett, JE AF Walker, Bryan Izumikawa, Koichi Tsai, Huie-Fung Bennett, John E. TI Milbemycin A4 oxime as a probe of azole transport in Candida glabrata SO FEMS YEAST RESEARCH LA English DT Article DE azole; resistance; Candida glabrata; milbemycin ID DRUG-RESISTANCE; FLUCONAZOLE RESISTANCE; MULTIDRUG-RESISTANCE; EFFLUX; GENE; TRANSCRIPTION; INHIBITORS; REGULATOR; PDH1 AB Azole resistance in Candida glabrata, a pathogenic yeast, has prompted studies of compounds that have therapeutic potential by reversing azole resistance. Milbemycin A4 oxime blocked azole efflux and enhanced azole susceptibility fourfold in 28 clinical isolates of C.glabrata. Specificity of the milbemycin A4 oxime effect depended on the drug transporter and the substrate being effluxed. The major effect of milbemycin A4 oxime was inhibition of azole and rhodamine 6G efflux by the ATP-binding cassette (ABC) transporters CgCDR1 and PDH1. Milbemycin A4 oxime effect did not extend to oligomycin, transported by the ABC transporter YOR1 or to benomyl, transported by the major facilitator superfamily transporter, CgFLR1. Milbemycin A4 oxime did not suppress transcription of CgCDR1 but increased CgCDR1 expression 126-fold. Selectivity of the effect is compatible with the concept that milbemycin A4 oxime may interact directly with one or more drug-binding sites of the major azole transporters. C1 [Walker, Bryan; Izumikawa, Koichi; Tsai, Huie-Fung; Bennett, John E.] NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Clin Ctr Room 12C103b, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov FU Division of Intramural Research, NIAID FX The authors have no conflicts of interest with this work. The work was supported by the Division of Intramural Research, NIAID. NR 20 TC 2 Z9 2 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1567-1356 EI 1567-1364 J9 FEMS YEAST RES JI FEMS Yeast Res. PD AUG PY 2014 VL 14 IS 5 BP 755 EP 761 DI 10.1111/1567-1364.12164 PG 7 WC Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biotechnology & Applied Microbiology; Microbiology; Mycology GA AN3IK UT WOS:000340480400008 PM 24838041 ER PT J AU Schoen, RE Pinsky, PF AF Schoen, Robert E. Pinsky, Paul F. TI Can Symptomatic Cancer Be Distinguished From Screen Detected Cancer? SO GASTROENTEROLOGY LA English DT Letter C1 [Schoen, Robert E.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Pinsky, Paul F.] NCI, Bethesda, MD 20892 USA. RP Schoen, RE (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2014 VL 147 IS 2 BP 545 EP 546 DI 10.1053/j.gastro.2014.05.044 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2WX UT WOS:000340447800047 PM 24973674 ER PT J AU Chiquet, M Birk, DE Bonnemann, CG Koch, M AF Chiquet, Matthias Birk, David E. Boennemann, Carsten G. Koch, Manuel TI Collagen XII: Protecting bone and muscle integrity by organizing collagen fibrils SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Collagen XII; Collagen fiber; Osteogenesis; Ehlers-Danlos syndrome; Bethlem myopathy ID 2 SPLICE VARIANTS; DIFFERENTIAL EXPRESSION; DOMAIN; FORM; SKIN; CARTILAGE; MOLECULE; TENDON; CHICK; IX AB Collagen XII, largest member of the fibril-associated collagens with interrupted triple helix (FACIT) family, assembles from three identical alpha-chains encoded by the COL12A1 gene. The molecule consists of three threadlike N-terminal noncollagenous NC3 domains, joined by disulfide bonds and a short interrupted collagen triple helix toward the C-terminus. Splice variants differ considerably in size and properties: "small" collagen XIIB (220 kDa subunit) is similar to collagen XIV, whereas collagen XIIA (350 kDa) has a much larger NC3 domain carrying glycosaminoglycan chains. Collagen XII binds to collagen I-containing fibrils via its collagenous domain, whereas its large noncollagenous arms interact with other matrix proteins such as tenascin-X. In dense connective tissues and bone, collagen XII is thought to regulate organization and mechanical properties of collagen fibril bundles. Accordingly, recent findings show that collagen XII mutations cause Ehlers-Danlos/myopathy overlap syndrome associated with skeletal abnormalities and muscle weakness in mice and humans. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Chiquet, Matthias] Univ Bern, Sch Dent Med, Dept Orthodont & Dentofacial Orthoped, CH-3010 Bern, Switzerland. [Birk, David E.] Univ S Florida, Dept Mol Pharmacol & Physiol, Tampa, FL USA. [Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Koch, Manuel] Univ Cologne, Fac Med, Ctr Mol Med Cologne, Inst Dent Res & Oral Musculoskeletal Biol, D-50931 Cologne, Germany. [Koch, Manuel] Univ Cologne, Fac Med, Ctr Biochem, D-50931 Cologne, Germany. [Koch, Manuel] Univ Lisbon, Fac Ciencias, Dept Biol Anim, Ctr Biol Ambiental, Lisbon, Portugal. RP Chiquet, M (reprint author), Univ Bern, Sch Dent Med, Dept Orthodont & Dentofacial Orthoped, Freiburgstr 7, CH-3010 Bern, Switzerland. EM matthias.chiquet@zmk.unibe.ch RI Birk, David/I-4072-2012 OI Birk, David/0000-0002-4865-9088 FU Swiss NSF [3100A0-107515, 31003A_146825]; NIH [NIAMS AR044745]; NINDS/NIH; DFG [SFB 829, A7]; Koln Fortune Programme of the Medical Faculty FX Own work was supported by grants 3100A0-107515 and 31003A_146825 from the Swiss NSF (MC), NIH grant NIAMS AR044745 (DEB), intramural funds from NINDS/NIH (CGB), DFG SFB 829 grant A7 and the Koln Fortune Programme of the Medical Faculty (MK). NR 32 TC 12 Z9 12 U1 4 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD AUG PY 2014 VL 53 BP 51 EP 54 DI 10.1016/j.biocel.2014.04.020 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN1KE UT WOS:000340340400007 PM 24801612 ER PT J AU Limon, J Miettinen, M Lasota, J AF Limon, Janusz Miettinen, Markku Lasota, Jerzy TI Rare cancers SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Editorial Material C1 [Limon, Janusz] Med Univ Gdansk, Gdansk, Poland. [Miettinen, Markku; Lasota, Jerzy] NCI, Bethesda, MD 20892 USA. RP Limon, J (reprint author), Med Univ Gdansk, Gdansk, Poland. EM jlimon@gumed.edu.pl NR 0 TC 0 Z9 0 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD AUG PY 2014 VL 53 BP 461 EP 461 DI 10.1016/j.biocel.2014.06.001 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN1KE UT WOS:000340340400054 PM 24907398 ER PT J AU Miettinen, M Lasota, J AF Miettinen, Markku Lasota, Jerzy TI Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - A review SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Review DE Gastrointestinal stromal tumor; GIST; SDH-complex; SDHA; SDHB ID CARNEY TRIAD; SDHA MUTATIONS; COMPLEX II; THERAPEUTIC TARGET; GERMLINE MUTATIONS; PDGFRA MUTATIONS; EXPRESSION; PARAGANGLIOMA; IGF1R; GENE AB Loss of function of the succinate dehydrogenase complex characterizes a rare group of human tumors including some gastrointestinal stromal tumors, paragangliomas, renal carcinomas, and pituitary adenomas, and these can all be characterized as SDH-deficient tumors. Approximately 7.5% of gastric gastrointestinal stromal tumors are SDH-deficient and not driven by KIT/PDGFRA mutations, as are most other GISTs. The occurrence of SDH-deficient GISTs is restricted to stomach, and they typically occur in children and young adults representing a spectrum of clinical behavior from indolent to progressive. Slow progression is a common feature even after metastatic spread has taken place, and many patients live years with metastases. SDH-deficient GISTs have characteristic morphologic features including multinodular gastric wall involvement, often multiple separate tumors, common lymphovascular invasion, and occasional lymph node metastases. Diagnostic is the loss of succinate dehydrogenase subunit B (SDHB) from the tumor cells and this can be practically assessed by immunohistochemistry. SDHA is lost in cases associated with SDHA mutations. Approximately half of the patients have SDH subunit gene mutations, often germline and most commonly A (30%), and B, C or D (together 20%), with both alleles inactivated in the tumor cells according to the classic tumor suppressor gene model. Half of the cases are not associated with SDH-mutations and epigenetic silencing of the SDH complex is the possible pathogenesis. Extensive genomic methylation has been observed in these tumors, which is in contrast with other GISTs. SDH-loss causes succinate accumulation and activation of pseudohypoxia signaling via overexpression of HIF-proteins. Activation of insulin-like growth factor 1-signaling is also typical of these tumors. SDH-deficient GISTs are a unique group of GISTs with an energy metabolism defect as the key oncogenic mechanism. Published by Elsevier Ltd. C1 [Miettinen, Markku; Lasota, Jerzy] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Miettinen, M (reprint author), NCI, Lab Surg Pathol, 9000 Rockville Pike,Bldg 10,Room 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU Intramural NIH HHS [ZID BC011291-04] NR 46 TC 21 Z9 27 U1 3 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD AUG PY 2014 VL 53 BP 514 EP 519 DI 10.1016/j.biocel.2014.05.033 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN1KE UT WOS:000340340400061 PM 24886695 ER PT J AU Hohenadel, MG Thearle, MS Grice, BA Huang, H Dai, MH Tao, YX Hunter, LA Palaguachi, GI Mou, Z Kim, RC Tsang, MM Haack, K Voruganti, VS Cole, SA Butte, NF Comuzzie, AG Muller, YL Baier, LJ Krakoff, J Knowler, WC Yanovski, JA Han, JC AF Hohenadel, M. G. Thearle, M. S. Grice, B. A. Huang, H. Dai, M-H Tao, Y-X Hunter, L. A. Palaguachi, G. I. Mou, Z. Kim, R. C. Tsang, M. M. Haack, K. Voruganti, V. S. Cole, S. A. Butte, N. F. Comuzzie, A. G. Muller, Y. L. Baier, L. J. Krakoff, J. Knowler, W. C. Yanovski, J. A. Han, J. C. TI Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE BDNF; MC4R; ELISA; SNP; leptin ID AGOUTI-RELATED PROTEIN; PHARMACOLOGICAL CHARACTERIZATION; CHILDHOOD OBESITY; PIMA-INDIANS; FOOD-INTAKE; FACTOR BDNF; MICE; PROOPIOMELANOCORTIN; POLYMORPHISMS; ANTAGONIST AB BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean +/- s.d.): age, 15.7 +/- 6.5 years; body mass index z-scores (BMI-Z), 1.63 +/- 1.03) and 69 subjects of Hispanic heritage (10.8 +/- 3.6 years; BMI-Z, 1.57 +/- 1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P = 0.29) or 20 GOF subjects versus 20 GOF-matched controls (P = 0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P = 0.006) and rs6265 (P = 0.009), but not rs7124442 (P = 0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P = 0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans. C1 [Hohenadel, M. G.; Thearle, M. S.; Grice, B. A.; Muller, Y. L.; Baier, L. J.; Krakoff, J.; Knowler, W. C.] NIDDK, NIH, Phoenix, AZ USA. [Huang, H.; Dai, M-H; Tao, Y-X] Auburn Univ, Coll Vet Med, Dept Anat Physiol & Pharmacol, Auburn, AL 36849 USA. [Hunter, L. A.; Palaguachi, G. I.; Mou, Z.; Kim, R. C.; Tsang, M. M.; Han, J. C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Metab & Neuroendocrinol, NIH, Bethesda, MD 20892 USA. [Hunter, L. A.; Palaguachi, G. I.; Mou, Z.; Kim, R. C.; Tsang, M. M.; Yanovski, J. A.; Han, J. C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, NIH, Bethesda, MD 20892 USA. [Haack, K.; Voruganti, V. S.; Cole, S. A.; Comuzzie, A. G.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Butte, N. F.] Baylor Coll Med, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA. RP Han, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Metab & Neuroendocrinol, NIH, Bldg 10-CRC,Room 1-3330,MSC 1103,10 Ctr Dr, Bethesda, MD 20892 USA. EM hanjo@mail.nih.gov RI Huang, Hui/E-3030-2015; OI Huang, Hui/0000-0003-2958-257X; Tao, Ya-Xiong/0000-0003-4737-749X FU International Hyperphagia Conference Best Idea Grant from the Prader-Willi Syndrome Association (USA); NIH Intramural Research Program of NICHD; NIH Intramural Research Program of NIDDK FX Funding for this study was provided by the International Hyperphagia Conference Best Idea Grant from the Prader-Willi Syndrome Association (USA) (JCH and JAY), by the NIH Intramural Research Programs of NICHD and NIDDK, American Diabetes Association grant 1-12-BS212 (Y-XT), NIH (R01 DK59264 and R01 DK080457 (NFB), and C06 RR013556 and C06 RR017515) and USDA/ARS under Cooperative Agreement 58-6250-51000-037. JK and JAY are Commissioned Officers of the United States Public Health Service. Clinical Trials Registry: Subjects in the Pima cohort were enrolled in observational, non-interventional studies, registered as NCT00339482. Subjects in the Hispanic cohort were enrolled in observational, non-interventional studies. NR 39 TC 5 Z9 5 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD AUG PY 2014 VL 38 IS 8 BP 1068 EP 1074 DI 10.1038/ijo.2013.221 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AN5XV UT WOS:000340666900007 PM 24276017 ER PT J AU Alstadhaug, KB Croughs, T Henriksen, S Leboeuf, C Sereti, I Hirsch, HH Rinaldo, CH AF Alstadhaug, Karl B. Croughs, Therese Henriksen, Stian Leboeuf, Celine Sereti, Irini Hirsch, Hans H. Rinaldo, Christine Hanssen TI Treatment of Progressive Multifocal Leukoencephalopathy With Interleukin 7 SO JAMA NEUROLOGY LA English DT Article ID LYMPHOCYTOPENIA; BIOLOGY; JCV; PML AB IMPORTANCE No reliable treatment options are known for progressive multifocal leukoencephalopathy with underlying immunodeficiency. We describe successful compassionate use of recombinant human interleukin 7 in a patient with idiopathic CD4(+) T-cell lymphocytopenia. OBSERVATIONS After the diagnoses of progressive multifocal leukoencephalopathy and idiopathic CD4(+) T-cell lymphocytopenia were established, a 61-year-old man was treated with recombinant human interleukin 7 on November 1, 2012. Except for an episode of epilepsia partialis continua on January 16, 2013, a gradual clinical improvement was observed until March. Abnormalities shown on magnetic resonance imaging regressed; JC virus DNA in plasma, likely originating from the brain based on sequencing data, cleared; and increases in peripheral CD4(+) T cells and JC virus intrathecal antibodies were observed. One year after treatment, the CD4(+) T-cell count returned to baseline and the clinical improvement waned, possibly due to the patient's complex epilepsy. On the latest evaluation on January 14, 2014, the patient's condition was unchanged, with no signs of ongoing central nervous system infection. CONCLUSIONS AND RELEVANCE The present case argues strongly for proof of the treatment concept. However, deeper insight into the JC virus and its pathogenesis and the immune response during central nervous system infection as well as further clinical studies are needed before recombinant human interleukin 7 can be recommended for the treatment of other cases of immunodeficiency and progressive multifocal leukoencephalopathy. C1 [Alstadhaug, Karl B.] Nordland Hosp Trust, Dept Neurol, N-8092 Bodo, Norway. [Alstadhaug, Karl B.; Rinaldo, Christine Hanssen] UiT Arctic Univ Tromso, Dept Clin Med, Tromso, Norway. [Croughs, Therese] Cytheris SA, Issy Les Moulineaux, France. [Henriksen, Stian; Rinaldo, Christine Hanssen] Univ Hosp North Norway, Dept Microbiol & Infect Control, Tromso, Norway. [Leboeuf, Celine; Hirsch, Hans H.] Univ Basel, Dept Biomed, Div Transplantat & Clin Virol, Basel, Switzerland. [Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. [Hirsch, Hans H.] Univ Basel Hosp, Div Infect Dis & Hosp Epidemiol, CH-4031 Basel, Switzerland. [Rinaldo, Christine Hanssen] UiT Arctic Univ Norway, Metab & Renal Res Grp, Tromso, Norway. RP Alstadhaug, KB (reprint author), Nordland Hosp Trust, Dept Neurol, N-8092 Bodo, Norway. EM Karl.bjornar.alstadhaug@nlsh.no FU National Institute of Allergy and Infectious Diseases FX Dr Sereti reported that her work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 15 TC 20 Z9 20 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD AUG PY 2014 VL 71 IS 8 BP 1030 EP 1035 DI 10.1001/jamaneurol.2014.825 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AN3IW UT WOS:000340481800014 PM 24979548 ER PT J AU Yang, JY Chandrasekharappa, SC Vilboux, T Smith, ACM Peterson, EJ AF Yang, Jianying Chandrasekharappa, Settara C. Vilboux, Thierry Smith, Ann C. M. Peterson, Erik J. TI Immune Complex-Mediated Autoimmunity in a Patient With Smith-Magenis Syndrome (del 17p11.2) SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article DE Smith-Magenis syndrome; del 17p11.2; systemic lupus erythematosus; autoimmunity; antiphospholipid antibody syndrome; autoimmune hepatitis ID B-CELLS; TACI; MICE; DEFICIENCY AB Smith-Magenis syndrome (SMS) is a sporadic congenital disorder involving multiple organ systems caused by chromosome 17p11.2 deletions. Smith-Magenis syndrome features craniofacial and skeletal anomalies, cognitive impairment, and neurobehavioral abnormalities. In addition, some SMS patients may exhibit hypogammaglobulinemia. We report the first case of SMS-associated autoimmunity in a woman who presented with adult onset of multiple autoimmune disorders, including systemic lupus erythematosus, antiphospholipid antibody syndrome, and autoimmune hepatitis. Molecular analysis using single-nucleotide polymorphism array confirmed a de novo 3.8-Mb deletion (breakpoints, chr17: 16,660,721-20,417,975), resulting in haploinsufficiency for TACI (transmembrane activator and CAML interactor). Our data are consistent with potential loss of function for the BAFF (B cell-activating factor) receptor TACI as a contributing factor to human autoimmune phenomena. C1 [Yang, Jianying; Peterson, Erik J.] Univ Minnesota, Div Rheumatol, Dept Med, Minneapolis, MN 55455 USA. [Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Vilboux, Thierry] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Smith, Ann C. M.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Peterson, EJ (reprint author), Univ Minnesota, Div Rheumatol, Dept Med, 2-112 MBB,2101 6th St SE, Minneapolis, MN 55455 USA. EM peter899@umn.edu FU National Human Genome Research Institute, National Institutes of Health, Bethesda, MD FX This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 EI 1536-7355 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD AUG PY 2014 VL 20 IS 5 BP 291 EP 293 DI 10.1097/RHU.0000000000000118 PG 3 WC Rheumatology SC Rheumatology GA AN1WM UT WOS:000340374700011 PM 25036569 ER PT J AU Greene, AD Patounakis, G Segars, JH AF Greene, Alexis D. Patounakis, George Segars, James H. TI Genetic associations with diminished ovarian reserve: a systematic review of the literature SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Review DE DOR; Poor ovarian reserve; Genetic causes; Genes; Premature ovarian aging; POR ID GROWTH-DIFFERENTIATION FACTOR-9; IN-VITRO FERTILIZATION; BONE MORPHOGENETIC PROTEIN-15; GRANULOSA-CELLS; POOR RESPONSE; YOUNG-WOMEN; EARLY MENOPAUSE; CGG REPEATS; FMR1 GENE; ESR1 GENE AB Diminished ovarian reserve (DOR) affects 10 % of women seeking fertility treatment. Although it is much more prevalent than premature ovarian failure, less is known about its etiology. The purpose of this article is to review the possible genetic causes of, and associations with, pathologic DOR. A systematic review was conducted using PubMed from 1966 through November 2013. Twenty-one articles identified genes associated with DOR: one gene mutation (FMR1), three polymorphisms (GDF9, FSHR, and ESR1), and seven genes differentially expressed between women with DOR and controls (AMH, LHCGR, IGF1, IGF2, IGF1R, IGF2R and GREM1). Six candidate genes were discovered in mice, including Foxl2, Gdf9, Bmp15, Aire, Wnt4, and Gpr3. Two case reports of chromosomal translocations were also identified. While the etiology of pathologic DOR is likely multifactorial, it is possible that many cases attributed to an idiopathic cause may have a genetic component. Larger studies are needed to expose the impact gene mutations, polymorphisms, and epigenetics have on pathologic DOR. C1 [Greene, Alexis D.] St Lukes Roosevelt Hosp, Dept Obstet & Gynecol, New York, NY 10019 USA. [Patounakis, George; Segars, James H.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), NICHD, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU Program in Reproductive and Adult Endocrinology, NICHD, NIH; ZIA [HD-008737-] FX This research was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH and ZIA HD-008737- to JHS. NR 60 TC 8 Z9 8 U1 2 U2 15 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 EI 1573-7330 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD AUG PY 2014 VL 31 IS 8 BP 935 EP 946 DI 10.1007/s10815-014-0257-5 PG 12 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA AN4HU UT WOS:000340549100002 PM 24840722 ER PT J AU Prasad, V AF Prasad, Vinay TI Balloon brachytherapy for breast cancer prove that it works? Or, prove that it doesn't? SO JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY LA English DT Editorial Material DE Balloon brachytherapy; Mammosite; Evidence-based medicine ID INITIAL CLINICAL-EXPERIENCE; PATIENT-CENTERED CARE; INTRAOPERATIVE RADIOTHERAPY; MEDICAL-PRACTICES; RANDOMIZED-TRIAL; IRRADIATION APBI; HINDERS SCIENCE; FOLLOW-UP; COMPLICATIONS; MASTECTOMY AB Balloon breast brachytherapy is a catheter-based technique to deliver high local concentration of radiation following breast-sparing surgery. Although this technique is logically appealing-providing more directed radiation to sites at high risk of local failure-there remains little empirical support that this intervention is non-inferior to external beam radiotherapy, a well-established standard. Additionally, observational studies suggest that balloon brachytherapy is associated with high rates of local complications, and higher rates of subsequent mastectomy, a marker of local failure. Here, I explore regulatory and clinical considerations that lead to the widespread adoption of breast brachytherapy. I argue that the therapy spread before its efficacy was confirmed. Breast brachytherapy illustrates ongoing complexities in the approval of novel devices. C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 31 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-5216 EI 1432-1335 J9 J CANCER RES CLIN JI J. Cancer Res. Clin. Oncol. PD AUG PY 2014 VL 140 IS 8 BP 1353 EP 1357 DI 10.1007/s00432-014-1705-4 PG 5 WC Oncology SC Oncology GA AN4LB UT WOS:000340558200011 PM 24858568 ER PT J AU Sharov, AA Nishiyama, A Qian, Y Dudekula, DB Longo, DL Schlessinger, D Ko, MSH AF Sharov, Alexei A. Nishiyama, Akira Qian, Yong Dudekula, Dawood B. Longo, Dan L. Schlessinger, David Ko, Minoru S. H. TI Chromatin Properties of Regulatory DNA Probed by Manipulation of Transcription Factors SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article DE chromatin modification; cis-regulatory module; embryonic stem cells; enhancer; target genes; transcription factor binding site ID EMBRYONIC STEM-CELLS; GENE-EXPRESSION; SELF-RENEWAL; HUMAN GENOME; ES CELLS; ENHANCERS; NETWORKS; DISTINCT; NANOG; DIFFERENTIATION AB Transcription factors (TFs) bind to DNA and regulate the transcription of nearby genes. However, only a small fraction of TF binding sites have such regulatory effects. Here we search for the predictors of functional binding sites by carrying out a systematic computational screening of a variety of contextual factors (histone modifications, nuclear laminbindings, and cofactor bindings). We used regression analysis to test if contextual factors are associated with upregulation or downregulation of neighboring genes following the induction or knockdown of the 9 TFs in mouse embryonic stem (ES) cells. Functional TF binding sites appeared to be either active (i.e., bound by P300, CHD7, mediator, cohesin, and SWI/SNF) or repressed (i.e., with H3K27me3 histone marks and bound by Polycomb factors). Active binding sites mediated the downregulation of nearby genes upon knocking down the activating TFs or inducing repressors. Repressed TF binding sites mediated the upregulation of nearby genes (e. g., poised developmental regulators) upon inducing TFs. In addition, repressed binding sites mediated repressive effects of TFs, identified by the downregulation of target genes after the induction of TFs or by the upregulation of target genes after the knockdown of TFs. The contextual factors associated with functions of DNA-bound TFs were used to improve the identification of candidate target genes regulated by TFs. C1 [Sharov, Alexei A.; Nishiyama, Akira; Qian, Yong; Dudekula, Dawood B.; Longo, Dan L.; Schlessinger, David; Ko, Minoru S. H.] NIA, Natl Inst Hlth, Baltimore, MD 21224 USA. [Ko, Minoru S. H.] Keio Univ, Sch Med, Dept Syst Med, Sakaguchi Lab, Tokyo 160, Japan. RP Ko, MSH (reprint author), Keio Univ, Sch Med, Dept Syst Med, Sakaguchi Lab,Shinjuku Ku, Shinanomachi 35, Tokyo 160, Japan. EM kom@z7.keio.jp OI Dudekula, Dawood/0000-0002-4054-1827; Ko, Minoru/0000-0002-3530-3015 FU National Institutes of Health, National Institute on Aging FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. We thank current and past lab members for discussion and contribution to data published previously and integrated into the meta-analysis in this article. NR 41 TC 2 Z9 2 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 EI 1557-8666 J9 J COMPUT BIOL JI J. Comput. Biol. PD AUG PY 2014 VL 21 IS 8 BP 569 EP 577 DI 10.1089/cmb.2013.0126 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AN4ED UT WOS:000340539500001 PM 24918633 ER PT J AU Wang, JHY Liang, WC Ma, GX Gehan, E Wang, HE Ji, CS Tu, SP Vernon, SW Mandelblatt, JS AF Wang, Judy Huei-yu Liang, Wenchi Ma, Grace X. Gehan, Edmund Wang, Haoying Echo Ji, Cheng-Shuang Tu, Shin-Ping Vernon, Sally W. Mandelblatt, Jeanne S. TI Promoting Chinese-Speaking Primary Care Physicians' Communication with Immigrant Patients about Colorectal Cancer Screening: A Cluster Randomized Trial Design SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Colorectal cancer screening; physician-based intervention; cluster RCT; Chinese primary care physician; self-efficacy; patient-centered communication ID AMERICAN WOMEN; BREAST-CANCER; SELF-EFFICACY; UNDERSERVED COMMUNITY; PREVENTIVE SERVICES; HEALTH; INTERVENTIONS; MAMMOGRAPHY; BARRIERS; SKILLS AB Chinese Americans underutilize colorectal cancer screening. This study evaluated a physician-based intervention guided by social cognitive theory (SCT) to inform future research involving minority physicians and patients. Twenty-five Chinese-speaking primary care physicians were randomized into intervention or usual care arms. The intervention included two 45-minute in-office training sessions paired with a dual-language communication guide detailing strategies in addressing Chinese patients' screening barriers. Physicians' feedback on the intervention, their performance data during training, and pre-post intervention survey data were collected and analyzed. Most physicians (similar to 85%) liked the intervention materials but similar to 84% spent less than 20 minutes reading the guide and only 46% found the length of time for in-office training acceptable. Despite this, the intervention increased physicians' perceived communication self-efficacy with patients (p<.01). This study demonstrated the feasibility of enrolling and intervening with minority physicians. Time constraints in primary care practice should be considered in the design and implementation of interventions. C1 [Wang, Judy Huei-yu; Gehan, Edmund; Wang, Haoying Echo; Ji, Cheng-Shuang; Mandelblatt, Jeanne S.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Wang, Judy Huei-yu; Wang, Haoying Echo; Ji, Cheng-Shuang; Mandelblatt, Jeanne S.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Washington, DC 20007 USA. [Liang, Wenchi] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. [Ma, Grace X.] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Ma, Grace X.] Temple Univ, Ctr Asian Hlth, Philadelphia, PA 19122 USA. [Gehan, Edmund] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Tu, Shin-Ping] Virginia Commonwealth Univ, Div Gen Internal Med, Richmond, VA 23284 USA. [Vernon, Sally W.] Univ Texas Houston, Sch Publ Hlth, Ctr Hlth Promot & Prevent Res, Houston, TX USA. RP Wang, JHY (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM jw235@georgetown.edu FU NCI NIH HHS [R01 CA121023, U54 CA153513] NR 58 TC 1 Z9 1 U1 3 U2 7 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2014 VL 25 IS 3 BP 1079 EP 1100 PG 22 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AN0XC UT WOS:000340306300011 PM 25130226 ER PT J AU Barazt-Goldstein, R Rubovitc, V Tweedie, D Scheriber, S Greig, NH Pick, CG AF Barazt-Goldstein, R. Rubovitc, V. Tweedie, D. Scheriber, S. Greig, N. H. Pick, C. G. TI The therapeutic impact of thalidomide analogue, 3,6 '-dithiothalidomide, on recovery from minimal traumatic brain injury SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 22nd Annual Meeting of the Israel-Society-for-Neuroscience (ISFN) / 2nd Bi National Italy-Israel Neuroscience Meeting CY DEC 14-17, 2013 CL Eilat, ISRAEL SP Israel Soc Neuroscience C1 [Barazt-Goldstein, R.; Rubovitc, V.; Scheriber, S.; Pick, C. G.] Tel Aviv Univ, Sackler Fac Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Tweedie, D.; Greig, N. H.] NIA, Drug Design & Dev Sect, IRP, NIH, Baltimore, MD 21224 USA. [Scheriber, S.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Psychiat, IL-69978 Tel Aviv, Israel. RI Pick, Chaim/D-4789-2009 NR 0 TC 0 Z9 0 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD AUG PY 2014 VL 53 SU 1 BP S12 EP S12 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AN3GN UT WOS:000340474000024 ER PT J AU Lin, T Vaisvaser, S Fruchter, E Admon, R Wald, I Pine, DS Bar-Haim, Y Hendler, T AF Lin, T. Vaisvaser, S. Fruchter, E. Admon, R. Wald, I Pine, D. S. Bar-Haim, Y. Hendler, T. TI Threat bias mediates the relation between hippocampus and anxiety SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 22nd Annual Meeting of the Israel-Society-for-Neuroscience (ISFN) / 2nd Bi National Italy-Israel Neuroscience Meeting CY DEC 14-17, 2013 CL Eilat, ISRAEL SP Israel Soc Neuroscience C1 [Lin, T.; Vaisvaser, S.; Admon, R.; Hendler, T.] Tel Aviv Sourasky Med Ctr, Wohl Inst Adv Imaging, Funct Brain Ctr, Tel Aviv, Israel. [Lin, T.; Wald, I; Bar-Haim, Y.; Hendler, T.] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Vaisvaser, S.; Hendler, T.] Tel Aviv Univ, Dept Physiol & Pharmacol, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Fruchter, E.] IDF, Med Corps, Div Mental Hlth, Tel Hashomer, Israel. [Pine, D. S.] Inst Mental Hlth, Intramural Res Program, Mood & Anxiety Disorders Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD AUG PY 2014 VL 53 SU 1 BP S79 EP S79 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AN3GN UT WOS:000340474000207 ER PT J AU Lots, IS Robinson, SE Abeles, M AF Lots, Shapira, I Robinson, S. E. Abeles, M. TI Extracting cortical current dipoles from MEG recordings SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 22nd Annual Meeting of the Israel-Society-for-Neuroscience (ISFN) / 2nd Bi National Italy-Israel Neuroscience Meeting CY DEC 14-17, 2013 CL Eilat, ISRAEL SP Israel Soc Neuroscience C1 [Lots, Shapira, I; Abeles, M.] Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, Ramat Gan, Israel. [Robinson, S. E.] NIMH, MEG Core Grp, NIH, Bethesda, MD 20892 USA. [Abeles, M.] Hebrew Univ Jerusalem, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD AUG PY 2014 VL 53 SU 1 BP S113 EP S114 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AN3GN UT WOS:000340474000302 ER PT J AU Moody, TW AF Moody, Terry W. TI SR48692 INHIBITS NON-SMALL CELL LUNG CANCER PROLIFERATION IN AN EGF RECEPTOR-DEPENDENT MECHANISM SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 22nd Annual Meeting of the Israel-Society-for-Neuroscience (ISFN) / 2nd Bi National Italy-Israel Neuroscience Meeting CY DEC 14-17, 2013 CL Eilat, ISRAEL SP Israel Soc Neuroscience C1 [Moody, Terry W.] NCI, Dept Hlth & Human Serv, Ctr Canc Res, Off Director, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD AUG PY 2014 VL 53 SU 1 BP S178 EP S178 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AN3GN UT WOS:000340474000456 ER PT J AU Little, RE Taylor, RJ Miller, JD Ambrose, EC Germanwala, AV Sasaki-Adams, DM Ewend, MG Zanation, AM AF Little, Ryan E. Taylor, Robert J. Miller, Justin D. Ambrose, Emily C. Germanwala, Anand V. Sasaki-Adams, Deanna M. Ewend, Matthew G. Zanation, Adam M. TI Endoscopic Endonasal Transclival Approaches: Case Series and Outcomes for Different Clival Regions SO JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE LA English DT Article DE clivus; skull base surgery; endoscopic endonasal approach; CSF leak ID RESECTION; CHORDOMAS; SURGERY; LESIONS AB Objective Transclival endoscopic endonasal approaches to the skull base are novel with few published cases. We report our institution's experience with this technique and discuss outcomes according to the clival region involved. Design Retrospective case series. Setting Tertiary care academic medical center Participants All patients who underwent endoscopic endonasal transclival approaches for skull base lesions from 2008 to 2012. Main Outcome Measures Pathologies encountered, mean intraoperative time, intraoperative complications, gross total resection, intraoperative cerebrospinal fluid (CSF) leak, postoperative CSF leak, postoperative complications, and postoperative clinical course. Results A total of 49 patients underwent 55 endoscopic endonasal transclival approaches. Pathology included 43 benign and 12 malignant lesions. Mean follow-up was 15.4 months. Mean operative time was 167.9 minutes, with one patient experiencing an intraoperative internal carotid artery injury. Of the 15 cases with intraoperative cerebrospinal fluid (CSF) leaks, 1 developed postoperative CSF leak (6.7%). There were six other postoperative complications: four systemic complications, one case of meningitis, and one retropharyngeal abscess. Gross total resection was achieved for all malignancies approached with curative intent. Conclusions This study provides evidence that endoscopic endonasal transclival approaches are a safe and effective strategy for the surgical management of a variety of benign and malignant lesions. C1 [Little, Ryan E.; Taylor, Robert J.; Miller, Justin D.; Ambrose, Emily C.; Zanation, Adam M.] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC 27599 USA. [Germanwala, Anand V.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Sasaki-Adams, Deanna M.; Ewend, Matthew G.] Univ N Carolina, Dept Neurosurg, Chapel Hill, NC 27599 USA. RP Zanation, AM (reprint author), Univ N Carolina, Dept Otolaryngol Head & Neck Surg, 170 Manning Dr,Phys Off Bldg,Ground Floor,CB 7070, Chapel Hill, NC 27599 USA. EM adam_zanation@med.unc.edu OI Little, Ryan/0000-0002-4000-946X FU Doris Duke Charitable Foundation FX This work was supported by a grant from the Doris Duke Charitable Foundation to the University of North Carolina at Chapel Hill to fund Clinical Research Fellow Robert Taylor. NR 22 TC 3 Z9 3 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2193-6331 EI 2193-634X J9 J NEUROL SURG PART B JI Journal of Neurol. Surg. Part B PD AUG PY 2014 VL 75 IS 4 BP 247 EP 254 DI 10.1055/s-0034-1371522 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AN3LG UT WOS:000340488900006 PM 25093148 ER PT J AU Wiener, L Sweeney, C Baird, K Merchant, MS Warren, KE Corner, GW Roberts, KE Lichtenthal, WG AF Wiener, Lori Sweeney, Corinne Baird, Kristin Merchant, Melinda S. Warren, Katherine E. Corner, Geoffrey W. Roberts, Kailey E. Lichtenthal, Wendy G. TI What Do Parents Want to Know When Considering Autopsy for Their Child With Cancer? SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE pediatric oncology; autopsy; postmortem examination; end of life ID INTENSIVE-CARE-UNIT; OF-LIFE CARE; PEDIATRIC PALLIATIVE CARE; INTRINSIC PONTINE GLIOMA; FAMILY PERSPECTIVES; HOSPITAL STAFF; QUALITY; RECOMMENDATIONS; DEATH AB Research has suggested that autopsy in pediatrics is a valued way for parents to better understand and process their child's death, yet physicians often express hesitancy in discussing this topic with parents. To better assist clinicians with initiating discussion about this often sensitive topic, the current study examined bereaved parents' preferences about the timing and content of the autopsy discussion as well as reasons for considering autopsy. This study explored the views of 30 parents who lost a child to a variety of malignancies between 6 months and 6 years ago. Results showed that 36.7% of parents recalled having a discussion about autopsy, and the vast majority of those who did not recall a discussion (89.5%) would have considered an autopsy if it had been discussed. The majority of participants in this study indicated their preference to have the first conversation about autopsy when it becomes clear that cure is no longer possible. Findings suggest that educating parents about the clinical, emotional, and potential research benefits of autopsy and tissue procurement will ultimately help them make informed decisions and understand the importance of autopsy in medical progress. The future research and clinical implications of these findings are discussed. C1 [Wiener, Lori; Baird, Kristin; Merchant, Melinda S.; Warren, Katherine E.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sweeney, Corinne; Corner, Geoffrey W.; Roberts, Kailey E.; Lichtenthal, Wendy G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Wiener, L (reprint author), NCI, Behav Sci Core, Psychosocial Support & Res Program, Pediat Oncol Branch,Ctr Canc Res, 10 Ctr Dr, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov OI Lichtenthal, Wendy/0000-0003-3597-7826 FU Center for Cancer Research, National Cancer Institute; National Cancer Institute [R03 CA 139944, K07 CA172216] FX Supported, in part, by the Center for Cancer Research, National Cancer Institute (L. W., K. B., M. S. M., and K. E. W.) and by National Cancer Institute grants R03 CA 139944 (W. G. L.) and K07 CA172216 (W.G.L.). NR 24 TC 0 Z9 0 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 EI 1536-3678 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD AUG PY 2014 VL 36 IS 6 BP 464 EP 470 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN1XA UT WOS:000340376100022 PM 24309611 ER PT J AU Hernandez, CM Cortez, I Gu, ZL Colon-Saez, JO Lamb, PW Wakamiya, M Yakel, JL Dineley, KT AF Hernandez, Caterina M. Cortez, Ibdanelo Gu, Zhenglin Colon-Saez, Jose O. Lamb, Patricia W. Wakamiya, Maki Yakel, Jerrel L. Dineley, Kelly T. TI Research tool: validation of floxed alpha 7 nicotinic acetylcholine receptor conditional knockout mice using in vitro and in vivo approaches SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; CHOLINERGIC MARKERS; SLICE CULTURES; ASTROCYTES; ACTIVATION; SUBUNITS; DEFICITS; CALCIUM; PROTEIN AB There is much interest in 7 nicotinic acetylcholine receptors (nAChRs) in CNS function since they are found throughout peripheral tissues as well as being highly expressed in brain regions implicated in attention, learning and memory. As such, the role of these receptors in many aspects of CNS function and disease is being actively investigated. To date, only one null mouse model (A7KO) is available which is non-conditional and constitutive. Since 7 nAChRs are present on neurons and glia (including astrocytes), as well as being developmentally regulated, there is an unmet need for the technical capability to control 7 nAChR gene expression. Therefore we have generated mice in which the fourth exon of the 7 nAChR gene (Chrna7) is flanked by loxP sites (B6-Chrna7(LBDEx4007Ehs)) which we refer to as floxed 7 nAChR conditional knockout or 7nAChR(flox). We validated the chosen approach by mating 7nAChR(flox) with mice expressing Cre recombinase driven by the glial acidic fibrillary protein (GFAP)-Cre promoter (GFAP-A7KO) to test whether 7nAChR(flox), GFAP-A7KO and appropriate littermate controls performed equally in our standard Rodent In Vivo Assessment Core battery to assess general health, locomotion, emotional and cognitive behaviours. Neither 7nAChR(flox) nor GFAP-A7KO exhibited significant differences from littermate controls in any of the baseline behavioural assessments we conducted, similar to the first generation' non-conditional A7KO mice. We also determined that 7 nAChR binding sites were absent on GFAP-positive astrocytes in hippocampal slices obtained from GFAP-A7KO offspring from 7nAChR(flox) and GFAP-Cre crosses. Finally, we validated that Cre recombinase (Cre)-mediated excision led to functional, cell- and tissue-specific loss of 7 nAChRs by demonstrating that choline-induced 7 nAChR currents were present in Cre-negative, but not synapsin promoter-driven Cre-positive, CA1 pyramidal neurons. Additionally, electrophysiological characterization of 7 nAChR-mediated current traces was similar in terms of amplitude and time constants of decay (during desensitization) for the 7nAChR(flox) and wild-type (WT) mice. Thus, we have in vivo and in vitro evidence that the Chrna7 exon 4 targeting strategy does not alter behavioural, cognitive, or electrophysiological properties compared to WT and that Cre-mediated excision is an effective approach to delete 7 nAChR expression in a cell-specific manner. C1 [Hernandez, Caterina M.; Cortez, Ibdanelo; Dineley, Kelly T.] Univ Texas Med Branch Galveston UTMB, Mitchell Ctr Neurodegenerat Dis, Galveston, TX USA. [Hernandez, Caterina M.; Cortez, Ibdanelo; Dineley, Kelly T.] UTMB, Dept Neurol, Galveston, TX USA. [Gu, Zhenglin; Colon-Saez, Jose O.; Lamb, Patricia W.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Wakamiya, Maki] UTMB, Anim Resource Ctr, Galveston, TX USA. [Wakamiya, Maki] UTMB, Inst Translat Sci, Galveston, TX USA. [Dineley, Kelly T.] UTMB, Rodent In Vivo Assessment Core, Galveston, TX USA. [Dineley, Kelly T.] UTMB, Addict Res Ctr, Galveston, TX USA. RP Dineley, KT (reprint author), 301 Univ Blvd, Galveston, TX 77555 USA. EM ktdinele@utmb.edu FU Intramural Research Program, NIEHS/NIH; Alzheimer's Association FX This work was supported by the Intramural Research Program, NIEHS/NIH to J.L.Y., a kind gift to K. T. D. from J. & W. Mohn, and an Independent Investigator Research Grant from the Alzheimer's Association to K.T.D. NR 57 TC 7 Z9 7 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 2014 VL 592 IS 15 BP 3201 EP 3214 DI 10.1113/jphysiol.2014.272054 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AN2HB UT WOS:000340404100009 PM 24879866 ER PT J AU Murphy, RA Patel, KV Kritchevsky, SB Houston, DK Newman, AB Koster, A Simonsick, EM Tylvasky, FA Cawthon, PM Harris, TB AF Murphy, Rachel A. Patel, Kushang V. Kritchevsky, Stephen B. Houston, Denise K. Newman, Anne B. Koster, Annemarie Simonsick, Eleanor M. Tylvasky, Frances A. Cawthon, Peggy M. Harris, Tamara B. CA Hlth Aging Body Composition Study TI Weight Change, Body Composition, and Risk of Mobility Disability and Mortality in Older Adults: A Population-Based Cohort Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; obesity; physical function; body composition; muscle loss ID FAT MASS; PHYSICAL FUNCTION; OBESE ADULTS; LEAN MASS; HEALTH; ASSOCIATION; OVERWEIGHT; WOMEN; MEN; FLUCTUATION AB OBJECTIVES: To examine associations between weight change, body composition, risk of mobility disability, and mortality in older adults. DESIGN: Prospective, longitudinal, population-based cohort. SETTING: The Health, Aging, and Body Composition Study. PARTICIPANTS: Women (n = 1,044) and men (n = 931) aged 70 to 79. MEASUREMENTS: Weight and lean and fat mass from dual-energy X-ray absorptiometry measured annually over 5 years. Weight was defined as stable (n = 664, reference), loss (n = 662), gain (n = 321), or cycling (gain and loss, n = 328) using change of 5% from year to year or from Year 1 to 6. Mobility disability (two consecutive reports of difficulty walking one-quarter mile or climbing 10 steps) and mortality were determined for 8 years after the weight change period. Associations were analyzed using Cox proportional hazards regression adjusted for covariates. RESULTS: During follow-up, 313 women and 375 men developed mobility disability, and 322 women and 378 men died. There was no risk of mobility disability or mortality with weight gain. Weight loss (hazard ratio (HR) = 1.88, 95% confidence interval (CI) = 1.40-2.53) and weight cycling (HR = 1.59, 95% CI = 1.11-2.29) were associated with mobility disability in women, and weight loss was associated with mobility disability in men (HR = 1.30, 95% CI = 1.01-1.69). Weight loss and weight cycling were associated with mortality risk in women (weight loss: HR = 1.47, 95% CI = 1.07-2.01; weight cycling: HR = 1.62, 95% CI = 1.15-2.30) and in men (weight loss: HR = 1.41, 95% CI = 1.09-1.83; weight cycling: HR = 1.50, 95% CI = 1.08-2.08). Adjustment for lean and fat mass and change in lean and fat mass from Year 1 to 6 attenuated the relationships between weight loss and mobility disability in men and between weight loss and mortality in men and women. CONCLUSION: Weight cycling and weight loss predict impending mobility disability and mortality in old age, underscoring the prognostic importance of weight history. C1 [Murphy, Rachel A.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20814 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Ctr Pain Res Impact Measurement & Effectiveness, Seattle, WA 98195 USA. [Kritchevsky, Stephen B.; Houston, Denise K.] Wake Forest Sch Med, Sticht Ctr Aging, Sect Gerontol & Geriatr Med, Winston Salem, NC USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Koster, Annemarie] Maastricht Univ, Dept Social Med, CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Simonsick, Eleanor M.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Tylvasky, Frances A.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Cawthon, Peggy M.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. RP Murphy, RA (reprint author), NIA, Lab Epidemiol & Populat Sci, 7201 Wisconsin Ave,3C-309, Bethesda, MD 20814 USA. EM rachel.murphy@nih.gov RI Koster, Annemarie/E-7438-2010; Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; National Institute of Nursing Research [R01-NR-012459]; National Institutes of Health, NIA; Banting Postdoctoral Fellowship FX National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA Grant R01-AG028050, and National Institute of Nursing Research Grant R01-NR-012459. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NIA. RAM is supported by a Banting Postdoctoral Fellowship. NR 32 TC 17 Z9 18 U1 3 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2014 VL 62 IS 8 BP 1476 EP 1483 DI 10.1111/jgs.12954 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3JE UT WOS:000340482800008 PM 25039391 ER PT J AU Fang, X Ahmad, I Blanka, A Schottkowski, M Cimdins, A Galperin, MY Romling, U Gomelsky, M AF Fang, Xin Ahmad, Irfan Blanka, Andrea Schottkowski, Marco Cimdins, Annika Galperin, Michael Y. Roemling, Ute Gomelsky, Mark TI GIL, a new c-di-GMP-binding protein domain involved in regulation of cellulose synthesis in enterobacteria SO MOLECULAR MICROBIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; ESCHERICHIA-COLI; ACETOBACTER-XYLINUM; SALMONELLA-TYPHIMURIUM; PILZ DOMAIN; AGGREGATIVE BEHAVIOR; STRUCTURE PREDICTION; CYCLIC DIGUANYLATE; CHROMOSOMAL GENES; MOTILITY AB In contrast to numerous enzymes involved in c-di-GMP synthesis and degradation in enterobacteria, only a handful of c-di-GMP receptors/effectors have been identified. In search of new c-di-GMP receptors, we screened the Escherichia coli ASKA overexpression gene library using the Differential Radial Capillary Action of Ligand Assay (DRaCALA) with fluorescently and radioisotope-labelled c-di-GMP. We uncovered three new candidate c-di-GMP receptors in E. coli and characterized one of them, BcsE. The bcsE gene is encoded in cellulose synthase operons in representatives of Gammaproteobacteria and Betaproteobacteria. The purified BcsE proteins from E. coli, Salmonella enterica and Klebsiella pneumoniae bind c-di-GMP via the domain of unknown function, DUF2819, which is hereby designated GIL, GGDEF I-site like domain. The RxGD motif of the GIL domain is required for c-di-GMP binding, similar to the c-di-GMP-binding I-site of the diguanylate cyclase GGDEF domain. Thus, GIL is the second protein domain, after PilZ, dedicated to c-di-GMP-binding. We show that in S. enterica, BcsE is not essential for cellulose synthesis but is required for maximal cellulose production, and that c-di-GMP binding is critical for BcsE function. It appears that cellulose production in enterobacteria is controlled by a two-tiered c-di-GMP-dependent system involving BcsE and the PilZ domain containing glycosyltransferase BcsA. C1 [Fang, Xin; Gomelsky, Mark] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Ahmad, Irfan; Blanka, Andrea; Schottkowski, Marco; Cimdins, Annika; Roemling, Ute] Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden. [Galperin, Michael Y.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Gomelsky, M (reprint author), Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. EM gomelsky@uwyo.edu OI Romling, Ute/0000-0003-3812-6621; Cimdins, Annika/0000-0001-7414-9914 FU United States National Science Foundation [MCB1052575]; NIH Intramural Research Program at the National Library of Medicine; Swedish Research Council Natural Sciences [621-2010-5755]; Petrus and Augusta Hedlund Foundation; Carl Tryggers Foundation [CTS 10: 324]; International Research Training Group 1273 - German Research Foundation (DFG); NIH Intramural Research Program at the National Library of Medicine [ZIA LM000073-14] FX We are thankful to Romy Reimann and Uwe Remminghorst for strain construction, Fitnat Yildiz and Gary Roberts for the VpsT and Clp overexpression plasmids, respectively, Hermann Schatzl for access to Typhoon, Galina Selivanova for the use of the multilabel reader, and Kurt Miller for manuscript proofreading. This study was supported by the United States National Science Foundation (MCB1052575 to MG), NIH Intramural Research Program at the National Library of Medicine (MYG) and the Swedish Research Council Natural Sciences (621-2010-5755 to UR), Petrus and Augusta Hedlund Foundation and Carl Tryggers Foundation CTS 10: 324 (to UR). Andrea Blanka was supported by the International Research Training Group 1273 funded by the German Research Foundation (DFG). Michael Y. Galperin was supported by NIH Intramural Research Program at the National Library of Medicine (ZIA LM000073-14). The authors have no conflict of interest to declare. NR 63 TC 25 Z9 26 U1 2 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2014 VL 93 IS 3 BP 439 EP 452 DI 10.1111/mmi.12672 PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AN1VF UT WOS:000340371200005 PM 24942809 ER PT J AU Vecchiarelli, AG Li, M Mizuuchi, M Mizuuchi, K AF Vecchiarelli, Anthony G. Li, Min Mizuuchi, Michiyo Mizuuchi, Kiyoshi TI Differential affinities of MinD and MinE to anionic phospholipid influence Min patterning dynamics in vitro SO MOLECULAR MICROBIOLOGY LA English DT Article ID DIVISION-SITE SELECTION; TO-POLE OSCILLATION; ESCHERICHIA-COLI; CELL-DIVISION; BACTERIAL DIVISION; BACILLUS-SUBTILIS; MEMBRANE INTERACTION; PROTEIN INTERACTIONS; PROPER PLACEMENT; INHIBITOR MINC AB The E. coli Min system forms a cell-pole-to-cell-pole oscillator that positions the divisome at mid-cell. The MinD ATPase binds the membrane and recruits the cell division inhibitor MinC. MinE interacts with and releases MinD (and MinC) from the membrane. The chase of MinD by MinE creates the in vivo oscillator that maintains a low level of the division inhibitor at mid-cell. In vitro reconstitution and visualization of Min proteins on a supported lipid bilayer has provided significant advances in understanding Min patterns in vivo. Here we studied the effects of flow, lipid composition, and salt concentration on Min patterning. Flow and no-flow conditions both supported Min protein patterns with somewhat different characteristics. Without flow, MinD and MinE formed spiraling waves. MinD and, to a greater extent MinE, have stronger affinities for anionic phospholipid. MinD-independent binding of MinE to anionic lipid resulted in slower and narrower waves. MinE binding to the bilayer was also more susceptible to changes in ionic strength than MinD. We find that modulating protein diffusion with flow, or membrane binding affinities with changes in lipid composition or salt concentration, can differentially affect the retention time of MinD and MinE, leading to spatiotemporal changes in Min patterning. C1 [Vecchiarelli, Anthony G.; Li, Min; Mizuuchi, Michiyo; Mizuuchi, Kiyoshi] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mizuuchi, K (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kiyoshimi@helix.nih.gov FU intramural research fund for National Institute of Diabetes and Digestive and Kidney Diseases; Nancy Nossal Fellowship FX This work was supported by the intramural research fund for National Institute of Diabetes and Digestive and Kidney Diseases (to K. M.) and the Nancy Nossal Fellowship (to A.G.V.). NR 47 TC 14 Z9 15 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2014 VL 93 IS 3 BP 453 EP 463 DI 10.1111/mmi.12669 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AN1VF UT WOS:000340371200006 PM 24930948 ER PT J AU Chen, Q Boulanger, A Hinton, DM Stibitz, S AF Chen, Qing Boulanger, Alice Hinton, Deborah M. Stibitz, Scott TI Strong inhibition of fimbrial 3 subunit gene transcription by a novel downstream repressive element in Bordetella pertussis SO MOLECULAR MICROBIOLOGY LA English DT Article ID RESPONSE REGULATOR BVGA; FILAMENTOUS HEMAGGLUTININ; VIRULENCE FACTORS; FHA PROMOTER; ACTIVATION; EXPRESSION; REGION; MUTAGENESIS; MECHANISM; SEQUENCES AB The Bvg-regulated promoters for the fimbrial subunit genes fim2 and fim3 of Bordetella pertussis behave differently from each other both in vivo and in vitro. In vivo P-fim2 is significantly stronger than P-fim3, even though predictions based on the DNA sequences of BvgA-binding motifs and core promoter elements would indicate the opposite. In vitro P-fim3 demonstrated robust BvgA similar to P-dependent transcriptional activation, while none was seen with P-fim2. This apparent contradiction was investigated further. By swapping sequence elements we created a number of hybrid promoters and assayed their strength in vivo. We found that, while P-fim3 promoter elements upstream of the +1 transcriptional start site do indeed direct Bvg-activated transcription more efficiently than those of P-fim2, the overall promoter strength of P-fim3 in vivo is reduced due to sequences downstream of +1 that inhibit transcription more than 250-fold. This element, the DRE (downstream repressive element), was mapped to the 15 bp immediately downstream of the P-fim3 +1. Placing the DRE in different promoter contexts indicated that its activity was not specific to fim promoters, or even to Bvg-regulated promoters. However it does appear to be specific to Bordetella species in that it did not function in Escherichia coli. C1 [Chen, Qing; Stibitz, Scott] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Boulanger, Alice; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Chen, Q (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM qing.chen@fda.hhs.gov FU Intramural NIH HHS [ZIA DK057813-07] NR 33 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2014 VL 93 IS 4 BP 748 EP 758 DI 10.1111/mmi.12690 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AN4LF UT WOS:000340558600013 PM 24963821 ER PT J AU Islam, MS Akhtar, MM Ciavattini, A Giannubilo, SR Protic, O Janjusevic, M Procopio, AD Segars, JH Castellucci, M Ciarmela, P AF Islam, Md Soriful Akhtar, Most Mauluda Ciavattini, Andrea Giannubilo, Stefano Raffaele Protic, Olga Janjusevic, Milijana Procopio, Antonio Domenico Segars, James H. Castellucci, Mario Ciarmela, Pasquapina TI Use of dietary phytochemicals to target inflammation, fibrosis, proliferation, and angiogenesis in uterine tissues: Promising options for prevention and treatment of uterine fibroids? SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Review DE Antifibrotic; Antiproliferative; Dietary phytochemicals; Inflammation; Uterine fibroid ID CELL-CYCLE ARREST; SMOOTH-MUSCLE-CELLS; HEPATIC STELLATE CELLS; BREAST-CANCER CELLS; FACTOR-KAPPA-B; LYCOPENE INHIBITS ANGIOGENESIS; RANDOMIZED CONTROLLED-TRIAL; KELOID-DERIVED FIBROBLASTS; ALLICIN INDUCES APOPTOSIS; LEUPROLIDE ACETATE DEPOT AB Uterine leiomyomas (fibroids, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70-80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pressure on the bladder, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 6 billion dollars annually in the United States. Unfortunately, no long-term medical treatments are available. Dysregulation of inflammatory processes are thought to be involved in the initiation of leiomyoma and extracellular matrix deposition, cell proliferation, and angiogenesis are the key cellular events implicated in leiomyoma growth. In modern pharmaceutical industries, dietary phytochemicals are used as source of new potential drugs for many kinds of tumors. Dietary phytochemicals may exert therapeutic effects by interfering with key cellular events of the tumorigenesis process. At present, a negligible number of phytochemicals have been tested as therapeutic agents against fibroids. In this context, our aim was to introduce some of the potential dietary phytochemicals that have shown anti-inflammatory, antiproliferative, antifibrotic, and antiangiogenic activities in different biological systems. This review could be useful to stimulate the evaluation of these phytochemicals as possible therapies for uterine fibroids. C1 [Islam, Md Soriful; Protic, Olga; Janjusevic, Milijana; Castellucci, Mario; Ciarmela, Pasquapina] Polytech Univ Marche, Fac Med, Dept Expt & Clin Med, I-60020 Ancona, Italy. [Islam, Md Soriful] Rajshahi Univ, Dept Bot, Biotechnol & Microbiol Lab, Rajshahi 6205, Bangladesh. [Akhtar, Most Mauluda; Procopio, Antonio Domenico] Polytech Univ Marche, Fac Med, Dept Clin & Mol Sci, I-60020 Ancona, Italy. [Ciavattini, Andrea; Giannubilo, Stefano Raffaele] Polytech Univ Marche, Dept Clin Sci, I-60020 Ancona, Italy. [Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Ciarmela, Pasquapina] Polytech Univ Marche, Dept Informat Engn, I-60020 Ancona, Italy. RP Ciarmela, P (reprint author), Polytech Univ Marche, Fac Med, Dept Expt & Clin Med, Via Tronto 10-A, I-60020 Ancona, Italy. EM p.ciarmela@univpm.it RI Islam, Md Soriful/E-6649-2015; OI Islam, Md Soriful/0000-0001-5595-626X; Ciarmela, Pasquapina/0000-0002-4400-3786 FU Fondazione Cassa di Risparmio di Fabriano e Cupramontana; Italian Ministry of the University and Research (PRIN) [20102CHST5_007] FX This work was supported by a grant from the "Fondazione Cassa di Risparmio di Fabriano e Cupramontana" (to M.C. and P.C.) and by Italian Ministry of the University and Research (PRIN 2010-2011, No. 20102CHST5_007, to S.R.G.). NR 224 TC 4 Z9 6 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD AUG PY 2014 VL 58 IS 8 SI SI BP 1667 EP 1684 DI 10.1002/mnfr.201400134 PG 18 WC Food Science & Technology SC Food Science & Technology GA AN3ZX UT WOS:000340528500009 PM 24976593 ER PT J AU Blanchard, H Taha, AY Cheon, Y Kim, HW Turk, J Rapoport, SI AF Blanchard, Helene Taha, Ameer Y. Cheon, Yewon Kim, Hyung-Wook Turk, John Rapoport, Stanley I. TI iPLA(2)beta Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology SO NEUROCHEMICAL RESEARCH LA English DT Article DE Calcium-independent phospholipase A2 (iPLA(2)beta) knockout; Brain; Parkinson disease; Arachidonic and docosahexaenoic acid; Motor disturbances; Neuropathology ID INDEPENDENT PHOSPHOLIPASE A(2); INFANTILE NEUROAXONAL DYSTROPHY; DOCOSAHEXAENOIC ACID METABOLISM; PARKINSONS-DISEASE; ARACHIDONIC-ACID; ALPHA-SYNUCLEIN; RAT-BRAIN; MOLECULAR-MECHANISMS; PLA2G6 MUTATIONS; PUFA DEPRIVATION AB Calcium-independent phospholipase A(2) group VIa (iPLA(2)beta) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4 months, PLA2G6 knockout mice (iPLA(2)beta(-/-)) show minimal neuropathology but altered brain DHA metabolism. By 1 year, they develop motor disturbances, cerebellar neuronal loss, and striatal alpha-synuclein accumulation. We hypothesized that older iPLA(2)beta(-/-) mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA(2)beta(-/-) or wild-type (WT) mice. These older iPLA(2)beta(-/-) mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-alpha messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA(2)gamma expression was unchanged. iPLA(2)beta deficient mice show evidence of neuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation. C1 [Blanchard, Helene; Taha, Ameer Y.; Cheon, Yewon; Kim, Hyung-Wook; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. [Kim, Hyung-Wook] Sejong Univ, Coll Life Sci, Seoul 143747, South Korea. [Turk, John] Washington Univ, Div Endocrinol, Med Dept Metab & Lipid Res, Sch Med, St Louis, MO 63110 USA. RP Blanchard, H (reprint author), NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bldg 9,Room 1S126,9000 Rockville Pike, Bethesda, MD 20892 USA. EM helene.blanchard@nih.gov FU Intramural Research Program of the National Institute on Aging; United States Public Health Service [R37-DK34388, P41-RR00954, P60-DK20579, P30-DK56341] FX The authors thank the NIH Fellow Editorial Board and Ms. Mairi Stevens for editorial assistance and Dr. Dede Greenstein for statistical support. Research was supported by the Intramural Research Program of the National Institute on Aging and, for JT, by United States Public Health Service Grants R37-DK34388, P41-RR00954, P60-DK20579, and P30-DK56341. NR 61 TC 4 Z9 6 U1 3 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 EI 1573-6903 J9 NEUROCHEM RES JI Neurochem. Res. PD AUG PY 2014 VL 39 IS 8 BP 1522 EP 1532 DI 10.1007/s11064-014-1342-y PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AN2GB UT WOS:000340401200015 PM 24919816 ER PT J AU Chong, EW Guymer, RH Klein, R Klein, BE Cotch, MF Wang, JJ Shlipak, MG Wong, TY AF Chong, Elaine W. Guymer, Robyn H. Klein, Ronald Klein, Barbara E. Cotch, Mary Frances Wang, Jie Jin Shlipak, Michael G. Wong, Tien Y. TI Is Renal Function Associated with Early Age-Related Macular Degeneration? SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE age-related macular degeneration; kidney; renal function ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; COMPLEMENT-FACTOR-H; BLUE-MOUNTAINS-EYE; GLOMERULONEPHRITIS TYPE-II; SERUM CYSTATIN-C; BEAVER DAM EYE; FUNDUS CHANGES; RISK; PREVALENCE AB Purpose. Age-related macular degeneration (AMD) and chronic kidney disease both involve immune dysregulation and may share underlying pathophysiologic changes to systemic homeostasis. Hence, we aim to evaluate associations between impaired kidney function and early AMD, in a search for urinary biomarkers for AMD. Methods. A population-based, cross-sectional analysis of persons aged 45 to 84 years was conducted with renal function measured using serum creatinine and cystatin C levels and the estimated glomerular filtration rate (eGFR) calculated. Age-related macular degeneration status was ascertained from retinal photographs. Results. Of 5874 participants, 221 had early AMD. High serum cystatin C and low eGFR (<= 60 ml/min/1.73 m(2)) were not associated with early AMD in our multivariate analyses. Among normotensive persons, however, highest versus other deciles of cystatin C were associated with an increased prevalence of early AMD (odds ratio, 1.80; 95% confidence interval, 1.00 to 3.23). Conclusions. Results could not confirm an association between kidney function and early AMD. The borderline association between cystatin C and early AMD in normotensive persons require further verification. C1 [Chong, Elaine W.; Guymer, Robyn H.; Wang, Jie Jin; Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic 3002, Australia. [Klein, Ronald; Klein, Barbara E.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Wang, Jie Jin] Univ Sydney, Ctr Vis Res, Sydney, NSW 2006, Australia. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore Eye Res Inst, Singapore 117595, Singapore. RP Chong, EW (reprint author), Univ Melbourne, Ctr Eye Res Australia, 32 Gisborne St, East Melbourne, Vic 3002, Australia. EM elainechongwt@alumni.unimelb.edu.au RI Wang, Jie Jin/P-1499-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Cotch, Mary Frances/0000-0002-2046-4350 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169] FX This study was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 40 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD AUG PY 2014 VL 91 IS 8 BP 860 EP 864 PG 5 WC Ophthalmology SC Ophthalmology GA AN4KL UT WOS:000340556500008 PM 24879085 ER PT J AU Hsu, YW Chou, CP Belcher, BR Nguyen-Rodriguez, ST Weigensberg, MJ McClain, AD Spruijt-Metz, D AF Hsu, Ya-Wen Chou, Chih-Ping Belcher, Britni R. Nguyen-Rodriguez, Selena T. Weigensberg, Marc J. McClain, Arianna D. Spruijt-Metz, Donna TI Double Jeopardy: Metabolic Syndrome Leads to Increased Sedentary Behavior in Peri-Pubertal Minority Females SO PEDIATRIC EXERCISE SCIENCE LA English DT Article ID NUTRITION EXAMINATION SURVEY; OVERWEIGHT LATINO YOUTH; 3RD NATIONAL-HEALTH; BODY-MASS INDEX; PHYSICAL-ACTIVITY; UNITED-STATES; WAIST CIRCUMFERENCE; CHILDREN; ADOLESCENTS; OBESITY AB While most studies have focused on investigating the preventive effects of physical activity on metabolic risk, the longitudinal impacts of metabolic syndrome (MetS) on activity levels is poorly understood. This study aims to examine the influence of MetS on initial activity levels and the trajectory of activity levels in Latina and African American female children over 12 months (n = 55, 9 +/- 1 years). Metabolic measures, including fat and lean tissue mass by BodPod, fasting glucose, lipids, blood pressure, and waist circumference, were collected at baseline. Moderate-to-vigorous physical activity and sedentary behavior by accelerometry were collected on a quarterly basis. There were no significant differences in either initial activity levels by MetS status (Moderate-to-vigorous physical activity: 33 +/- 12 mins/day for MetS, 48 +/- 28 mins/day for Non-MetS, p = .12; sedentary behavior: 408 +/- 57 mins/day for MetS, 421 +/- 72 mins/day for Non-MetS, p = .67). Longitudinal declines in moderate-to-vigorous physical activity (p = .038) and increases in sedentary behavior (p = .003) were found. Daily sedentary behavior increased by 82.64 more minutes in youth with MetS than in those without over one year (p = .015). This study yields the first evidence of the adverse effect of MetS on sedentary behavior. Targeted intervention strategies to reduce progressive sedentariness evident in minority youth with MetS are warranted. C1 [Hsu, Ya-Wen] Chia Nan Univ Pharm & Sci, Dept Hosp & Hlth Care Adm, Tainan, Taiwan. [Chou, Chih-Ping; Spruijt-Metz, Donna] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Spruijt-Metz, Donna] Univ So Calif, Domsife Ctr Econ & Social Res, Los Angeles, CA USA. [Belcher, Britni R.] NCI, NIH, Bethesda, MD 20892 USA. [Nguyen-Rodriguez, Selena T.] Calif State Univ Long Beach, Dept Hlth Sci, Long Beach, CA 90840 USA. [Weigensberg, Marc J.] Univ So Calif, Los Angeles Cty Med Ctr, Dept Pediat, Los Angeles, CA 90033 USA. [McClain, Arianna D.] Stanford Univ, Prevent Res Ctr, Sch Med, Stanford, CA 94305 USA. RP Hsu, YW (reprint author), Chia Nan Univ Pharm & Sci, Dept Hosp & Hlth Care Adm, Tainan, Taiwan. EM janiceywhsu@gmail.com FU USC Center for Transdisciplinary Research on Energetics and Cancer (NCI) [U54 CA 116848] FX This work was supported by the USC Center for Transdisciplinary Research on Energetics and Cancer (NCI, U54 CA 116848). The authors wish to thank Ana Romero, LuzAntunez-Castillo, Adriana Padilla, Javier Diaz and the study participants, without whom this research would not have been possible. NR 38 TC 0 Z9 0 U1 0 U2 6 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 0899-8493 EI 1543-2920 J9 PEDIATR EXERC SCI JI Pediatr. Exerc. Sci. PD AUG PY 2014 VL 26 IS 3 BP 266 EP 273 DI 10.1123/pes.2013-0149 PG 8 WC Pediatrics; Physiology; Sport Sciences SC Pediatrics; Physiology; Sport Sciences GA AN3UH UT WOS:000340513700006 PM 24722884 ER PT J AU Cantor, D AF Cantor, David TI Before Survivorship: The Moment of Recovery in Twentieth-century American Cancer Campaigns SO SOCIAL HISTORY OF MEDICINE LA English DT Article DE cancer; rehabilitation; survivorship; Reach to Recovery; Terese Lasser; cancer nursing; corsetieres; prostheses; self-presentation; emotional management AB This paper concerns what I call "the moment of recovery," the time when, in the 1950s, American cancer campaigns abandoned an earlier tendency to downplay post-operative recovery in their public education programs. This change was signalled by the emergence of new patients groups such as Reach to Recovery (founded 1953), and by a new interest in cancer rehabilitation among physicians, nurses, and manufacturers and sellers of equipment and clothing for patients. My focus is on breast cancer and the nurse-patient-industrial complex that drove the new interest in rehabilitation and recovery, but I also argue that the "moment of recovery" in breast cancer was part of a larger "moment" in cancer more generally. Finally, I seek to distinguish the "moment of recovery" of the 1950s from the discourses around the survivor that have emerged since the 1970s and 1980s, what might be called the "moment of survivorship.". C1 NIH, Off Hist, Bethesda, MD 20814 USA. RP Cantor, D (reprint author), NIH, Off Hist, 1 Cloister Court,Bldg 60,Room 262, Bethesda, MD 20814 USA. EM cantord@mail.nih.gov NR 54 TC 0 Z9 0 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0951-631X EI 1477-4666 J9 SOC HIST MED JI Soc. Hist. Med. PD AUG PY 2014 VL 27 IS 3 BP 440 EP 465 DI 10.1093/shm/hkt100 PG 26 WC History; History & Philosophy Of Science SC History; History & Philosophy of Science GA AM7KN UT WOS:000340046000002 ER PT J AU Ronkainen, S Xie, Y Battiwalla, M Barrett, AJ Stock, F Dekker, JP Danner, RL AF Ronkainen, S. Xie, Y. Battiwalla, M. Barrett, A. J. Stock, F. Dekker, J. P. Danner, R. L. TI Persistence of Pseudomonas aeruginosa in a pulmonary nodule with late relapse SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE lung abscess; septic pulmonary embolus; hematopoietic stem cell transplant; Pseudomonas aeruginosa; recrudescent infection ID FIELD GEL-ELECTROPHORESIS; CARBAPENEM RESISTANCE MECHANISMS; ENDOCARDITIS; BACTEREMIA; EMBOLISM; FEATURES; DETROIT; ABSCESS AB Lung nodules are common diagnostic challenges in hematopoietic stem cell transplantation and solid organ transplantation. Pseudomonas aeruginosa is a known cause of lung abscess in these patients, but its ability to persist for months in a quiescent lung nodule and later cause recurrent infection is not well known or documented. A patient with a history of acute pre-B-cell lymphoblastic leukemia had enlargement and cavitation of a small right upper lobe pulmonary nodule 10months after allogeneic hematopoietic stem cell transplantation. The nodule was the remnant of a presumed P.aeruginosa septic embolus that occurred 2.5months after transplantation. With antibiotic treatment, the nodule had shrunk in size to <1cm and remained stable. Transthoracic needle aspiration grew P.aeruginosa indistinguishable by molecular typing from isolates obtained 7.5months earlier from blood and bronchoalveolar lavage fluid. Sub-centimeter pulmonary nodules attributable to previously treated P.aeruginosa may harbor viable organisms and lead to recrudescent infection. C1 [Ronkainen, S.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Xie, Y.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Battiwalla, M.; Barrett, A. J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Stock, F.; Dekker, J. P.] NIH, Microbiol Serv, Dept Lab Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Danner, R. L.] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP Danner, RL (reprint author), NIH, Infect Dis Sect, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM rdanner@nih.gov FU Intramural National Institutes of Health, Bethesda, Maryland USA FX Intramural National Institutes of Health, Bethesda, Maryland USA. NR 19 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-2273 EI 1399-3062 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD AUG PY 2014 VL 16 IS 4 BP 666 EP 671 DI 10.1111/tid.12253 PG 6 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA AN3IS UT WOS:000340481300021 PM 24964912 ER PT J AU Hess, CN Roe, MT Gibson, CM Temple, RJ Pencina, MJ Zarin, DA Anstrom, KJ Alexander, JH Sherman, RE Fiedorek, FT Mahaffey, KW Lee, KL Chow, SC Armstrong, PW Califf, RM AF Hess, Connie N. Roe, Matthew T. Gibson, C. Michael Temple, Robert J. Pencina, Michael J. Zarin, Deborah A. Anstrom, Kevin J. Alexander, John H. Sherman, Rachel E. Fiedorek, Fred T. Mahaffey, Kenneth W. Lee, Kerry L. Chow, Shein-Chung Armstrong, Paul W. Califf, Robert M. TI Independent data monitoring committees: Preparing a path for the future SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROME; CLINICALTRIALS.GOV; TRIALS AB Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs. C1 [Hess, Connie N.; Roe, Matthew T.; Pencina, Michael J.; Alexander, John H.; Lee, Kerry L.] Duke Clin Res Inst, Durham, NC USA. [Gibson, C. Michael; Anstrom, Kevin J.] Beth Israel Deaconess Med Ctr, PERFUSE Study Grp, Boston, MA 02215 USA. [Gibson, C. Michael; Anstrom, Kevin J.] Harvard Univ, Sch Med, Boston, MA USA. [Temple, Robert J.; Sherman, Rachel E.] US FDA, Silver Spring, MD USA. [Zarin, Deborah A.] NIH, Bethesda, MD 20892 USA. [Fiedorek, Fred T.] Bristol Myers Squibb Co, New York, NY 10154 USA. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Chow, Shein-Chung; Califf, Robert M.] Duke Univ, Sch Med, Durham, NC 27705 USA. [Armstrong, Paul W.] Univ Alberta, Edmonton, AB, Canada. RP Roe, MT (reprint author), Duke Univ, Med Ctr, 2400 Pratt St,Rm 7035, Durham, NC 27705 USA. EM matthew.roe@duke.edu FU National Institutes of Health (NIH) [5T32HL069749-09]; Bristol-Myers Squibb (New York, NY); AstraZeneca (Wilmington, DE); Pfizer (New York, NY) FX Connie N. Hess received support from the National Institutes of Health (NIH) (5T32HL069749-09). Funding sources had no role in the design, conduct, or reporting of the study. The independent data monitoring committee (IDMC) think tank meeting was supported by unrestricted grants to Duke University from Bristol-Myers Squibb (New York, NY), AstraZeneca (Wilmington, DE), and Pfizer (New York, NY). NR 16 TC 3 Z9 3 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2014 VL 168 IS 2 BP 135 EP + DI 10.1016/j.ahj.2014.05.003 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9NG UT WOS:000340207700006 PM 25066551 ER PT J AU Truog, RD Miller, FG AF Truog, Robert D. Miller, Franklin G. TI Changing the Conversation About Brain Death SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE brain death; dead donor rule; definition of death; health policy; organ donation; organ transplantation ID DONOR RULE; LEGAL FICTIONS; ORGAN DONATION; DEFINITION; RATIONALE; ABANDON; LIFE AB We seek to change the conversation about brain death by highlighting the distinction between brain death as a biological concept versus brain death as a legal status. The fact that brain death does not cohere with any biologically plausible definition of death has been known for decades. Nevertheless, this fact has not threatened the acceptance of brain death as a legal status that permits individuals to be treated as if they are dead. The similarities between "legally dead" and "legally blind" demonstrate how we may legitimately choose bright-line legal definitions that do not cohere with biological reality. Not only does this distinction bring conceptual coherence to the conversation about brain death, but it has practical implications as well. Once brain death is recognized as a social construction not grounded in biological reality, we create the possibility of changing the social construction in ways that may better serve both organ donors and recipients alike. C1 [Truog, Robert D.] Boston Childrens Hosp, Boston, MA USA. [Truog, Robert D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Miller, Franklin G.] NIH, Bethesda, MD USA. RP Truog, RD (reprint author), Harvard Univ, Sch Med, Div Crit Care Med, Boston Childrens Hosp,Ctr Bioeth, 641 Huntington Ave, Boston, MA 02115 USA. EM Robert.truog@childrens.harvard.edu NR 31 TC 18 Z9 19 U1 0 U2 16 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD AUG PY 2014 VL 14 IS 8 BP 9 EP 14 DI 10.1080/15265161.2014.925154 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AM9II UT WOS:000340194200003 PM 25046286 ER PT J AU Friesen, MC Park, DU Colt, JS Baris, D Schwenn, M Karagas, MR Armenti, KR Johnson, A Silverman, DT Stewart, PA AF Friesen, Melissa C. Park, Dong-Uk Colt, Joanne S. Baris, Dalsu Schwenn, Molly Karagas, Margaret R. Armenti, Karla R. Johnson, Alison Silverman, Debra T. Stewart, Patricia A. TI Developing Estimates of Frequency and Intensity of Exposure to Three Types of Metalworking Fluids in a Population-Based Case-Control Study of Bladder Cancer SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE metalworking fluids; bladder cancer; case-control study; retrospective exposure assessment; exposure prediction model ID DIESEL EXHAUST EXPOSURE; OCCUPATIONAL RISKS; UNITED-STATES; SMOKING; MEN AB Background A systematic, transparent, and data-driven approach was developed to estimate frequency and intensity of exposure to straight, soluble, and synthetic/semi-synthetic metalworking fluids (MWFs) within a case-control study of bladder cancer in New England. Methods We assessed frequency using individual-level information from job-specific questionnaires wherever possible, then derived and applied job group-level patterns to likely exposed jobs with less information. Intensity estimates were calculated using a statistical model developed from measurements and determinants extracted from the published literature. Results For jobs with probabilities of exposure >= 0.5, median frequencies were 8-10 hr/week, depending on MWF type. Median intensities for these jobs were 2.5, 2.1, and 1.0 mg/m(3) for soluble, straight, and synthetic/semi-synthetic MWFs, respectively. Conclusions Compared to case-by-case assessment, these data-driven decision rules are transparent and reproducible and may result in less biased estimates. These rules can also aid future exposure assessments of MWFs in population-based studies. (C) 2014 Wiley Periodicals, Inc. C1 [Friesen, Melissa C.; Park, Dong-Uk; Colt, Joanne S.; Baris, Dalsu; Silverman, Debra T.; Stewart, Patricia A.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. [Park, Dong-Uk] Korea Natl Open Univ, Dept Environm Hlth, Seoul, South Korea. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Karagas, Margaret R.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Armenti, Karla R.] Bur Publ Hlth Stat & Informat, New Hampshire Dept Hlth & Human Serv, Div Publ Hlth Serv, Concord, NH USA. [Johnson, Alison] Vermont Dept Hlth, Burlington, VT 05402 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. RP Friesen, MC (reprint author), Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,Room 6E608, North Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Friesen, Melissa/A-5362-2009 FU National Cancer Institute Intramural Research Program; National Institutes of Health FX Contract grant sponsor: National Cancer Institute Intramural Research Program; Contract grant sponsor: National Institutes of Health. NR 24 TC 5 Z9 5 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD AUG PY 2014 VL 57 IS 8 BP 915 EP 927 DI 10.1002/ajim.22328 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM9EH UT WOS:000340182800007 PM 25060071 ER PT J AU Scheibye-Knudsen, M Fang, EF Croteau, DL Bohr, VA AF Scheibye-Knudsen, Morten Fang, Evandro Fei Croteau, Deborah L. Bohr, Vilhelm A. TI Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders SO AUTOPHAGY LA English DT Editorial Material DE autophagy; DNA repair; mitophagy; SIRT1; xeroderma pigmentosum group A AB DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD(+) (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging. C1 [Scheibye-Knudsen, Morten; Fang, Evandro Fei; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM BohrV@grc.nia.nih.gov OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 NR 0 TC 16 Z9 16 U1 1 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD AUG PY 2014 VL 10 IS 8 BP 1468 EP 1469 DI 10.4161/auto.29321 PG 2 WC Cell Biology SC Cell Biology GA AN0HU UT WOS:000340266200012 PM 24991831 ER PT J AU Zhang, H Wheeler, W Wang, ZM Taylor, PR Yu, K AF Zhang, Han Wheeler, William Wang, Zhaoming Taylor, Philip R. Yu, Kai TI A fast and powerful tree-based association test for detecting complex joint effects in case-control studies SO BIOINFORMATICS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GENE-GENE AB Motivation: Multivariate tests derived from the logistic regression model are widely used to assess the joint effect of multiple predictors on a disease outcome in case-control studies. These tests become less optimal if the joint effect cannot be approximated adequately by the additive model. The tree-structure model is an attractive alternative, as it is more apt to capture non-additive effects. However, the tree model is used most commonly for prediction and seldom for hypothesis testing, mainly because of the computational burden associated with the resampling-based procedure required for estimating the significance level. Results: We designed a fast algorithm for building the tree-structure model and proposed a robust TREe-based Association Test (TREAT) that incorporates an adaptive model selection procedure to identify the optimal tree model representing the joint effect. We applied TREAT as a multilocus association test on >20 000 genes/regions in a study of esophageal squamous cell carcinoma (ESCC) and detected a highly significant novel association between the gene CDKN2B and ESCC (P = 6.0 x 10(-8)). We also demonstrated, through simulation studies, the power advantage of TREAT over other commonly used tests. C1 [Zhang, Han; Wang, Zhaoming; Taylor, Philip R.; Yu, Kai] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20850 USA. [Wheeler, William] Informat Management Serv Inc, Silver Spring, MD 20904 USA. [Wang, Zhaoming] NCI, Div Canc Epidemiol & Genet, Canc Genom Res Lab, Gaithersburg, MD 20877 USA. RP Yu, K (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20850 USA. EM yuka@mail.nih.gov RI Zhang, Han/K-2118-2016 OI Zhang, Han/0000-0001-7977-9616 FU Intramural Program of the National Institutes of Health; National Cancer Institute and the Division of Cancer Epidemiology and Genetics FX The work of H. Z., P.R.T. and K.Y. was supported by the Intramural Program of the National Institutes of Health, the National Cancer Institute and the Division of Cancer Epidemiology and Genetics. NR 21 TC 2 Z9 2 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2014 VL 30 IS 15 BP 2171 EP 2178 DI 10.1093/bioinformatics/btu186 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AM7LQ UT WOS:000340049100012 PM 24794927 ER PT J AU Bureau, A Younkin, SG Parker, MM Bailey-Wilson, JE Marazita, ML Murray, JC Mangold, E Albacha-Hejazi, H Beaty, TH Ruczinski, I AF Bureau, Alexandre Younkin, Samuel G. Parker, Margaret M. Bailey-Wilson, Joan E. Marazita, Mary L. Murray, Jeffrey C. Mangold, Elisabeth Albacha-Hejazi, Hasan Beaty, Terri H. Ruczinski, Ingo TI Inferring rare disease risk variants based on exact probabilities of sharing by multiple affected relatives SO BIOINFORMATICS LA English DT Article ID CLEFT-PALATE; GENOME; STRATEGIES; LIP AB Motivation: Family-based designs are regaining popularity for genomic sequencing studies because they provide a way to test cosegregation with disease of variants that are too rare in the population to be tested individually in a conventional case-control study. Results: Where only a few affected subjects per family are sequenced, the probability that any variant would be shared by all affected relatives-given it occurred in any one family member-provides evidence against the null hypothesis of a complete absence of linkage and association. A P-value can be obtained as the sum of the probabilities of sharing events as (or more) extreme in one or more families. We generalize an existing closed-form expression for exact sharing probabilities to more than two relatives per family. When pedigree founders are related, we show that an approximation of sharing probabilities based on empirical estimates of kinship among founders obtained from genome-wide marker data is accurate for low levels of kinship. We also propose a more generally applicable approach based on Monte Carlo simulations. We applied this method to a study of 55 multiplex families with apparent non-syndromic forms of oral clefts from four distinct populations, with whole exome sequences available for two or three affected members per family. The rare single nucleotide variant rs149253049 in ADAMTS9 shared by affected relatives in three Indian families achieved significance after correcting for multiple comparisons (p = 2 x 10(-6)). C1 [Bureau, Alexandre] Inst Univ Sante Mentale Quebec, Ctr Rech, Quebec City, PQ G1J 2G3, Canada. [Bureau, Alexandre] Univ Laval, Dept Social & Prevent Med, Quebec City, PQ G1V OA6, Canada. [Younkin, Samuel G.; Ruczinski, Ingo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Parker, Margaret M.; Beaty, Terri H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Bailey-Wilson, Joan E.] Natl Inst Hlth, Natl Human Genome Res Inst, Inherited Dis Res Branch, Baltimore, MD 21224 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Ctr Craniofacial & Dent Genet, Dept Oral Biol, Pittsburgh, PA 15219 USA. [Murray, Jeffrey C.] Univ Iowa, Sch Med, Dept Pediat, Iowa City, IA 52242 USA. [Mangold, Elisabeth] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Albacha-Hejazi, Hasan] Dr Hejazi Clin, Riyadh 11461, Saudi Arabia. RP Bureau, A (reprint author), Inst Univ Sante Mentale Quebec, Ctr Rech, Quebec City, PQ G1J 2G3, Canada. EM alexandre.bureau@msp.ulaval.ca; ingo@jhu.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920; Bureau, Alexandre/0000-0001-8220-9999 FU NIH [R10-DE-014581, R01-DE016148, R01-DE009886, R37-DE008559, X01-HG006177, R01 GM083084]; Center for Inherited Disease Research; Deutsche Forschungsgemeinschaft [MA 2546/3-1, KR 1912/7-1, NO 246/6-1, WI 1555/5-1]; German support group; Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health, USA; Fonds de recherche du Quebec - Sante FX This work was supported by NIH grants (R10-DE-014581, R01-DE016148, R01-DE009886, R37-DE008559 and X01-HG006177), which supported the whole exome sequencing at the Center for Inherited Disease Research. Recruitment of German families was supported by the Deutsche Forschungsgemeinschaft (FOR 423 and individual grants MA 2546/3-1, KR 1912/7-1, NO 246/6-1, WI 1555/5-1). Contacting patients and their families was supported by the German support group for individuals with cleft lip and/or palate (Deutsche Selbsthilfevereinigung fur Lippen-Gaumen-Fehlbildungen e.V.). Recruitment of Syrian families was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA. A Bureau is supported by a research fellowship from the Fonds de recherche du Quebec - Sante. I. Ruczinski was further supported by NIH (grant R01 GM083084). NR 13 TC 5 Z9 5 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2014 VL 30 IS 15 BP 2189 EP 2196 DI 10.1093/bioinformatics/btu198 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AM7LQ UT WOS:000340049100014 PM 24740360 ER PT J AU Dizon, DS Mackay, HJ Thomas, GM Werner, TL Kohn, EC Hess, D Rose, PG Covens, AL AF Dizon, Don S. Mackay, Helen J. Thomas, Gillian M. Werner, Theresa L. Kohn, Elise C. Hess, Dina Rose, Peter G. Covens, Allan L. TI State of the Science in Cervical Cancer: Where We Are Today and Where We Need to Go SO CANCER LA English DT Review DE cervical cancer; clinical trials; human papillomavirus; immunotherapy; anti-angiogenesis; screening; prevention ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-III TRIAL; PELVIC RADIATION-THERAPY; PLUS CISPLATIN; RIBONUCLEOTIDE REDUCTASE; CONCURRENT CHEMOTHERAPY; ADJUVANT GEMCITABINE; IMMUNE-RESPONSES; IVA CARCINOMA; STAGE IIB AB Invasive cervical cancer remains an important global cause of death, despite the declining prevalence within the United States. Definitive therapies, including surgical resection of early-stage disease and chemoradiation for locally advanced disease, can be curative. For women who experience local or distant recurrences, the prognosis remains poor and better treatments are required. On July 18, 2013, The Gynecologic Oncology Group sponsored a State of the Science in Cervical Cancer Symposium with experts, researchers, clinicians, and interested stakeholders. This article summarize the progress that has been made, questions that require further investigation, and contemporary genomic findings and innovative treatments that may help inform the next generation of clinical trials for patients with cervical cancer. (C) 2014 American Cancer Society. C1 [Dizon, Don S.] Massachusetts Gen Hosp, Ctr Canc, Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA. [Dizon, Don S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Mackay, Helen J.] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Mackay, Helen J.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Thomas, Gillian M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Thomas, Gillian M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Obstet & Gynecol, Toronto, ON, Canada. [Werner, Theresa L.] Univ Utah, Sch Med, Dept Med, Div Oncol, Salt Lake City, UT USA. [Kohn, Elise C.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hess, Dina] NCI, Gynecol Oncol Steering Comm, EMMES Corp, Rockville, MD USA. [Rose, Peter G.] Cleveland Clin Fdn, Dept Obstet & Gynecol, Div Gynecol Oncol, Cleveland, OH 44195 USA. [Covens, Allan L.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Gynecol Oncol, Dept Obstet & Gynecol, Toronto, ON, Canada. RP Dizon, DS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Gillette Ctr Gynecol Oncol, 55 Fruit St, Boston, MA 02114 USA. EM ddizon@mgh.harvard.edu NR 37 TC 12 Z9 14 U1 0 U2 19 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 1 PY 2014 VL 120 IS 15 BP 2282 EP 2288 DI 10.1002/cncr.28722 PG 7 WC Oncology SC Oncology GA AM9ZV UT WOS:000340241500010 PM 24737608 ER PT J AU Parsons, HM Schmidt, S Harlan, LC Kent, EE Lynch, CF Smith, AW Keegan, THM AF Parsons, Helen M. Schmidt, Susanne Harlan, Linda C. Kent, Erin E. Lynch, Charles F. Smith, Ashley W. Keegan, Theresa H. M. CA AYA HOPE Collaborative TI Young and Uninsured: Insurance Patterns of Recently Diagnosed Adolescent and Young Adult Cancer Survivors in the AYA HOPE Study SO CANCER LA English DT Article DE adolescents and young adults; insurance; Surveillance; Epidemiology; and End Results (SEER); Patient Protection and Affordable Care Act ID AFFORDABLE CARE ACT; CHILDHOOD-CANCER; HEALTH-INSURANCE; PATIENT PROTECTION; MEDICAL-CARE; DISPARITIES; POPULATION; COVERAGE; IMPACT; AGE AB BACKGROUND: Young adults have historically been the least likely to have health insurance in the United States. Previous studies of survivors of childhood cancer found lower rates of insurance and less access to medical care compared with siblings; however, to the authors' knowledge, no studies to date have examined continuity of insurance after a cancer diagnosis in adolescents and young adults (AYAs). METHODS: Using the AYA Health Outcomes and Patient Experience study, a cohort of 465 individuals aged 15 to 39 years from participating Surveillance, Epidemiology, and End Results registries, we evaluated changes in and sponsors of health insurance coverage after diagnosis, coverage of physician-recommended tests, and factors associated with lack of insurance after a cancer diagnosis using chi-square tests and multivariable logistic regression. RESULTS: Greater than 25% of AYA survivors of cancer (118 survivors) experienced some period without insurance up to 35 months after diagnosis. Insurance rates were high in the initial year after diagnosis (6 months-14 months; 93.3%) but decreased substantially at follow-up (15 months-35 months; 85.2%). The most common sponsor of health insurance was employer/school coverage (43.7%). Multivariable analysis indicated that older survivors (those aged 25-39 years vs 15-19 years; odds ratio, 3.35 [P<.01]) and those with less education (high school or less vs college graduate; odds ratio, 2.80 [P<.01]) were more likely to experience a period without insurance after diagnosis. Furthermore, > 20% of survivors indicated there were physician-recommended tests/treatments that were not covered by insurance, but > 80% received them regardless of coverage. CONCLUSIONS: Insurance rates appear to decrease with time since diagnosis in AYA survivors of cancer. Future studies should examine how new policies under the Patient Protection and Affordable Care Act extend access and insurance coverage beyond initial treatment. (C) 2014 American Cancer Society. C1 [Parsons, Helen M.; Schmidt, Susanne] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Harlan, Linda C.; Kent, Erin E.; Smith, Ashley W.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. RP Parsons, HM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, 7703 Floyd Curl Dr,MC 7933, San Antonio, TX 78229 USA. EM parsonsh@uthscsa.edu FU National Cancer Institute [HHSN2612010 00024C, HSN261201000025C, HHSN261201000032C, HHSN 261201000027C, HHSN261201000026C, HHSN26120100014 0C, HHSN261201000037C, HHSN261201000033C, HHSN26 1201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, HHSN26 1201000030C] FX Supported by National Cancer Institute contracts HHSN2612010 00024C, HSN261201000025C, HHSN261201000032C, HHSN 261201000027C, HHSN261201000026C, HHSN26120100014 0C, HHSN261201000037C, HHSN261201000033C, HHSN26 1201000034C, HHSN261201000035C, HHSN261201000029C, HHSN261201000031C, HHSN261201000028C, and HHSN26 1201000030C. NR 25 TC 9 Z9 9 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2014 VL 120 IS 15 BP 2352 EP 2360 DI 10.1002/cncr.28685 PG 9 WC Oncology SC Oncology GA AM9ZV UT WOS:000340241500018 PM 24899580 ER PT J AU de Souza, LB Ambudkar, IS AF de Souza, Lorena Brito Ambudkar, Indu S. TI Trafficking mechanisms and regulation of TRPC channels SO CELL CALCIUM LA English DT Review DE TRPC channels; Intracellular trafficking; Microdomains; Ca2+ signaling; Regulation ID SMOOTH-MUSCLE-CELLS; OPERATED CA2+ ENTRY; PLASMA-MEMBRANE LOCALIZATION; ENDOTHELIAL-CELLS; SURFACE EXPRESSION; SIGNALING COMPLEX; CALCIUM-CHANNELS; HUMAN PLATELETS; CATION CHANNEL; HUMAN HOMOLOG AB TRPC channels are Ca2+-permeable cation channels which are regulated downstream from receptor-coupled PIP2 hydrolysis. These channels contribute to a wide variety of cellular functions. Loss or gain of channel function has been associated with dysfunction and aberrant physiology. TRPC channel functions are influenced by their physical and functional interactions with numerous proteins that determine their regulation, scaffolding, trafficking, as well as their effects on the downstream cellular processes. Such interactions also compartmentalize the Ca2+ signals arising from TRPC channels. A large number of studies demonstrate that trafficking is a critical mode by which plasma membrane localization and surface expression of TRPC channels are regulated. This review will provide an overview of intracellular trafficking pathways as well as discuss the current state of knowledge regarding the mechanisms and components involved in trafficking of the seven members of the TRPC family (TRPC1-TRPC7). Published by Elsevier Ltd. C1 [de Souza, Lorena Brito; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP de Souza, LB (reprint author), NIDCR, Mol Physiol & Therapeut Branch, Bldg 10,Room 1N-113 NIH, Bethesda, MD 20892 USA. EM lorena.britodesouza@nih.gov; indu.ambudkar@nih.gov RI Brito de Souza, Lorena/N-3385-2014 OI Brito de Souza, Lorena/0000-0002-2462-6759 NR 89 TC 5 Z9 5 U1 2 U2 18 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD AUG PY 2014 VL 56 IS 2 BP 43 EP 50 DI 10.1016/j.ceca.2014.05.001 PG 8 WC Cell Biology SC Cell Biology GA AN1DT UT WOS:000340323600001 PM 25012489 ER PT J AU Ronan, L Voets, N Rua, C Alexander-Bloch, A Hough, M Mackay, C Crow, TJ James, A Giedd, JN Fletcher, PC AF Ronan, Lisa Voets, Natalie Rua, Catarina Alexander-Bloch, Aaron Hough, Morgan Mackay, Clare Crow, Tim J. James, Anthony Giedd, Jay N. Fletcher, Paul C. TI Differential Tangential Expansion as a Mechanism for Cortical Gyrification SO CEREBRAL CORTEX LA English DT Article DE cortical development; differential expansion; gyrification; intrinsic curvature ID SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; BASAL RADIAL GLIA; COORDINATE SYSTEM; LISSENCEPHALIC PRIMATE; INTRINSIC CURVATURE; BRAIN; MODEL; CONNECTIVITY; NEOCORTEX AB Gyrification, the developmental buckling of the cortex, is not a random process-the forces that mediate expansion do so in such a way as to generate consistent patterns of folds across individuals and even species. Although the origin of these forces is unknown, some theories have suggested that they may be related to external cortical factors such as axonal tension. Here, we investigate an alternative hypothesis, namely, whether the differential tangential expansion of the cortex alone can account for the degree and pattern-specificity of gyrification. Using intrinsic curvature as a measure of differential expansion, we initially explored whether this parameter and the local gyrification index (used to quantify the degree of gyrification) varied in a regional-specific pattern across the cortical surface in a manner that was replicable across independent datasets of neurotypicals. Having confirmed this consistency, we further demonstrated that within each dataset, the degree of intrinsic curvature of the cortex was predictive of the degree of cortical folding at a global and regional level. We conclude that differential expansion is a plausible primary mechanism for gyrification, and propose that this perspective offers a compelling mechanistic account of the co-localization of cytoarchitecture and cortical folds. C1 [Ronan, Lisa; Rua, Catarina; Alexander-Bloch, Aaron; Fletcher, Paul C.] Univ Cambridge, Brain Mapping Unit, Dept Psychiat, Cambridge CB2 3EB, England. [Voets, Natalie; Hough, Morgan; Mackay, Clare] Univ Oxford, Nuffield Dept Clin Neurosci, FMRIB Ctr, Oxford OX3 9DU, England. [Crow, Tim J.] Univ Oxford, Warneford Hosp, Dept Psychiat, SANE POWIC, Oxford OX3 7JX, England. [James, Anthony] Warneford Hosp, Highfield Adolescent Unit, Oxford OX3 7JX, England. [Alexander-Bloch, Aaron; Giedd, Jay N.] NIH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Ronan, L (reprint author), Univ Cambridge, Brain Mapping Unit, Sir William Hardy Bldg,Downing Site,Downing St, Cambridge CB2 3EB, England. EM lr344@cam.ac.uk RI crow, timothy/M-8327-2014; Giedd, Jay/J-9644-2015; OI crow, timothy/0000-0002-5482-6655; Giedd, Jay/0000-0003-2002-8978; Alexander-Bloch, Aaron/0000-0001-6554-1893; Mackay, Clare/0000-0001-6111-8318 FU Wellcome Trust; Bernard Wolfe Health Neuroscience Fund FX This work was supported by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 55 TC 26 Z9 26 U1 3 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2014 VL 24 IS 8 BP 2219 EP 2228 DI 10.1093/cercor/bht082 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AM7SL UT WOS:000340068500023 PM 23542881 ER PT J AU Moiola, CP De Luca, P Zalazar, F Cotignola, J Rodriguez-Segui, SA Gardner, K Meiss, R Vallecorsa, P Pignataro, O Mazza, O Vazquez, ES De Siervi, A AF Moiola, Cristian P. De Luca, Paola Zalazar, Florencia Cotignola, Javier Rodriguez-Segui, Santiago A. Gardner, Kevin Meiss, Roberto Vallecorsa, Pablo Pignataro, Omar Mazza, Osvaldo Vazquez, Elba S. De Siervi, Adriana TI Prostate Tumor Growth Is Impaired by CtBP1 Depletion in High-Fat Diet-Fed Mice SO CLINICAL CANCER RESEARCH LA English DT Article ID TERMINAL-BINDING-PROTEIN; CANCER PROGRESSION; EXPRESSION; BRCA1; TRANSFORMATION; SENSOR; MODEL AB Purpose: Clinical and epidemiologic data suggest that obesity is associated with more aggressive forms of prostate cancer, poor prognosis, and increased mortality. C-terminal-binding protein 1 (CtBP1) is a transcription repressor of tumor suppressor genes and is activated by NADH binding. High calorie intake decreases intracellular NAD(+)/NADH ratio. The aim of this work was to assess the effect of high-fat diet (HFD) and CtBP1 expression modulation over prostate xenograft growth. Experimental Design: We developed a metabolic syndrome-like disease in vivo model by feeding male nude mice with HFD during 16 weeks. Control diet (CD)-fed animals were maintained at the same conditions. Mice were inoculated with PC3 cells stable transfected with shCtBP1 or control plasmids. Genome-wide expression profiles and Gene Set Enrichment Analysis (GSEA) were performed from PC3. shCtBP1 versus PC3. pGIPZ HFD-fed mice tumors. Results: No significant differences were observed in tumor growth on CD-fed mice; however, we found that only 60% of HFD-fed mice inoculated with CtBP1-depleted cells developed a tumor. Moreover these tumors were significantly smaller than those generated by PC3. pGIPZ control xenografts. We found 823 genes differentially expressed in shCtBP1 tumors from HFD-fed mice. GSEA from expression dataset showed that most of these genes correspond to cell adhesion, metabolic process, and cell cycle. Conclusions: Metabolic syndrome-like diseases and CtBP1 expression cooperate to induce prostate tumor growth. Hence, targeting of CtBP1 expression might be considered for prostate cancer management and therapy in the subset of patients withmetabolic syndromes. (C) 2014 AACR. C1 [Moiola, Cristian P.; De Luca, Paola; Zalazar, Florencia; De Siervi, Adriana] IBYME CONICET, Lab Oncol Mol & Nuevos Blancos Terapeut, RA-2490 Buenos Aires, DF, Argentina. [Moiola, Cristian P.; De Luca, Paola; Zalazar, Florencia; Cotignola, Javier; Vazquez, Elba S.; De Siervi, Adriana] Univ Buenos Aires, Fac Ciencias Exactas & Nat, IQUIBICEN CONICET, Lab Inflamac & Canc,Dept Quim Biol, Buenos Aires, DF, Argentina. [Pignataro, Omar] Univ Buenos Aires, Fac Ciencias Exactas & Nat, IQUIBICEN CONICET,Dept Quim Biol, Lab Endocrinol Mol & Transducc Senales,IBYME CONI, Buenos Aires, DF, Argentina. [Rodriguez-Segui, Santiago A.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol Biol Mol & Celular, Buenos Aires, DF, Argentina. [Rodriguez-Segui, Santiago A.] Consejo Nacl Invest Cient & Tecn, Inst Fisiol Biol Mol & Neurociencias IFIBYNE, RA-1033 Buenos Aires, DF, Argentina. [Meiss, Roberto; Vallecorsa, Pablo] Acad Nacl Med Buenos Aires, Inst Estudios Oncol, Dept Patol, Buenos Aires, DF, Argentina. [Mazza, Osvaldo] Hosp Clin Jose San Martin, Buenos Aires, DF, Argentina. [Gardner, Kevin] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP De Siervi, A (reprint author), IBYME CONICET, Lab Oncol Mol & Nuevos Blancos Terapeut, Vuelta Obligado 2490,C1428ADN, RA-2490 Buenos Aires, DF, Argentina. EM adesiervi@qb.fcen.uba.ar OI Rodriguez-Segui, Santiago/0000-0003-2952-8485; Cotignola, Javier/0000-0003-4473-9854 FU Argentinean Agency of Science and Technology [ANPCyT PICT 2010-00431]; National Cancer Institute from Argentina FX This work was supported by the Argentinean Agency of Science and Technology (ANPCyT PICT 2010-00431) and the National Cancer Institute (2011) from Argentina. NR 27 TC 6 Z9 6 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2014 VL 20 IS 15 BP 4086 EP 4095 DI 10.1158/1078-0432.CCR-14-0322 PG 10 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500019 PM 24842953 ER PT J AU Kim, HS Anderson, P Weinshilboum, RM Vasiliou, V Heard, K Gonzalez, FJ Monte, AA AF Kim, H. S. Anderson, P. Weinshilboum, R. M. Vasiliou, V. Heard, K. Gonzalez, F. J. Monte, A. A. TI The accuracy of self-reported therapeutic drug ingestion history in ED patients SO CLINICAL TOXICOLOGY LA English DT Meeting Abstract DE Drug Monitoring; Ingestion; Drug of abuse C1 [Anderson, P.; Vasiliou, V.] Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Weinshilboum, R. M.; Gonzalez, F. J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Heard, K.; Monte, A. A.] Univ Colorado, Sch Med, Aurora, CO USA. [Kim, H. S.] Denver Hlth Med Ctr, Denver, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1556-3650 EI 1556-9519 J9 CLIN TOXICOL JI Clin. Toxicol. PD AUG PY 2014 VL 52 IS 7 MA 230 BP 786 EP 786 PG 1 WC Toxicology SC Toxicology GA AN0UE UT WOS:000340298700236 ER PT J AU Chuang-Stein, C Follman, D Chappell, R French, B Russek-Cohen, E Chappell, RJ Collins, L Lynch, K Kidwell, KM Whyte, J Chakraborty, B Ellenberg, SS AF Chuang-Stein, Christy Follman, Dean Chappell, Rick French, Benjamin Russek-Cohen, Estelle Chappell, Richard J. Collins, Linda Lynch, Kevin Kidwell, Kelley M. Whyte, John Chakraborty, Bibhas Ellenberg, Susan S. TI University of Pennsylvania 6th annual conference on statistical issues in clinical trials: Dynamic treatment regimes (afternoon session) SO CLINICAL TRIALS LA English DT Editorial Material ID AGENTS; DESIGN C1 [French, Benjamin; Lynch, Kevin; Ellenberg, Susan S.] Univ Penn, Philadelphia, PA 19104 USA. [Chuang-Stein, Christy] Pfizer, New York, NY 10017 USA. [Follman, Dean] NIAID, Bethesda, MD USA. [Russek-Cohen, Estelle] FDA, Philadelphia, PA USA. [Chappell, Rick] Univ Wisconsin Madison, Madison, WI USA. [Collins, Linda] Penn State Univ, University Pk, PA 16802 USA. [Kidwell, Kelley M.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Whyte, John] Moss Rehabil Res Inst, Elkins Pk, PA USA. [Chakraborty, Bibhas] Columbia Univ, New York, NY 10027 USA. RP Chuang-Stein, C (reprint author), Pfizer, New York, NY 10017 USA. NR 8 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2014 VL 11 IS 4 BP 457 EP 466 DI 10.1177/1740774514538552 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN0WX UT WOS:000340305800009 PM 25053777 ER PT J AU Elm, JJ Palesch, Y Easton, JD Lindblad, A Barsan, W Silbergleit, R Conwit, R Dillon, C Farrant, M Battenhouse, H Perlmutter, A Johnston, SC AF Elm, Jordan J. Palesch, Yuko Easton, J. Donald Lindblad, Anne Barsan, William Silbergleit, Robert Conwit, Robin Dillon, Catherine Farrant, Mary Battenhouse, Holly Perlmutter, Aaron Johnston, S. Claiborne TI Screen failure data in clinical trials: Are screening logs worth it? SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania 6th Annual Conference on Statistical Issues in Clinical Trials - Dynamic Treatment Regimes CY 2013 CL Univ Pennsylvania, Philadelphia, PA HO Univ Pennsylvania ID GROUP RANDOMIZED-TRIALS; UPDATED GUIDELINES; UNITED-STATES; CONSORT; COMPLETION; HIPAA AB Background Clinical trials frequently spend considerable effort to collect data on patients who were assessed for eligibility but not enrolled. The Consolidated Standards of Reporting Trials (CONSORT) guidelines' recommended flow diagram for randomized clinical trials reinforces the belief that the collection of screening data is a necessary and worthwhile endeavor. The rationale for collecting screening data includes scientific, trial management, and ethno-socio-cultural reasons. Purpose We posit that the cost of collecting screening data is not justified, in part due to inability to centrally monitor and verify the screening data in the same manner as other clinical trial data. Methods To illustrate the effort and site-to-site variability, we analyzed the screening data from a multicenter, randomized clinical trial of patients with transient ischemic attack or minor ischemic stroke (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke (POINT)). Results Data were collected on over 27,000 patients screened across 172 enrolling sites, 95% of whom were not enrolled. Although the rate of return of screen failure logs was high overall (95%), there were a considerable number of logs that were returned with 'no data to report' (23%), often due to administrative reasons rather than no patients screened. Conclusion In spite of attempts to standardize the collection of screening data, due to differences in site processes, multicenter clinical trials face challenges in collecting those data completely and uniformly. The efforts required to centrally collect high-quality data on an extensive number of screened patients may outweigh the scientific value of the data. Moreover, the lack of a standardized definition of 'screened' and the challenges of collecting meaningful characteristics for patients who have not signed consent limits the ability to compare across studies and to assess generalizability and selection bias as intended. C1 [Elm, Jordan J.; Palesch, Yuko; Dillon, Catherine; Battenhouse, Holly; Perlmutter, Aaron] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Easton, J. Donald; Farrant, Mary; Johnston, S. Claiborne] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Easton, J. Donald; Farrant, Mary; Johnston, S. Claiborne] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lindblad, Anne] EMMES Corp, Rockville, MD USA. [Barsan, William; Silbergleit, Robert] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. [Conwit, Robin] NINDS, Bethesda, MD 20892 USA. RP Elm, JJ (reprint author), Med Univ S Carolina, Dept Publ Hlth Sci, 135 Cannon St,Suite 303,POB 250835, Charleston, SC 29425 USA. EM elmj@musc.edu FU NINDS NIH HHS [U01 NS056975, U01 NS059041, U01 NS062835] NR 9 TC 3 Z9 3 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2014 VL 11 IS 4 BP 467 EP 472 DI 10.1177/1740774514538706 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN0WX UT WOS:000340305800010 PM 24925082 ER PT J AU AbdulSabur, NY Xu, YS Liu, SY Chow, HM Baxter, M Carson, J Braun, AR AF AbdulSabur, Nuria Y. Xu, Yisheng Liu, Siyuan Chow, Ho Ming Baxter, Miranda Carson, Jessica Braun, Allen R. TI Neural correlates and network connectivity underlying narrative production and comprehension: A combined fMRI and PET study SO CORTEX LA English DT Article DE Discourse; Language; Theory of mind; fMRI; Functional connectivity ID EVENT-RELATED FMRI; MEDIAL PREFRONTAL CORTEX; ANTERIOR TEMPORAL-LOBE; TEXT COMPREHENSION; DISCOURSE COMPREHENSION; HUMAN BRAIN; RIGHT-HEMISPHERE; FUNCTIONAL NEUROANATOMY; LANGUAGE COMPREHENSION; STORY COMPREHENSION AB The neural correlates of narrative production and comprehension remain poorly understood. Here, using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), contrast and functional network connectivity analyses we comprehensively characterize the neural mechanisms underlying these complex behaviors. Eighteen healthy subjects told and listened to fictional stories during scanning. In addition to traditional language areas (e.g., left inferior frontal and posterior middle temporal gyri), both narrative production and comprehension engaged regions associated with mentalizing and situation model construction (e.g., dorsomedial prefrontal cortex, precuneus and inferior parietal lobules) as well as neocortical premotor areas, such as the pre-supplementary motor area and left dorsal premotor cortex. Narrative comprehension alone showed marked bilaterality, activating right hemisphere homologs of perisylvian language areas. Narrative production remained predominantly left lateralized, uniquely activating executive and motor-related regions essential to language formulation and articulation. Connectivity analyses revealed strong associations between language areas and the superior and middle temporal gyri during both tasks. However, only during storytelling were these same language-related regions connected to cortical and subcortical motor regions. In contrast, during story comprehension alone, they were strongly linked to regions supporting mentalizing. Thus, when employed in a more complex, ecologically-valid context, language production and comprehension show both overlapping and idiosyncratic patterns of activation and functional connectivity. Importantly, in each case the language system is integrated with regions that support other cognitive and sensorimotor domains. (C) 2014 Published by Elsevier Ltd. C1 [AbdulSabur, Nuria Y.; Xu, Yisheng; Liu, Siyuan; Chow, Ho Ming; Baxter, Miranda; Carson, Jessica; Braun, Allen R.] NIDCD, Language Sect, NIH, Bethesda, MD 20982 USA. [AbdulSabur, Nuria Y.] Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. RP AbdulSabur, NY (reprint author), NIDCD, Language Sect, NIH, 9000 Rockville Pike,Bldg 10,Rm 5D45, Bethesda, MD 20982 USA. EM nuria.abdulsabur@nih.gov FU Intramural Research Program of the NIDCD, NIH FX The authors would like to acknowledge the kind assistance of the staff and technicians in the NIH MM Research Facility Center and the NIH Clinical Center PET Department. We would also like to thank the study participants for their interest and cooperation. This work was supported by the Intramural Research Program of the NIDCD, NIH. NR 133 TC 11 Z9 13 U1 4 U2 28 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD AUG PY 2014 VL 57 BP 107 EP 127 DI 10.1016/j.cortex.2014.01.017 PG 21 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AN1BK UT WOS:000340317500008 PM 24845161 ER PT J AU Schintu, S Hadj-Bouziane, F Dal Monte, O Knutson, KM Pardini, M Wassermann, EM Grafman, J Krueger, F AF Schintu, Selene Hadj-Bouziane, Fadila Dal Monte, Olga Knutson, Kristine M. Pardini, Matteo Wassermann, Eric M. Grafman, Jordan Krueger, Frank TI Object and space perception - Is it a matter of hemisphere? SO CORTEX LA English DT Article DE Dorsal stream; Ventral stream; Lateralization; VLSM; Insula ID TRANSCRANIAL MAGNETIC STIMULATION; VISUOSPATIAL ATTENTION; BRAIN-LESIONS; FUNCTIONAL NEUROANATOMY; UNILATERAL NEGLECT; VISUAL RECOGNITION; NEURAL FRAMEWORK; PARIETAL CORTEX; MACAQUE MONKEY; NETWORK AB In the 1980s, following Newcombe's observations, Ungerleider and Mishkin put forward the functional subdivision of the visual system into a ventral stream dedicated to object perception and a dorsal stream dedicated to space perception. Ten years after this discovery, the perception-action model re-defined the dorsal stream as responsible for nonconscious visual guidance, and most recently a tripartition has been suggested to account for a variety of visuospatial functions. Here, we investigated the neural underpinnings of object and space perception by combining the administration of the Visual Object Space Perception (VOSP) battery with a voxel-based lesion symptom mapping (VLSM) approach in a large sample of patients with penetrating traumatic brain injury (pTBI). First, our results provided new support for the complementary role of both hemispheres in object recognition. The right lateral occipital complex was found to be critical in early perceptual discrimination, whereas more anterior temporal and frontal regions in the left hemisphere were found to be critical in more complex forms of object discrimination and recognition. Second, our findings confirmed that space perception depended on the integrity of the right inferior parietal lobule (IPL) and revealed that a network linking the right IPL with the right premotor cortex was critical for the perception of spatial relationships in both 2D and 3D representations. Taken together, our results supported the functional subdivision of the visual system and shed new light on the specific processes involved along both the dorsal and the ventral streams. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Schintu, Selene; Hadj-Bouziane, Fadila] CNRS, INSERM, Lyon Neurosci Res Ctr, ImpAct Team,UMR5292,U1028, Lyon, France. [Schintu, Selene; Hadj-Bouziane, Fadila] Univ UCBL Lyon 1, Lyon, France. [Dal Monte, Olga] Univ Turin, Dept Neuropsychol, Turin, Italy. [Knutson, Kristine M.; Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, Behav Neurol Unit, Natl Inst Hlth, Bethesda, MD USA. [Pardini, Matteo] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet, Genoa, Italy. [Grafman, Jordan] Inst Chicago, Cognit Neurosci Lab Rehabil, Chicago, IL USA. [Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. RP Schintu, S (reprint author), CRNL, ImpAct Team, 16 Ave Doyen Lepine, F-69676 Bron, France. EM selene.schintu@gmail.com; fkrueger@gmu.edu OI dal monte, olga/0000-0002-7823-4769 FU U.S. National Institute of Neurological Disorders and Stroke intramural research program; States Army Medical Research and Material Command; Henry M. Jackson Foundation [DAMD17-01-1-0675]; NEURODIS Foundation FX The work was supported by the U.S. National Institute of Neurological Disorders and Stroke intramural research program, and a project grant from the United States Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, Grant DAMD17-01-1-0675). Selene Schintu was supported with funding from the Henry M. Jackson Foundation, and Fadila Hadj-Bouziane by the NEURODIS Foundation. The authors are grateful to all the Vietnam veterans who participated in this study and the National Naval Medical Center for their support and provision of facilities, as well as V. Raymont, S. Bonifant, B. Cheon, C. Ngo, A. Greathouse, K. Reding, and G. Tasick for their invaluable help with the testing of participants and organization of this study. Note that the views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, nor the U.S. Government. For further information about the Vietnam Head Injury Study, contact J. G. at jgrafman@northwestern.edu. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. NR 77 TC 11 Z9 11 U1 3 U2 31 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD AUG PY 2014 VL 57 BP 244 EP 253 DI 10.1016/j.cortex.2014.04.009 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AN1BK UT WOS:000340317500018 PM 24929474 ER PT J AU Gros, P Belkaid, Y AF Gros, Philippe Belkaid, Yasmine TI Host pathogens SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 [Gros, Philippe] McGill Univ, Dept Biochem, Montreal, PQ, Canada. [Belkaid, Yasmine] NIAID, LPD, NIH, Bethesda, MD 20892 USA. RP Gros, P (reprint author), McGill Univ, Dept Biochem, Montreal, PQ, Canada. EM philippe.gros@mcgill.ca; ybelkaid@niaid.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2014 VL 29 BP IV EP VI DI 10.1016/j.coi.2014.06.008 PG 3 WC Immunology SC Immunology GA AM9TC UT WOS:000340222900001 PM 25027097 ER PT J AU Mandl, JN Torabi-Parizi, P Germain, RN AF Mandl, Judith N. Torabi-Parizi, Parizad Germain, Ronald N. TI Visualization and dynamic analysis of host-pathogen interactions SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; CENTRAL-NERVOUS-SYSTEM; LYMPH-NODE; DENDRITIC CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; MYCOBACTERIAL GRANULOMAS; EFFECTOR FUNCTION; RECALL RESPONSES; VIRAL-INFECTION; IN-VIVO AB To contain invading microbes, the immune system must efficiently recognize the presence of the invader, mobilize cells to the site of infection, and deploy effector function. Rare antigen-specific T cells must find small numbers of antigen-presenting cells, proliferate and differentiate in secondary lymphoid tissues, then traffic to the infected site and be activated by antigen again to contribute to host defense. Our understanding of the dynamic processes involved has benefited enormously from tools that enable the visualization of cell location and behavior in complex tissue environments. Here we summarize recent insights into T cell trafficking and migration through secondary lymphoid organs and at peripheral infection sites, highlighting cell-intrinsic and extrinsic factors optimizing antigen surveillance at steady-state and delivery of an effector response during infection. C1 [Mandl, Judith N.; Torabi-Parizi, Parizad; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rgermain@nih.gov FU NIAID at the National Institutes of Health FX This work was supported by the Intramural Research Program of NIAID at the National Institutes of Health. The authors would like to thank Tetsuya Honda and Jackson Egen for their permission to reproduce movie S1. The authors also apologize for not citing all relevant publications due to space limitations. NR 68 TC 5 Z9 5 U1 0 U2 10 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2014 VL 29 BP 8 EP 15 DI 10.1016/j.coi.2014.03.002 PG 8 WC Immunology SC Immunology GA AM9TC UT WOS:000340222900004 PM 24705104 ER PT J AU Sakai, S Mayer-Barber, KD Barber, DL AF Sakai, Shunsuke Mayer-Barber, Katrin D. Barber, Daniel L. TI Defining features of protective CD4 T cell responses to Mycobacterium tuberculosis SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID IFN-GAMMA; INTERFERON-GAMMA; IN-VIVO; INFECTION; MICE; IMMUNITY; MEMORY; MIGRATION; VACCINATION; RESISTANCE AB CD4 T cells are critical for control of Mycobacterium tuberculosis (Mtb) infection and represent the best hope for vaccine-elicited protection. However, little is understood about the properties of Mtb-specific CD4 T cells that mediate control, and the lack of correlates of protection present a significant barrier to the rational development of new vaccination and therapeutic strategies which are sorely needed. Here we discuss the features of protective CD4 T cells including recent evidence for IFN-gamma dependent and independent mechanisms of protection, poor protection by terminally differentiated cells and the importance of T cell migratory capacity for the control of Mtb infection. C1 [Sakai, Shunsuke; Barber, Daniel L.] NIAID, T Lymphocyte Biol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Mayer-Barber, Katrin D.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Mayer-Barber, KD (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM barberd@niaid.nih.gov FU NIAID, National Institutes of Health [AI001171-01]; Japan Society for the Promotion of Science FX This work was supported by the Intramural Research Program of the NIAID, National Institutes of Health (AI001171-01). S.S. received additional support from the Japan Society for the Promotion of Science. NR 45 TC 11 Z9 11 U1 9 U2 36 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2014 VL 29 BP 137 EP 142 DI 10.1016/j.coi.2014.06.003 PG 6 WC Immunology SC Immunology GA AM9TC UT WOS:000340222900022 PM 25000593 ER PT J AU Lansford, JE Woodlief, D Malone, PS Oburu, P Pastorelli, C Skinner, AT Sorbring, E Tapanya, S Tirado, LMU Zelli, A Al-Hassan, SM Alampay, LP Bacchini, D Bombi, AS Bornstein, MH Chang, L Deater-Deckard, K Di Giunta, L Dodge, KA AF Lansford, Jennifer E. Woodlief, Darren Malone, Patrick S. Oburu, Paul Pastorelli, Concetta Skinner, Ann T. Sorbring, Emma Tapanya, Sombat Tirado, Liliana Maria Uribe Zelli, Arnaldo Al-Hassan, Suha M. Alampay, Liane Pena Bacchini, Dario Bombi, Anna Silvia Bornstein, Marc H. Chang, Lei Deater-Deckard, Kirby Di Giunta, Laura Dodge, Kenneth A. TI A longitudinal examination of mothers' and fathers' social information processing biases and harsh discipline in nine countries SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID MULTITRAIT-MULTIMETHOD MATRIX; SELF-REPORTED DISCIPLINE; CORPORAL PUNISHMENT; ADJUSTMENT PROBLEMS; CHILD-ABUSE; PARENTING ATTRIBUTIONS; RELATIONAL AGGRESSION; PHYSICAL DISCIPLINE; HOSTILE ATTRIBUTION; FIT INDEXES AB This study examined whether parents' social information processing was related to their subsequent reports of their harsh discipline. Interviews were conducted with mothers (n = 1,277) and fathers (n = 1,030) of children in 1,297 families in nine countries (China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States), initially when children were 7 to 9 years old and again 1 year later. Structural equation models showed that parents' positive evaluations of aggressive responses to hypothetical childrearing vignettes at Time 1 predicted parents' self-reported harsh physical and nonphysical discipline at Time 2. This link was consistent across mothers and fathers, and across the nine countries, providing support for the universality of the link between positive evaluations of harsh discipline and parents' aggressive behavior toward children. The results suggest that international efforts to eliminate violence toward children could target parents' beliefs about the acceptability and advisability of using harsh physical and nonphysical forms of discipline. C1 [Lansford, Jennifer E.; Skinner, Ann T.; Dodge, Kenneth A.] Duke Univ, Durham, NC 27708 USA. [Woodlief, Darren; Malone, Patrick S.] Univ S Carolina, Columbia, SC 29208 USA. [Oburu, Paul] Maseno Univ, Maseno, Kenya. [Pastorelli, Concetta; Tirado, Liliana Maria Uribe; Bombi, Anna Silvia; Di Giunta, Laura] Univ Roma La Sapienza, Rome, Italy. [Sorbring, Emma] Univ West, Trollhattan, Sweden. [Tapanya, Sombat] Chiang Mai Univ, Chiang Mai, Thailand. [Tirado, Liliana Maria Uribe] Univ San Buenaventura, Bogota, Colombia. [Zelli, Arnaldo] Univ Rome Foro Ital, Rome, Italy. [Al-Hassan, Suha M.] Hashemite Univ, Zarqa, Abdallah Ghoshe, Jordan. [Alampay, Liane Pena] Ateneo Manila Univ, Lungsod Quezon, Philippines. [Bacchini, Dario] Univ Naples 2, Caserta, Italy. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Chang, Lei] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Deater-Deckard, Kirby] Virginia Tech, Blacksburg, VA USA. RP Lansford, JE (reprint author), Duke Univ, Ctr Child & Family Policy, Box 90545, Durham, NC 27708 USA. EM lansford@duke.edu RI ZELLI, ARNALDO/N-2333-2015; OI ZELLI, ARNALDO/0000-0003-4020-8159; Bacchini, Dario/0000-0001-6140-9377 FU FIC NIH HHS [R03 TW008141, R03-TW008141]; Intramural NIH HHS; NICHD NIH HHS [R01 HD054805, R01-HD054805]; NIDA NIH HHS [K01 DA024116, 2K05 DA015226, K01DA024116, K05 DA015226] NR 76 TC 4 Z9 4 U1 11 U2 36 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD AUG PY 2014 VL 26 IS 3 SI SI BP 561 EP 573 DI 10.1017/S0954579414000236 PG 13 WC Psychology, Developmental SC Psychology GA AM8VQ UT WOS:000340156800002 PM 24762321 ER PT J AU Banny, AM Tseng, WL Murray-Close, D Pitula, CE Crick, NR AF Banny, Adrienne M. Tseng, Wan-Ling Murray-Close, Dianna Pitula, Clio E. Crick, Nicki R. TI Borderline personality features as a predictor of forms and functions of aggression during middle childhood: Examining the roles of gender and physiological reactivity SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID SOCIAL-PSYCHOLOGICAL ADJUSTMENT; RELATIONAL AGGRESSION; PROACTIVE AGGRESSION; DEVELOPMENTAL PSYCHOPATHOLOGY; CARDIOVASCULAR REACTIVITY; PROSPECTIVE ASSOCIATIONS; INTENT ATTRIBUTIONS; SCHOOL-CHILDREN; DISORDER; BOYS AB The present longitudinal investigation examined borderline personality features as a predictor of aggression 1 year later. Moderation by physiological reactivity and gender was also explored. One hundred ninety-six children (M = 10.11 years, SD = 0.64) participated in a laboratory stress protocol in which their systolic blood pressure, diastolic blood pressure, and skin conductance reactivity to recounting a relational stressor (e. g., threats to relationships or exclusion) were assessed. Teachers provided reports on subtypes of aggressive behavior (i.e., reactive relational, proactive relational, reactive physical, and proactive physical), and children completed a self-report measure of borderline personality features. Path analyses indicated that borderline personality features predicted increases in reactive relational aggression and proactive relational aggression among girls who evinced heightened physiological reactivity to interpersonal stress. In contrast, borderline personality features predicted decreases in proactive physical aggression in girls. Findings suggest that borderline personality features promote engagement in relationally aggressive behaviors among girls, particularly in the context of emotional dysregulation. C1 [Banny, Adrienne M.; Pitula, Clio E.; Crick, Nicki R.] Univ Minnesota, Minneapolis, MN 55455 USA. [Tseng, Wan-Ling] NIMH, Bethesda, MD USA. [Murray-Close, Dianna] Univ Vermont, Burlington, VT 05405 USA. RP Banny, AM (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. EM banny001@umn.edu NR 78 TC 3 Z9 3 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD AUG PY 2014 VL 26 IS 3 SI SI BP 789 EP 804 DI 10.1017/S095457941400039X PG 16 WC Psychology, Developmental SC Psychology GA AM8VQ UT WOS:000340156800018 PM 25047299 ER PT J AU Pacher, P AF Pacher, P. TI Role of the Endocannabinoid System in Cardiovascular Injury and Inflammation SO DIGESTIVE DISEASES AND SCIENCES LA English DT Meeting Abstract C1 [Pacher, P.] NIAAA, NIH, DICBR Lab Physiol Studies, Sect Oxidat Stress Tissue Injury, Bethesda, MD USA. EM pacher@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2014 VL 59 IS 8 BP 1660 EP 1660 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AM7MJ UT WOS:000340051200038 ER PT J AU Mahabir, S AF Mahabir, S. TI Dietary magnesium and inflammation SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter ID CANCER; RISK C1 NCI, Modifiable Risk Factors Branch, Epidemiol & Genom Res Program, Div Canc Prevent & Populat Sci, Rockville, MD 20892 USA. RP Mahabir, S (reprint author), NCI, Modifiable Risk Factors Branch, Epidemiol & Genom Res Program, Div Canc Prevent & Populat Sci, Rockville, MD 20892 USA. EM mahabir@mail.nih.gov NR 8 TC 0 Z9 0 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD AUG PY 2014 VL 68 IS 8 BP 970 EP 970 DI 10.1038/ejcn.2014.110 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AN0XV UT WOS:000340308200020 PM 24939436 ER PT J AU Hajishengallis, G Moutsopoulos, NM AF Hajishengallis, George Moutsopoulos, Niki M. TI Etiology of leukocyte adhesion deficiency-associated periodontitis revisited: not a raging infection but a raging inflammatory response SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Editorial Material DE IL-17; inflammation; leukocyte adhesion deficiency; neutrophils; periodontitis ID BONE LOSS; PATHOGENESIS; HOMEOSTASIS; NEUTROPHILS; IL-17; IL-23; MAC-1 AB In leukocyte adhesion deficiency type I, neutrophils fail to adhere to blood vessel walls and thus cannot transmigrate to peripheral tissues. Leukocyte adhesion deficiency type I patients invariably experience an aggressive form of generalized periodontitis, which has been historically attributed to defective neutrophil surveillance of the periodontal infection. This time-honored notion has now been challenged by a recent study, which showed that the underlying etiology involves a dysregulated host response that leads to overexpression of the proinflammatory and bone-resorptive cytokine IL-17. C1 [Hajishengallis, George] Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, Oral Immun & Infect Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Hajishengallis, G (reprint author), Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. EM geoh@upenn.edu FU NIDCR NIH HHS [DE015254, DE017138, DE021685, R01 DE015254, R01 DE017138, R01 DE021685] NR 20 TC 6 Z9 7 U1 2 U2 3 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X EI 1744-8409 J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD AUG PY 2014 VL 10 IS 8 BP 973 EP 975 DI 10.1586/1744666X.2014.929944 PG 3 WC Immunology SC Immunology GA AM9AL UT WOS:000340171500001 PM 24931458 ER PT J AU Ganesh, SK Morissette, R Xu, Z Schoenhoff, F Griswold, BF Yang, JD Tong, L Yang, ML Hunker, K Sloper, L Kuo, SN Raza, R Milewicz, DM Francomano, CA Dietz, HC Van Eyk, J McDonnell, NB AF Ganesh, Santhi K. Morissette, Rachel Xu, Zhi Schoenhoff, Florian Griswold, Benjamin F. Yang, Jiandong Tong, Lan Yang, Min-Lee Hunker, Kristina Sloper, Leslie Kuo, Shinie Raza, Rafi Milewicz, Dianna M. Francomano, Clair A. Dietz, Harry C. Van Eyk, Jennifer McDonnell, Nazli B. TI Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-10.1096/fj.14-251207 beta expression and connective tissue features SO FASEB JOURNAL LA English DT Article DE biomarker; FMD; TGF-beta; pathway aneurysm; human genetics ID GROWTH-FACTOR-BETA; MAGNETIC-RESONANCE SCANS; EHLERS-DANLOS-SYNDROME; MARFAN-SYNDROME; RENOVASCULAR HYPERTENSION; ARTERIAL FIBRODYSPLASIA; ASYMPTOMATIC SUBJECTS; JOINT HYPERMOBILITY; CAROTID-ARTERY; DISORDERS AB Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor beta (TGF-beta) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P< 0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-beta 1 (P = 0.009), TGF-beta 2 (P = 0.004) and additional inflammatory markers, and increased TGF-beta 1 (P = 0.0009) and TGF-beta 2 (P = 0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age-and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-beta signaling and offers TGF-beta as a marker of FMD. C1 [Ganesh, Santhi K.; Tong, Lan; Yang, Min-Lee; Hunker, Kristina; Kuo, Shinie] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Ganesh, Santhi K.; Tong, Lan; Yang, Min-Lee; Hunker, Kristina; Kuo, Shinie] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Morissette, Rachel; Xu, Zhi; Griswold, Benjamin F.; Yang, Jiandong; Sloper, Leslie; Raza, Rafi; McDonnell, Nazli B.] NIA, Lab Clin Invest, Baltimore, MD 21225 USA. [Schoenhoff, Florian; Van Eyk, Jennifer] Johns Hopkins Univ, Dept Med, Johns Hopkins Bayview Prote Ctr, Baltimore, MD USA. [Milewicz, Dianna M.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Med Genet, Houston, TX 77030 USA. [Francomano, Clair A.] Greater Baltimore Med Ctr, Towson, MD USA. [Dietz, Harry C.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD USA. [Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP McDonnell, NB (reprint author), NIA, Clin Unit, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM sganesh@umich.edu; nazli.mcdonnell@gmail.com FU Intramural Research Program of the U.S. National Institutes of Health (NIH), National Institute on Aging; University of Michigan [R00HL089413]; Johns Hopkins Institutional Clinical and Translational Science Award (CTSA) grant [1U54RR023561-01A1]; American Recovery and Reinvestment Act (ARRA) Novel Biomarkers in Aortic Aneurysms and Acute Aortic Dissection grant [5RC1HL100021-02]; National Heart, Lung, and Blood Institute/NIH [P30HL101290]; Doris Duke Charitable Foundation FX This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health (NIH), National Institute on Aging. FACS analysis studies were supported in part by grant R00HL089413 at the University of Michigan. The Johns Hopkins Institutional Clinical and Translational Science Award (CTSA) grant 1U54RR023561-01A1 and the American Recovery and Reinvestment Act (ARRA) Novel Biomarkers in Aortic Aneurysms and Acute Aortic Dissection grant 5RC1HL100021-02 were used for plasma biomarker studies. S. K. G. was supported by grants from the National Heart, Lung, and Blood Institute/NIH (P30HL101290) and the Doris Duke Charitable Foundation. S. K. G. and N.B.M. are unpaid medical advisors for the nonprofit Fibromuscular Dysplasia Society of America (FMDSA). No FMDSA funds were used in this study. NR 48 TC 12 Z9 13 U1 2 U2 6 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 AUG PY 2014 VL 28 IS 8 BP 3313 EP 3324 DI 10.1096/fj.14-251207 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AN0HM UT WOS:000340265400004 PM 24732132 ER PT J AU Fortin, J Boehm, U Deng, CX Treier, M Bernard, DJ AF Fortin, Jerome Boehm, Ulrich Deng, Chu-Xia Treier, Mathias Bernard, Daniel J. TI Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2 SO FASEB JOURNAL LA English DT Article DE FSH; activin; pituitary ID GONADOTROPIN-RELEASING-HORMONE; BETA-SUBUNIT TRANSCRIPTION; ACTIVIN-A; RECEPTOR GENE; HYPOGONADOTROPIC HYPOGONADISM; ESTROGEN-RECEPTOR; LUTEINIZING-HORMONE; PROXIMAL PROMOTER; OVARIAN FAILURE; KNOCKOUT MICE AB Follicle-stimulating hormone (FSH) is an essential regulator of gonadal function and fertility. Loss-of-function mutations in the FSHB/Fshb gene cause hypogonadotropic hypogonadism in humans and mice. Both gonadotropin-releasing hormone (GnRH) and activins, members of the transforming growth factor beta (TGF beta) superfamily, stimulate FSH synthesis; yet, their relative roles and mechanisms of action in vivo are unknown. Here, using conditional gene-targeting, we show that the canonical mediator of TGF beta superfamily signaling, SMAD4, is absolutely required for normal FSH synthesis in both male and female mice. Moreover, when the Smad4 gene is ablated in combination with its DNA binding cofactor Foxl2 in gonadotrope cells, mice make essentially no FSH and females are sterile. Indeed, the phenotype of these animals is remarkably similar to that of Fshb-knockout mice. Not only do these results establish SMAD4 and FOXL2 as essential master regulators of Fshb transcription in vivo, they also suggest that activins, or related ligands, could play more important roles in FSH synthesis than GnRH. C1 [Fortin, Jerome; Bernard, Daniel J.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada. [Boehm, Ulrich] Univ Saarland, Sch Med, Dept Pharmacol & Toxicol, Homburg, Germany. [Deng, Chu-Xia] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Treier, Mathias] Max Delbruck Ctr Mol Med, Berlin, Germany. RP Fortin, J (reprint author), McGill Univ, Dept Pharmacol & Therapeut, 3655 Promenade Sir William Osler,Rm 1315, Montreal, PQ H3G 1Y6, Canada. EM jerome.fortin@mail.mcgill.ca; daniel.bernard@mcgill.ca RI deng, chuxia/N-6713-2016 FU Doctoral Research Award from the Canadian Institutes of Health Research (CIHR); Samuel Solomon Fellowship in Endocrinology from the Endocrine Division and McGill Faculty of Medicine (McGill University); CIHR [MOP-89991/-123447]; DFG [BO1743/2]; U.S. National Institutes of Health/National Institute of Child Health and Human Development (Specialized Cooperative Centers Program in Reproduction Research) grant [U54-HD28934] FX The authors thank Ken McDonald for assistance with FACS, as well as the Goodman Cancer Research Center Histology Facility (McGill University) and the Center for Bone and Periodontal Research Histology Platform (McGill University) for the preparation of histological sections. The authors also thank Dr. Alfredo Ribeiro-da-Silva for generously providing access to the Zeiss Axioplan 2 microscope and Dr. Derek Boerboom for insightful comments on ovarian histology. J.F. was supported by a Doctoral Research Award from the Canadian Institutes of Health Research (CIHR) and the Samuel Solomon Fellowship in Endocrinology from the Endocrine Division and McGill Faculty of Medicine (McGill University). This work was funded by CIHR operating grants MOP-89991/-123447 (to D.J.B.). D.J.B. was a Senior Research Scholar of the Fonds de la Recherche en Sante de Quebec. U. B. is funded by DFG BO1743/2. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core (Charlottesville, VA, USA) is supported by the U.S. National Institutes of Health/National Institute of Child Health and Human Development (Specialized Cooperative Centers Program in Reproduction Research) grant U54-HD28934. NR 64 TC 19 Z9 19 U1 0 U2 8 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 AUG PY 2014 VL 28 IS 8 BP 3396 EP 3410 DI 10.1096/fj.14-249532 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AN0HM UT WOS:000340265400011 PM 24739304 ER PT J AU Camps, J Wangsa, D Falke, M Brown, M Case, CM Erdos, MR Ried, T AF Camps, Jordi Wangsa, Darawalee Falke, Martin Brown, Markus Case, Chanelle M. Erdos, Michael R. Ried, Thomas TI Loss of lamin B1 results in prolongation of S phase and decondensation of chromosome territories SO FASEB JOURNAL LA English DT Article DE nuclear organization; alternative splicing ID GILFORD-PROGERIA-SYNDROME; LARGE GENE LISTS; DNA-REPLICATION; NUCLEAR LAMINS; HUMAN FIBROBLASTS; HUMAN-CELLS; ORGANIZATION; CHROMATIN; ARCHITECTURE; SENESCENCE AB Nuclear lamin B1 (LMNB1) constitutes one of the major structural proteins in the lamina mesh. We silenced the expression of LMNB1 by RNA interference in the colon cancer cell line DLD-1 and showed a dramatic redistribution of H3K27me3 from the periphery to a more homogeneous nuclear dispersion. In addition, we observed telomere attrition and an increased frequency of micronuclei and nuclear blebs. By 3D-FISH analyses, we demonstrated that the volume and surface of chromosome territories were significantly larger in LMNB1-depleted cells, suggesting that LMNB1 is required to maintain chromatin condensation in interphase nuclei. These changes led to a prolonged S phase due to activation of Chk1. Finally, silencing of LMNB1 resulted in extensive changes in alternative splicing of multiple genes and in a higher number of enlarged nuclear speckles. Taken together, our results suggest a mechanistic role of the nuclear lamina in the organization of chromosome territories, maintenance of genome integrity and proper gene splicing. C1 [Camps, Jordi; Wangsa, Darawalee; Falke, Martin; Brown, Markus; Case, Chanelle M.; Ried, Thomas] NCI, Sect Canc Genom, Genet Branch, Bethesda, MD 20893 USA. [Erdos, Michael R.] NHGRI, Genome Technol Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ried, T (reprint author), NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, 50 South Dr,Bldg 50,Rm 1408, Bethesda, MD 20893 USA. EM riedt@mail.nih.gov FU Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute FX The authors thank Dr. Abdel Elkalhoun (director of the Microarray Core, National Human Genome Research Institute), Dr. Stephen M. Wincovitch and Dr. Amalia Dutra (Cytogenetics and Microscopy Core, National Human Genome Research Institute), and Barbara J. Taylor (Facility Head of the FACS Core Laboratory, National Cancer Institute) for technical support. The authors also thank Buddy Chen for editorial assistance. This project was supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute. The authors declare no conflicts of interest. NR 39 TC 13 Z9 13 U1 1 U2 10 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 AUG PY 2014 VL 28 IS 8 BP 3423 EP 3434 DI 10.1096/fj.14-250456 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AN0HM UT WOS:000340265400013 PM 24732130 ER PT J AU Boutin, A Eliseeva, E Gershengorn, MC Neumann, S AF Boutin, Alisa Eliseeva, Elena Gershengorn, Marvin C. Neumann, Susanne TI beta-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation SO FASEB JOURNAL LA English DT Article DE TSH receptor; signaling; phosphokinases; bone; osteopontin ID THYROID-STIMULATING HORMONE; PROTEIN-COUPLED RECEPTOR; PARATHYROID-HORMONE; ERK1/2 ACTIVATION; BONE LOSS; KINASE-A; TSH; GROWTH; ANTAGONIST; PATHWAYS AB Thyrotropin (TSH) activation of the TSH receptor (TSHR), a 7-transmembrane-spanning receptor (7TMR), may have osteoprotective properties by direct effects on bone. TSHR activation by TSH phosphorylates protein kinases AKT1, p38 alpha, and ERK1/2 in some cells. We found TSH-induced phosphorylation of these kinases in 2 cell lines engineered to express TSHRs, human embryonic kidney HEK-TSHR cells and human osteoblastic U2OS-TSHR cells. In U2OS-TSHR cells, TSH up-regulated pAKT1 (7.1 +/- 0.5-fold), p38 alpha (2.9 +/- 0.4-fold), and pERK1/2 (3.1 +/- 0.2-fold), whereas small molecule TSHR agonist C2 had no or little effect on pAKT1 (1.8 +/- 0.08-fold), p38 alpha (1.2 +/- 0.09-fold), and pERK1/2 (1.6 +/- 0.19-fold). Furthermore, TSH increased expression of osteoblast marker genes ALPL (8.2 +/- 4.6-fold), RANKL (21 +/- 5.9-fold), and osteopontin (OPN; 17 +/- 5.3-fold), whereas C2 had little effect (ALPL, 1.7 +/- 0.5-fold; RANKL, 1.3 +/- 0.6-fold; and OPN, 2.2 +/- 0.7fold). beta-Arrestin-1 and -2 can mediate activatory signals by 7TMRs. TSH stimulated translocation of beta-arrestin-1 and -2 to TSHR, whereas C2 failed to translocate either beta-arrestin. Down-regulation of beta-arrestin-1 by siRNA inhibited TSH-stimulated phosphorylation of ERK1/2, p38 alpha, and AKT1, whereas down-regulation of beta-arrestin-2 increased phosphorylation of AKT1 in both cell types and of ERK1/2 in HEK-TSHR cells. Knockdown of beta-arrestin- 1 inhibited TSH-stimulated up-regulation of mRNAs for OPN by 87 +/- 1.7% and RANKL by 73 +/- 2.4%, and OPN secretion by 74 +/- 10%. We conclude that TSH enhances osteoblast differentiation in U2OS cells that is, in part, caused by activatory signals mediated by beta-arrestin- 1. C1 [Boutin, Alisa; Eliseeva, Elena; Gershengorn, Marvin C.; Neumann, Susanne] Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Neumann, S (reprint author), Natl Inst Diabet & Digest & Kidney Dis, 50 South Dr,Bldg 50 Rm 4128, Bethesda, MD 20892 USA. EM susannen@intra.niddk.nih.gov FU Intramural Research Program of the U.S. National Institutes of Health [1 Z01 DK047044] FX This research was supported by the Intramural Research Program of the U.S. National Institutes of Health (1 Z01 DK047044). NR 36 TC 9 Z9 9 U1 0 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 AUG PY 2014 VL 28 IS 8 BP 3446 EP 3455 DI 10.1096/fj.14-251124 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AN0HM UT WOS:000340265400015 PM 24723693 ER PT J AU Barnes, AJ Young, S Spinelli, E Martin, TM Klette, KL Huestis, MA AF Barnes, Allan J. Young, Sheena Spinelli, Eliani Martin, Thomas M. Klette, Kevin L. Huestis, Marilyn A. TI Evaluation of a homogenous enzyme immunoassay for the detection of synthetic cannabinoids in urine SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE Immunoassay; Synthetic cannabinoids; HEIA ID DESIGNER DRUGS; CANNABIMIMETIC INDOLES; JWH-018 METABOLITES; RECEPTOR AGONISTS; MASS-SPECTROMETRY; ORAL FLUID; LC-MS/MS; ABUSE; CB2; SPECIMENS AB Introduction: The recent emergence and widespread availability of many new synthetic cannabinoids support the need for an accurate and high-throughput urine screen for these new designer drugs. We evaluated performance of the immunalysis homogeneous enzyme immunoassay (HEIA) to sensitively, selectively, and rapidly identify urinary synthetic cannabinoids. Methods: 2443 authentic urine samples were analyzed with the HEIA that targets JWH-018 N-pentanoic acid, and a validated LC-MS/MS method for 29 synthetic cannabinoids and metabolites. Semi-quantitative HEIA results were obtained, permitting performance evaluation at and around three cutoffs (5, 10 and 20 mu g/L), and diagnostic sensitivity, specificity and efficiency determination. Performance challenges at +/- 25 and +/- 50% of each cutoff level, cross-reactivity and interferences also were evaluated. Results: Sensitivity, specificity, and efficiency of the immunalysis HEIA K2 Spice kit with the manufacturer's recommended 10 mg/L cutoff were 75.6%, 99.6% and 96.8%, respectively, as compared to the reference LC-MS/MS method with limits of detection of 0.1-10 mu g/L. Performance at 5 mu g/L was 92.2%, 98.1% and 97.4%, and for the 20 mu g/L cutoff were 62.9%, 99.7% and 95.4%. Semi-quantitative results for in-house prepared standards were obtained from 2.5-30 mu g/L, and documented acceptable linearity from 5-25 mu g/L, with inter-day imprecision <30% (n = 17). Thirteen of 74 synthetic cannabinoids evaluated were classified as highly cross-reactive (>= 50% at 10 mu g/L); 4 showed moderate cross-reactivity (10-50% at 10 mu g/L), 30 low cross-reactivity (<10% at 500 mu g/L), and 27 <1% cross-reactivity at 500 mu g/L. There was no interference from 102 investigated compounds. Only a mixture containing 1000 mu g/L each of buprenorphine/norbuprenorphine produced a positive result above our proposed cutoff (5 mu g/L) but below the manufacturer's recommended cutoff concentration (10 mu g/L). Conclusion: The Immunalysis HEIA K2 Spice kit required no sample preparation, had a high-throughput, and acceptable sensitivity, specificity and efficiency, offering a viable method for screening synthetic cannabinoids in urine that cross-react with JWH-018 N-pentanoic acid antibodies. Published by Elsevier Ireland Ltd. C1 [Barnes, Allan J.; Young, Sheena; Spinelli, Eliani; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Intramural Res Prog, NIH, Baltimore, MD 21224 USA. [Spinelli, Eliani] Univ Fed Fluminense, Sch Pharm, CAPES Fdn, Rio De Janeiro, Brazil. [Martin, Thomas M.; Klette, Kevin L.] Off Secretary Def Operat Readiness & Safety, Drug Testing & Prog Policy, Washington, DC USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intramural Res Prog, NIH, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Spinelli, Eliani/0000-0001-5488-2545 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. We also thank Immunalysis, Inc. for their support during the conduct of this research including providing the assays, calibrators and controls for urine analyses. NR 38 TC 10 Z9 11 U1 3 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 EI 1872-6283 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD AUG PY 2014 VL 241 BP 27 EP 34 DI 10.1016/j.forsciint.2014.04.020 PG 8 WC Medicine, Legal SC Legal Medicine GA AM7KU UT WOS:000340046700011 PM 24845968 ER PT J AU Smith, ML Nichols, DC Underwood, P Fuller, Z Moser, MA LoDico, C Gorelick, DA Newmeyer, MN Concheiro, M Huestis, MA AF Smith, Michael L. Nichols, Daniel C. Underwood, Paula Fuller, Zachary Moser, Matthew A. LoDico, Charles Gorelick, David A. Newmeyer, Matthew N. Concheiro, Marta Huestis, Marilyn A. TI Morphine and codeine concentrations in human urine following controlled poppy seeds administration of known opiate content SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE Poppy seeds; Urine; Morphine; Codeine; Controlled dose ID 6-ACETYLMORPHINE; CONSUMPTION AB Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45 g oral poppy seed doses 8 h apart, each containing 15.7 mg morphine and 3 mg codeine. Urine was collected ad libitum up to 32 h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2000 and 300 mu g/L cutoffs, and the ThermoFisher CEDIA (R) heroin metabolite (6-acetylmorphine, 6-AM) and Lin-Zhi 6-AM immunoassays with 10 mu g/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N = 22) provided 391 urine specimens over 32 h following dosing; 26.6% and 83.4% were positive for morphine at 2000 and 300 mu g/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7522 mu g/L with a median peak concentration of 5239 mu g/L. The median first morphine-positive urine sample at 2000 mu g/L cutoff concentration occurred at 6.6 h (1.2-12.1), with the last positive from 2.6 to 18 h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2000 mu g/L, but 20.2% exceeded 300 mu g/L, with peak concentrations of 658 mu g/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300 mu g/L cutoffs. The CEDIA 6-AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. (C) 2014 Published by Elsevier Ireland Ltd. C1 [Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.] US Army, Forens Toxicol Drug Testing Lab, Ft George G Meade, MD USA. [LoDico, Charles] Dept Hlth & Human Serv, Abuse Mental Hlth Serv Adm, Div Workplace Programs, Rockville, MD USA. [Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Rm O5A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Concheiro, Marta/0000-0002-3858-1280; Newmeyer, Matthew/0000-0002-0653-1553 FU Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse; Division of Workplace Programs, Substance Abuse Mental Health Services Administration, USA FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse and the Division of Workplace Programs, Substance Abuse Mental Health Services Administration, USA. The opinions in this article are those of the authors and do not necessarily reflect the views of the United States Department of Army or Department of Defense. NR 15 TC 8 Z9 8 U1 0 U2 33 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 EI 1872-6283 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD AUG PY 2014 VL 241 BP 87 EP 90 DI 10.1016/j.forsciint.2014.04.042 PG 4 WC Medicine, Legal SC Legal Medicine GA AM7KU UT WOS:000340046700018 PM 24887324 ER PT J AU Castonguay, V Lheureux, S Welch, S Mackay, HJ Hirte, H Fleming, G Morgan, R Wang, LS Blattler, C Ivy, PS Oza, AM AF Castonguay, Vincent Lheureux, Stephanie Welch, Stephen Mackay, Helen J. Hirte, Hal Fleming, Gini Morgan, R. Wang, Lisa Blattler, Chantale Ivy, Percy S. Oza, Amit M. TI A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret, Chicago and California Consortia SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; Recurrence; Sunitinib; Phase II ID GYNECOLOGIC-ONCOLOGY-GROUP; RENAL-CELL CARCINOMA; OVARIAN-CANCER; ANGIOGENESIS; BEVACIZUMAB; PERSISTENT; CHEMOTHERAPY; PACLITAXEL; EVEROLIMUS; EFFICACY AB Objective. Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC. Methods. We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on-2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate. Results. 34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (303%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea and hematologic. Conclusion. Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit. (C) 2014 Elsevier Inc. All rights reserved. C1 [Castonguay, Vincent; Lheureux, Stephanie; Mackay, Helen J.; Wang, Lisa; Blattler, Chantale; Oza, Amit M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Welch, Stephen] London Hlth Sci Ctr, London, ON, Canada. [Hirte, Hal] Juravinski Canc Ctr, Hamilton, ON, Canada. [Fleming, Gini] Univ Chicago, Med Ctr, Chicago Phase Consortium 2, Chicago, IL 60637 USA. [Morgan, R.] City Hope Comprehens Canc Ctr, Calif Phase Consortium 2, Duarte, CA USA. [Ivy, Percy S.] NCI, CTEP, Bethesda, MD 20892 USA. RP Oza, AM (reprint author), Univ Toronto, Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON MSG 2M9, Canada. EM amit.oza@uhn.ca NR 41 TC 19 Z9 19 U1 0 U2 4 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 AUG PY 2014 VL 134 IS 2 BP 274 EP 280 DI 10.1016/j.ygyno.2014.05.016 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900012 PM 24882554 ER PT J AU Stratton, P AF Stratton, Pamela TI The association of clinical symptoms with deep infiltrating endometriosis: the importance of the preoperative clinical assessment SO HUMAN REPRODUCTION LA English DT Editorial Material ID OVARIAN ENDOMETRIOMA; FERTILITY INDEX; STAGING SYSTEM; PELVIC PAIN; SURGERY C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bldg 10,CRC,Room 1-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM ps79c@nih.gov NR 9 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 2014 VL 29 IS 8 BP 1627 EP 1628 DI 10.1093/humrep/deu131 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AM7TG UT WOS:000340071000006 PM 24903200 ER PT J AU Kissell, KA Danaher, MR Schisterman, EF Wactawski-Wende, J Ahrens, KA Schliep, K Perkins, NJ Sjaarda, L Weck, J Mumford, SL AF Kissell, K. A. Danaher, M. R. Schisterman, E. F. Wactawski-Wende, J. Ahrens, K. A. Schliep, K. Perkins, N. J. Sjaarda, L. Weck, J. Mumford, S. L. TI Biological variability in serum anti-Mullerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women SO HUMAN REPRODUCTION LA English DT Article DE menstrual cycle; anovulation; anti-Mullerian hormone ID CONTROLLED OVARIAN STIMULATION; IN-VITRO FERTILIZATION; MLLERIAN HORMONE; ANTIMULLERIAN HORMONE; FERTILITY MONITOR; FOLLICULAR ARREST; REPRODUCTIVE AGE; CLINICAL UTILITY; II ASSAY; RESERVE AB Does serum anti-Mullerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women? Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women. Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation. We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007. Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration a parts per thousand currency sign5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle. Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03). Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential. This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare. C1 [Kissell, K. A.; Danaher, M. R.; Schisterman, E. F.; Ahrens, K. A.; Schliep, K.; Perkins, N. J.; Sjaarda, L.; Weck, J.; Mumford, S. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Kissell, K. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Danaher, M. R.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Wactawski-Wende, J.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, MSC7510,6100 Execut Blvd, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Weck, Jennifer/0000-0002-3246-7380; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD [HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). NR 47 TC 17 Z9 18 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 2014 VL 29 IS 8 BP 1764 EP 1772 DI 10.1093/humrep/deu142 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AM7TG UT WOS:000340071000021 PM 24925522 ER PT J AU Wang, SM Shao, Y Li, SZ AF Wang, Shumin Shao, Yu Li, Shizhe TI Rapid Local Specific Absorption Rate Estimation for Magnetic Resonance Imaging SO IEEE TRANSACTIONS ON ELECTROMAGNETIC COMPATIBILITY LA English DT Article DE Hybrid numerical method; magnetic resonance imaging (MRI); specific absorption rate (SAR) ID MOBILE TELEPHONES; HUMAN HEAD; IN-VIVO; COILS; APPROXIMATION; TRANSMISSION; SIMULATIONS; SCATTERING; MODELS; SHAPE AB The local specific absorption rate (SAR) is a critical concern of the safety in high-field magnetic resonance imaging (MRI). In order to provide rapid and subject-specific local SAR evaluation, a hybrid numerical technique that combines fast direct method of moments (MoM) and the finite-difference time-domain (FDTD) method was developed. Its validity was demonstrated by comparing with conventional numerical methods and experimental results. An example with a real human head model was further provided to demonstrate its utility. C1 [Wang, Shumin; Shao, Yu] Auburn Univ, Dept Elect & Comp Engn, Auburn, AL 36849 USA. [Li, Shizhe] NIMH, Magnet Resonance Spect Core Facil, NIH, Bethesda, MD 20892 USA. RP Wang, SM (reprint author), Auburn Univ, Dept Elect & Comp Engn, Auburn, AL 36849 USA. EM james.wang@ieee.org; steveli@mail.nih.gov FU U.S. National Institutes of Health FX This work was supported in part by intramural research program of the U.S. National Institutes of Health. NR 38 TC 1 Z9 1 U1 2 U2 12 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9375 EI 1558-187X J9 IEEE T ELECTROMAGN C JI IEEE Trans. Electromagn. Compat. PD AUG PY 2014 VL 56 IS 4 BP 771 EP 779 DI 10.1109/TEMC.2013.2287881 PG 9 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA AM9NX UT WOS:000340209400004 ER PT J AU Cohen, JH Chavez, NM AF Cohen, J. H. Chavez, N. M. TI Latino Immigrants, Discrimination and Reception in Columbus, Ohio. International Migration (vol 51, pg 24, 2013) SO INTERNATIONAL MIGRATION LA English DT Correction C1 [Cohen, J. H.; Chavez, N. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Cohen, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7985 EI 1468-2435 J9 INT MIGR JI Int. Migr. PD AUG PY 2014 VL 52 IS 4 DI 10.1111/imig.12172 PG 1 WC Demography SC Demography GA AM6FR UT WOS:000339959300017 ER PT J AU Binkley, N Sempos, CT AF Binkley, Neil Sempos, Christopher T. CA Vitamin D Standardization Program TI Standardizing Vitamin D Assays: The Way Forward SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE VITAMIN D; STANDARDIZATION; VITAMIN D STANDARDIZATION PROGRAM; VDSP; 25-HYDROXYVITAMIN D ID TANDEM MASS-SPECTROMETRY; 25-HYDROXYVITAMIN D; D METABOLITES; HUMAN SERUM; D-3; NUTRITION; PROGRAM AB For a number of years it has been widely assumed that measurement of serum 25-hydroxyvitamin D [25(OH)D] concentration is the best approach to assessing an individual's vitamin D status.((1,2)) However, it has also been recognized that there is substantial within-assay variation in 25(OH)D measurement and even greater between-assay variability.((3-5)) Such assay variation clearly confounds attempts to define what constitutes the diagnosis of hypovitaminosis D. Importantly, assay variability makes pooling of 25(OH)D results from different studies in systematic reviews for the specific purpose of determining dose-response and/or clinical cut points at best problematic. Therefore, to develop and implement evidence-based clinical guidelines, it is essential that 25(OH)D measurement be standardized in both clinical and research laboratories. In this Perspective we outline a way forward toward achieving this goal-the Vitamin D Standardization Program (VDSP). (C) 2014 American Society for Bone and Mineral Research C1 [Binkley, Neil] Univ Wisconsin, Osteoporosis Clin Res Program, Madison, WI USA. [Binkley, Neil] Univ Wisconsin, Inst Aging, Madison, WI USA. [Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Sempos, CT (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Rm 3B01, Bethesda, MD 20892 USA. EM semposch@mail.nih.gov FU NIH National Center on Minority Health and Health Disparities (NCMHD) Comprehensive Centers of Excellence [1P60/R01 MD 003428-01] FX This work was supported in part by the NIH National Center on Minority Health and Health Disparities (NCMHD) Comprehensive Centers of Excellence (1P60/R01 MD 003428-01). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the NIH, or the U.S. Department of Health and Human Services. NR 31 TC 39 Z9 39 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2014 VL 29 IS 8 BP 1709 EP 1714 DI 10.1002/jbmr.2252 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN0AQ UT WOS:000340243900001 PM 24737265 ER PT J AU Chen, HH Anstrom, KJ Stevens, SR Deswal, A Felker, GM Givertz, MM Bart, BA Tang, WHW McNulty, SE Velazquez, EJ Lee, KL Borlaug, BA Shah, MR Hernandez, AF Braunwald, E Redfield, MM AF Chen, Horng H. Anstrom, Kevin J. Stevens, Susanna R. Deswal, Anita Felker, G. Michael Givertz, Michael M. Bart, Bradley A. Tang, W. H. Wilson McNulty, Steven E. Velazquez, Eric J. Lee, Kerry L. Borlaug, Barry A. Shah, Monica R. Hernandez, Adrian F. Braunwald, Eugene Redfield, Margaret M. TI Differential Response to Low Dose Dopamine or Nesiritide in Patients with Acute Heart Failure and Renal Dysfunction in Accordance to LV EF: Sub-Group Analysis of the ROSE AHF Trial SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 18th Annual Scientific Meeting of the Heart-Failure-Society-of-America (HFSA) CY SEP 14-17, 2014 CL Las Vegas, NV SP Heart Failure Soc Amer C1 [Chen, Horng H.; Borlaug, Barry A.; Redfield, Margaret M.] Mayo Clin, Rochester, MN USA. [Anstrom, Kevin J.; Stevens, Susanna R.; McNulty, Steven E.; Lee, Kerry L.; Hernandez, Adrian F.] DCRI, Durham, NC USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Felker, G. Michael] Duke Univ, Durham, NC USA. [Givertz, Michael M.; Braunwald, Eugene] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bart, Bradley A.] Univ Minnesota, Minneapolis, MN USA. [Tang, W. H. Wilson] Cleveland Clin, Cleveland, OH 44106 USA. [Velazquez, Eric J.] DRCI, Durham, NC USA. [Shah, Monica R.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2014 VL 20 IS 8 SU S MA 236 BP S94 EP S94 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9PS UT WOS:000340214100234 ER PT J AU Hummel, SL Marolt, C Healy, A Tang, WHW Weder, AB Fedorova, OV Bagrov, AY Kennedy, DJ AF Hummel, Scott L. Marolt, Cara Healy, Ava Tang, W. H. Wilson Weder, Alan B. Fedorova, Olga V. Bagrov, Alexei Y. Kennedy, David J. TI Cardiotonic Steroids and Sodium Excretion in Heart Failure with Preserved Ejection Fraction SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 18th Annual Scientific Meeting of the Heart-Failure-Society-of-America (HFSA) CY SEP 14-17, 2014 CL Las Vegas, NV SP Heart Failure Soc Amer C1 [Hummel, Scott L.; Marolt, Cara; Healy, Ava; Weder, Alan B.] Univ Michigan, Ann Arbor, MI 48109 USA. [Hummel, Scott L.] Ann Arbor Vet Affairs Hlth Syst, Ann Arbor, MI USA. [Tang, W. H. Wilson; Kennedy, David J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Fedorova, Olga V.; Bagrov, Alexei Y.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2014 VL 20 IS 8 SU S MA 201 BP S79 EP S80 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9PS UT WOS:000340214100199 ER PT J AU Maltais, DB Wiart, L Fowler, E Verschuren, O Damiano, DL AF Maltais, Desiree B. Wiart, Lesley Fowler, Eileen Verschuren, Olaf Damiano, Diane L. TI Health-Related Physical Fitness for Children With Cerebral Palsy SO JOURNAL OF CHILD NEUROLOGY LA English DT Review DE physical activity; physical fitness; cerebral palsy ID RANDOMIZED CONTROLLED-TRIAL; YOUNG-PEOPLE; RESISTANCE EXERCISE; MUSCLE POWER; SEDENTARY BEHAVIOR; WALKING ABILITY; SCHOOL-CHILDREN; CLINICAL-TRIAL; ADOLESCENTS; STRENGTH AB Low levels of physical activity are a global health concern for all children. Children with cerebral palsy have even lower physical activity levels than their typically developing peers. Low levels of physical activity, and thus an increased risk for related chronic diseases, are associated with deficits in health-related physical fitness. Recent research has provided therapists with the resources to effectively perform physical fitness testing and physical activity training in clinical settings with children who have cerebral palsy, although most testing and training data to date pertains to those who walk. Nevertheless, on the basis of the present evidence, all children with cerebral palsy should engage, to the extent they are able, in aerobic, anaerobic, and muscle-strengthening activities. Future research is required to determine the best ways to evaluate health-related physical fitness in nonambulatory children with cerebral palsy and foster long-term changes in physical activity behavior in all children with this condition. C1 [Maltais, Desiree B.] Univ Laval, Dept Rehabil, Quebec City, PQ G1M 2S8, Canada. [Maltais, Desiree B.] Ctr Interdisciplinary Res Rehabil & Social Integr, Quebec City, PQ, Canada. [Wiart, Lesley] Alberta Hlth Serv, Glenrose Rehabil Hosp, Edmonton, AB, Canada. [Wiart, Lesley] Univ Alberta, Dept Phys Therapy, Edmonton, AB, Canada. [Fowler, Eileen] Univ Calif Los Angeles, Dept Orthopaed Surg, Tarjan Ctr, Ctr Cerebral Palsy,Orthopaed Inst Children, Los Angeles, CA USA. [Verschuren, Olaf] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Verschuren, Olaf] Univ Med Ctr Utrecht, Ctr Excellence Rehabil Med, Utrecht, Netherlands. [Verschuren, Olaf] Rehabil Ctr Hoogstraat, Utrecht, Netherlands. [Damiano, Diane L.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Maltais, DB (reprint author), Univ Laval, Dept Rehabil, Rm H-1716,525 Blvd Wilfrid Hamel, Quebec City, PQ G1M 2S8, Canada. EM Desiree.Maltais@rea.ulaval.ca RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU NIH FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the intramural research program of the NIH. NR 87 TC 7 Z9 7 U1 3 U2 23 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD AUG PY 2014 VL 29 IS 8 SI SI BP 1091 EP 1100 DI 10.1177/0883073814533152 PG 10 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AM8ZG UT WOS:000340167900018 PM 24820339 ER PT J AU Suneja, G Shiels, MS Angulo, R Copeland, GE Gonsalves, L Hakenewerth, AM Macomber, KE Melville, SK Engels, EA AF Suneja, Gita Shiels, Meredith S. Angulo, Rory Copeland, Glenn E. Gonsalves, Lou Hakenewerth, Anne M. Macomber, Kathryn E. Melville, Sharon K. Engels, Eric A. TI Cancer Treatment Disparities in HIV-Infected Individuals in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; SQUAMOUS-CELL CARCINOMA; LUNG-CANCER; CLINICAL-TRIALS; HODGKIN-LYMPHOMA; AIDS; CHEMOTHERAPY; POPULATION; DIAGNOSIS AB Purpose HIV-infected individuals with cancer have worse survival rates compared with their HIV-uninfected counterparts. One explanation may be differing cancer treatment; however, few studies have examined this. Patients and Methods We used HIV and cancer registry data from Connecticut, Michigan, and Texas to study adults diagnosed with non-Hodgkin's lymphoma, Hodgkin's lymphoma, or cervical, lung, anal, prostate, colorectal, or breast cancers from 1996 to 2010. We used logistic regression to examine associations between HIV status and cancer treatment, adjusted for cancer stage and demographic covariates. For a subset of local-stage cancers, we used logistic regression to assess the relationship between HIV status and standard treatment modality. We identified predictors of cancer treatment among individuals with both HIV and cancer. Results We evaluated 3,045 HIV-infected patients with cancer and 1,087,648 patients with cancer without HIV infection. A significantly higher proportion of HIV-infected individuals did not receive cancer treatment for diffuse large B-cell lymphoma (DLBCL; adjusted odds ratio [aOR], 1.67; 95% CI, 1.41 to 1.99), lung cancer (aOR, 2.18; 95% CI, 1.80 to 2.64), Hodgkin's lymphoma (aOR, 1.77; 95% CI, 1.33 to 2.37), prostate cancer (aOR, 1.79; 95% CI, 1.31 to 2.46), and colorectal cancer (aOR, 2.27; 95% CI, 1.38 to 3.72). HIV infection was associated with a lack of standard treatment modality for local-stage DLBCL (aOR, 2.02; 95% CI, 1.50 to 2.72), non-small-cell lung cancer (aOR, 2.43; 95% CI, 1.46 to 4.03), and colon cancer (aOR, 4.77; 95% CI, 1.76 to 12.96). Among HIV-infected individuals, factors independently associated with lack of cancer treatment included low CD4 count, male sex with injection drug use as mode of HIV exposure, age 45 to 64 years, black race, and distant or unknown cancer stage. Conclusion HIV-infected individuals are less likely to receive treatment for some cancers than uninfected people, which may affect survival rates. (C) 2014 by American Society of Clinical Oncology C1 [Suneja, Gita] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Shiels, Meredith S.; Engels, Eric A.] NCI, Bethesda, MD 20892 USA. [Angulo, Rory; Gonsalves, Lou] Connecticut Dept Publ Hlth, Hartford, CT USA. [Copeland, Glenn E.; Macomber, Kathryn E.] Michigan Dept Community Hlth, Lansing, MI USA. [Hakenewerth, Anne M.] Texas Dept State Hlth Serv, Austin, TX USA. [Melville, Sharon K.] Texas Dept State Hlth Serv, Temple, TX USA. RP Suneja, G (reprint author), 3400 Civ Ctr Blvd,TRC2 West, Philadelphia, PA 19104 USA. EM gita.suneja@icloud.com FU Intramural Research Program of the National Cancer Institute; SEER Program of the National Cancer Institute (Connecticut cancer registry) [HHSN261201000024C]; National Program of Cancer Registries of the Centers for Disease Control and Prevention [5U58DP000812-03, 5U58DP000824-04] FX Supported in part by the Intramural Research Program of the National Cancer Institute, Grant No. HHSN261201000024C of the SEER Program of the National Cancer Institute (Connecticut cancer registry), as well as Grants No. 5U58DP000812-03 and 5U58DP000824-04 (Michigan and Texas cancer registries, respectively) from the National Program of Cancer Registries of the Centers for Disease Control and Prevention. NR 54 TC 27 Z9 27 U1 0 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 1 PY 2014 VL 32 IS 22 BP 2344 EP U228 DI 10.1200/JCO.2013.54.8644 PG 8 WC Oncology SC Oncology GA AM9JF UT WOS:000340196900013 PM 24982448 ER PT J AU Chaturvedi, AK Graubard, BI Pickard, RKL Xiao, WH Gillison, ML AF Chaturvedi, Anil K. Graubard, Barry I. Pickard, Robert K. L. Xiao, Weihong Gillison, Maura L. TI High-Risk Oral Human Papillomavirus Load in the US Population, National Health and Nutrition Examination Survey 2009-2010 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Human papillomavirus (HPV); oral; viral load; NHANES; smoking; oropharynx ID CARCINOMA IN-SITU; VIRAL LOAD; OROPHARYNGEAL CANCER; UNITED-STATES; INFECTION; CLEARANCE; PREDICTOR AB We investigated the association of demographic and behavioral factors with oral human papillomavirus (HPV) load for 18 high-risk types among 211 individuals with prevalent high-risk HPV within the National Health and Nutrition Examination Survey 2009-2010. Factors independently associated with HPV load above the median included older age (odds ratio, 1.04 per year increase [95% confidence interval, 1.01-1.07]; P = .004) and intensity of current smoking (P for trend <.001). A marginally greater percentage of men than women had an HPV load above the median (55.7% vs 32.8%; P = .069), and HPV load increased marginally with increasing alcohol use (P for trend = .062). In conclusion, older age and current smoking are associated with a high oral load of high-risk HPV types among individuals with a prevalent infection. C1 [Chaturvedi, Anil K.; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Pickard, Robert K. L.; Xiao, Weihong; Gillison, Maura L.] Ohio State Univ, Columbus, OH 43210 USA. RP Gillison, ML (reprint author), Ohio State Univ, Ctr Comprehens Canc, Arthur G James Canc Hosp, 690 Tzagournis Res Facil,420 W 12th Ave, Columbus, OH 43210 USA. EM maura.gillison@osumc.edu RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Ohio State University; National Cancer Institute FX This work was supported by The Ohio State University and the Intramural Program of the National Cancer Institute. NR 15 TC 13 Z9 13 U1 0 U2 6 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 1 PY 2014 VL 210 IS 3 BP 441 EP 447 DI 10.1093/infdis/jiu116 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AN0AI UT WOS:000340242900015 PM 24625808 ER PT J AU Wilson, L Pawlita, M Castle, PE Waterboer, T Sahasrabuddhe, V Gravitt, PE Schiffman, M Wentzensen, N AF Wilson, Lauren Pawlita, Michael Castle, Phillip E. Waterboer, Tim Sahasrabuddhe, Vikrant Gravitt, Patti E. Schiffman, Mark Wentzensen, Nicolas TI Seroprevalence of 8 Oncogenic Human Papillomavirus Genotypes and Acquired Immunity Against Reinfection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Human papillomavirus; natural immunity; serology ID SQUAMOUS INTRAEPITHELIAL LESION; GLUTATHIONE-S-TRANSFERASE; VIRUS-LIKE PARTICLES; ASCUS-LSIL TRIAGE; NATURAL-HISTORY; YOUNG-WOMEN; UNDETERMINED SIGNIFICANCE; QUADRIVALENT VACCINE; HPV INFECTION; DNA DETECTION AB Background. Natural human papillomavirus (HPV) antibody titers have shown protection against subsequent HPV infection, but previous studies were restricted to few HPV genotypes. We examined the association of naturally occurring antibodies against 8 carcinogenic HPV types with subsequent infections. Methods. A total of 2302 women enrolled in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study provided blood samples at baseline. Serum samples were tested for antibodies against 8 carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52, and 58) using a multiplex serology assay. We analyzed the relationship between HPV antibodies and HPV infection during 2 years of follow-up among women negative for the specific HPV type at baseline. Results. Baseline seroprevalence for HPV16 L1 was associated with decreased risk of DNA positivity for HPV16 (odds ratio, 0.39 [95% confidence interval, .18-.86]) at >= 2 follow-up visits. We observed similar but nonsignificant decreased risks for HPV18 and 31. These findings were restricted to women reporting a new sex partner during follow-up. There was no association between baseline seroprevalence and detection of precancer during follow-up. Conclusions. Seroprevalence conferred protection against subsequent HPV infection for HPV16 and indicated possible protection for 2 other genotypes, suggesting that this effect is common to several HPV genotypes. C1 [Wilson, Lauren; Sahasrabuddhe, Vikrant; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Castle, Phillip E.] Global Canc Initiat, Chestertown, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Wilson, Lauren] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Pawlita, Michael; Waterboer, Tim] German Canc Res Ctr, Heidelberg, Germany. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7-E114, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov RI Waterboer, Tim/G-1252-2010; OI Wilson, Lauren/0000-0002-5953-2293; Pawlita, Michael/0000-0002-4720-8306 FU National Cancer Institute, National Institutes of Health Department of Health and Human Services [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105] FX This work was supported by the National Cancer Institute, National Institutes of Health Department of Health and Human Services (contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105 for the ALTS). NR 40 TC 15 Z9 15 U1 0 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 1 PY 2014 VL 210 IS 3 BP 448 EP 455 DI 10.1093/infdis/jiu104 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AN0AI UT WOS:000340242900016 PM 24569064 ER PT J AU Scaglione, A Foffani, G Moxon, KA AF Scaglione, Alessandro Foffani, Guglielmo Moxon, Karen A. TI Spike count, spike timing and temporal information in the cortex of awake, freely moving rats SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE somatosensory processing; information theory; behavioral states; S1 cortex; awake freely moving ID SOMATIC SENSORY TRANSMISSION; PRIMARY SOMATOSENSORY CORTEX; MANY-NEURON ENSEMBLES; STIMULUS LOCATION; CORTICAL REPRESENTATION; BASAL FOREBRAIN; VISUAL-CORTEX; TACTILE DISCRIMINATION; RECEPTIVE-FIELDS; RESPONSES AB Objective. Sensory processing of peripheral information is not stationary but is, in general, a dynamic process related to the behavioral state of the animal. Yet the link between the state of the behavior and the encoding properties of neurons is unclear. This report investigates the impact of the behavioral state on the encoding mechanisms used by cortical neurons for both detection and discrimination of somatosensory stimuli in awake, freely moving, rats. Approach. Neuronal activity was recorded from the primary somatosensory cortex of five rats under two different behavioral states (quiet versus whisking) while electrical stimulation of increasing stimulus strength was delivered to the mystacial pad. Information theoretical measures were then used to measure the contribution of different encoding mechanisms to the information carried by neurons in response to the whisker stimulation. Main results. We found that the behavioral state of the animal modulated the total amount of information conveyed by neurons and that the timing of individual spikes increased the information compared to the total count of spikes alone. However, the temporal information, i.e. information exclusively related to when the spikes occur, was not modulated by behavioral state. Significance. We conclude that information about somatosensory stimuli is modulated by the behavior of the animal and this modulation is mainly expressed in the spike count while the temporal information is more robust to changes in behavioral state. C1 [Scaglione, Alessandro; Foffani, Guglielmo; Moxon, Karen A.] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USA. [Scaglione, Alessandro] NIA, NIH, Baltimore, MD 21224 USA. [Foffani, Guglielmo] Hosp Nacl Paraplej, SESCAM, Neurosignals Grp, Toledo 45071, Spain. RP Scaglione, A (reprint author), Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, 3141 Chestnut St, Philadelphia, PA 19104 USA. EM karen.moxon@drexel.edu RI Moxon, Karen/K-7407-2012 OI Moxon, Karen/0000-0002-5790-097X FU National Institutes of Health [R01 NS05741]; Shriners Hospital for Children [89500]; Internationale Stiftung fur Forschung in Paraplegie [P113] FX This work was supported by grant R01 NS05741 from the National Institutes of Health, grant #89500 from Shriners Hospital for Children and grant #P113 from Internationale Stiftung fur Forschung in Paraplegie. NR 69 TC 0 Z9 0 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD AUG PY 2014 VL 11 IS 4 AR 046022 DI 10.1088/1741-2560/11/4/046022 PG 14 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA AM7KS UT WOS:000340046500022 PM 25024291 ER PT J AU Adesina, SK Holly, A Kramer-Marek, G Capala, J Akala, EO AF Adesina, Simeon K. Holly, Alesia Kramer-Marek, Gabriela Capala, Jacek Akala, Emmanuel O. TI Polylactide-Based Paclitaxel-Loaded Nanoparticles Fabricated by Dispersion Polymerization: Characterization, Evaluation in Cancer Cell Lines, and Preliminary Biodistribution Studies SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE macromonomer; dispersion polymerization; drug release; cytotoxicity; intracellular localization; cell culture; stealth nanoparticle; biodegradable polymers; controlled release; delivery; polymer synthesis; PLA ID HUMAN BREAST-CANCER; CROSS-LINKED NANOPARTICLES; ALBUMIN-BOUND PACLITAXEL; IN-VITRO; DRUG-DELIVERY; BIODEGRADABLE POLYMERS; INDUCED CYTOTOXICITY; ANTITUMOR-ACTIVITY; HER2 EXPRESSION; FORMULATION AB The macromonomer method was used to prepare cross-linked, paclitaxel-loaded polylactide (PLA)-polyethylene glycol (stealth) nanoparticles using free-radical dispersion polymerization. The method can facilitate the attachment of other molecules to the nanoparticle surface to make it multifunctional. Proton nuclear magnetic resonance and Fourier transform infrared spectra confirm the synthesis of PLA macromonomer and cross-linking agent. The formation of stealth nanoparticles was confirmed by scanning and transmission electron microscopy. The drug release isotherm of paclitaxel-loaded nanoparticles shows that the encapsulated drug is released over 7 days. In vitro cytotoxicity assay in selected breast and ovarian cancer cell lines reveal that the blank nanoparticle is biocompatible compared with medium-only treated controls. In addition, the paclitaxel-loaded nanoparticles exhibit similar cytotoxicity compared with paclitaxel in solution. Confocal microscopy reveals that the nanoparticles are internalized by MCF-7 breast cancer cells within 1 h. Preliminary biodistribution studies also show nanoparticle accumulation in tumor xenograft model. The nanoparticles are suitable for the controlled delivery of bioactive agents. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2546-2555, 2014 C1 [Adesina, Simeon K.; Akala, Emmanuel O.] Howard Univ, Dept Pharmaceut Sci, Washington, DC 20059 USA. [Holly, Alesia; Kramer-Marek, Gabriela; Capala, Jacek] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Akala, EO (reprint author), Howard Univ, Dept Pharmaceut Sci, Washington, DC 20059 USA. EM eakala@howard.edu FU NCI/NIH [1 SC2 CA138179-01]; NIH/NIAID [5P30A1087714-02 (11-M56R CFDA), 93.855]; NCRR/NIH [1 C06 RR 02060801, 1 C06 RR 14469-01] FX This work was supported in part by NCI/NIH Grant: #1 SC2 CA138179-01, and NIH/NIAID Grant #5P30A1087714-02 (11-M56R CFDA #93.855). This work was carried out in facilities supported by NCRR/NIH Grants #1 C06 RR 020608-01 and #1 C06 RR 14469-01. We thank Professor Winston A. Anderson and Dr. A. Guggsa (Department of Biology, Howard University) for access to Zeiss Libra 120 electron microscope and help with transmission electron microscopy studies. NR 52 TC 7 Z9 7 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD AUG PY 2014 VL 103 IS 8 BP 2546 EP 2555 DI 10.1002/jps.24061 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AN0MC UT WOS:000340277700035 PM 24961596 ER PT J AU Follmann, D Qin, J Guerrero, ML Breugelmans, JG Pedraza, GR Gessner, BD Ruiz-Palacios, GM AF Follmann, Dean Qin, Jing Guerrero, M. Lourdes Breugelmans, J. Gabrielle Pedraza, Gustave Rosales Gessner, Bradford D. Ruiz-Palacios, Guillermo M. TI Estimating the burden of pertussis in Mexican adolescents from paired serological data by using a bivariate mixture model SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Conditioning; Cut-off value; Discordance; Empirical Bayes posterior probabilities ID BORDETELLA-PERTUSSIS; VACCINE; INFECTION; RUBELLA; MEASLES; TOXIN AB In recent decades there has been an increase in the reported incidence of clinical pertussis in many countries. Estimation of the true circulation of the bacterium Bordetella pertussis is most reliably made on the basis of studies that measure antibody concentrations against pertussis toxin. Antibody levels decay over time and provide a fading memory of the infection. We develop a discrete bivariate mixture model for paired antibody levels in a cohort of 1002 Mexican adolescents who were followed over the 2008-2009 school year. This model postulates three groups of children based on past pertussis infection; never, prior and new. On the basis of this model we directly estimate incidence and prevalence, and select a diagnostic cut-off for classifying children as recently infected. We also discuss a relatively simple approach that uses only 'discordant' children who test positively on one visit and negatively on the other. The discordant approach provides inferences that are very similar to those of the full model when the data follow the assumed full model. Additionally, the discordant method is much more robust to model misspecification than the full model which has substantial problems with optimization. We estimate the school year incidence of pertussis to be about 3% and the prevalence to be about 8%. A cut-off of 50 was estimated to have about 99.5% specificity and 68% sensitvity. C1 [Follmann, Dean] NIAID, Bethesda, MD 20892 USA. [Guerrero, M. Lourdes; Pedraza, Gustave Rosales; Ruiz-Palacios, Guillermo M.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Breugelmans, J. Gabrielle; Gessner, Bradford D.] Agcy Prevent Med, Paris, France. RP Follmann, D (reprint author), NIAID, Biostat Res Branch, 6700B Rockledge Dr,MSC 7609, Bethesda, MD 20892 USA. EM dean.follmann@nih.gov NR 20 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD AUG PY 2014 VL 63 IS 4 BP 621 EP 637 DI 10.1111/rssc.12051 PG 17 WC Statistics & Probability SC Mathematics GA AM9CX UT WOS:000340178600006 ER PT J AU Tse, LA Yu, ITS Rothman, N Ji, BT Qiu, H Wang, XR Hu, W Au, JSK Lan, Q AF Tse, Lap Ah Yu, Ignatius Tak-sun Rothman, Nathaniel Ji, Bu-Tian Qiu, Hong Wang, Xiao-rong Hu, Wei Au, Joseph Siu-kie Lan, Qing TI Joint Effects of Environmental Exposures and Familial Susceptibility to Lung Cancer in Chinese Never Smoking Men and Women SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Environmental risk factors; Lung neoplasm; Familial susceptibility; Interaction ID RISK-FACTORS; OCCUPATIONAL RISKS; TOBACCO-SMOKE; CASE-REFERENT; HONG-KONG; NONSMOKERS; CESSATION; HISTORY; EUROPE; RADON AB Objectives: Previous epidemiological studies had limited power to investigate the joint effects of individual environmental risk factors and familial susceptibility to lung cancer. This study aimed to address this shortcoming. Methods: We recruited 345 never smoking lung cancer cases and 828 community referents. We developed a collective environmental exposure index by assigning a value of 1 to subjects at high risks regarding environmental risk factors and 0 otherwise, and then summed over using weights equivalent to the excess odds ratio. Potential additive and multiplicative interactions between environmental exposure index and family cancer history were examined. Results: Compared with "low environmental exposure and without family cancer history", the odds ratio was 6.80 (95% confidence interval - 3.31-13.98) for males who had high environmental exposures but without family cancer history, whereas it increased to 30.61 (95% confidence interval = 9.38-99.87) if they also had a positive family history. The corresponding associations became weaker in never smoking females. No multiplicative interaction was observed for both genders and an additive interaction was restricted among males. Conclusions: This study developed a novel environmental exposure index that offers sufficient interest deserving further studies on the interactions between environmental exposures and familial susceptibility to lung cancer risk. C1 [Tse, Lap Ah; Yu, Ignatius Tak-sun; Qiu, Hong; Wang, Xiao-rong] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Div Occupat & Environm Hlth, Hong Kong, Hong Kong, Peoples R China. [Rothman, Nathaniel; Ji, Bu-Tian; Hu, Wei; Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Au, Joseph Siu-kie] Queen Elizabeth Hosp, Dept Clin Oncol, Kowloon, Hong Kong, Peoples R China. RP Yu, ITS (reprint author), Prince Wales Hosp, Sch Publ Hlth 4F, Shatin, Hong Kong, Peoples R China. EM iyu@cuhk.edu.hk RI Yu, Ignatius Tak Sun/A-9936-2008 NR 36 TC 2 Z9 2 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD AUG PY 2014 VL 9 IS 8 BP 1066 EP 1072 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AM8PG UT WOS:000340138700007 PM 24852518 ER PT J AU Libonati, MH Dennis, AF Ramani, S McDonald, SM Akopov, A Kirkness, EF Kang, G Patton, JT AF Libonati, Margaret H. Dennis, Allison F. Ramani, Sasirekha McDonald, Sarah M. Akopov, Asmik Kirkness, Ewen F. Kang, Gagandeep Patton, John T. TI Absence of Genetic Differences among G10P[11] Rotaviruses Associated with Asymptomatic and Symptomatic Neonatal Infections in Vellore, India SO JOURNAL OF VIROLOGY LA English DT Article ID GROUP-A ROTAVIRUSES; GENOME SEQUENCE-ANALYSIS; HOST-RANGE RESTRICTION; MOLECULAR EPIDEMIOLOGY; ACUTE GASTROENTERITIS; IMMUNE-RESPONSE; YOUNG-CHILDREN; NONSTRUCTURAL GLYCOPROTEIN; SPORADIC GASTROENTERITIS; VIRAL GASTROENTERITIS AB Rotaviruses (RVs) are leading causes of severe diarrhea and vomiting in infants and young children. RVs with G10P[11] genotype specificity have been associated with symptomatic and asymptomatic neonatal infections in Vellore, India. To identify possible viral genetic determinants responsible for differences in symptomology, the genome sequences of G10P[11] RVs in stool samples of 19 neonates with symptomatic infections and 20 neonates with asymptomatic infections were determined by Sanger and next-generation sequencing. The data showed that all 39 viruses had identical genotype constellations (G10-P[11]-I2-R2-C2-M2-A1-N1-T1-E2-H3), the same as those of the previously characterized symptomatic N155 Vellore isolate. The data also showed that the RNA and deduced protein sequences of all the Vellore G10P[11] viruses were nearly identical; no nucleotide or amino acid differences were found that correlated with symptomatic versus asymptomatic infection. Next-generation sequencing data revealed that some stool samples, both from neonates with symptomatic infections and from neonates with asymptomatic infections, also contained one or more positive-strand RNA viruses (Aichi virus, astrovirus, or salivirus/klassevirus) suspected of being potential causes of pediatric gastroenteritis. However, none of the positive-strand RNA viruses could be causally associated with the development of symptoms. These results indicate that the diversity of clinical symptoms in Vellore neonates does not result from genetic differences among G10P[11] RVs; instead, other undefined factors appear to influence whether neonates develop gastrointestinal disease symptoms. C1 [Libonati, Margaret H.; Dennis, Allison F.; McDonald, Sarah M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Ramani, Sasirekha; Kang, Gagandeep] Christian Med Coll & Hosp, Wellcome Trust Res Lab, Vellore, Tamil Nadu, India. [Akopov, Asmik; Kirkness, Ewen F.] J Craig Venter Inst, Rockville, MD USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014; OI Kang, Gagandeep/0000-0002-3656-564X FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH); NIAID, NIH [HHSN272200900007C] FX M.H.L., A.F.D., S.M.M., and J.T.P. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). This project was also supported by funds provided by NIAID, NIH, contract number HHSN272200900007C. NR 98 TC 4 Z9 4 U1 0 U2 5 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 AUG PY 2014 VL 88 IS 16 BP 9060 EP 9071 DI 10.1128/JVI.01417-14 PG 12 WC Virology SC Virology GA AM7HP UT WOS:000340036800029 PM 24899175 ER PT J AU Ogden, KM Snyder, MJ Dennis, AF Patton, JT AF Ogden, Kristen M. Snyder, Matthew J. Dennis, Allison F. Patton, John T. TI Predicted Structure and Domain Organization of Rotavirus Capping Enzyme and Innate Immune Antagonist VP3 SO JOURNAL OF VIROLOGY LA English DT Article ID MESSENGER-RNA CAP; BAMBOO-MOSAIC-VIRUS; GUANYLYLTRANSFERASE ACTIVITY; ANGSTROM RESOLUTION; MAXIMUM-LIKELIHOOD; PORCINE ROTAVIRUS; PROTEIN-STRUCTURE; CRYSTAL-STRUCTURE; BLUETONGUE VIRUS; OPEN CORES AB Rotaviruses and orbiviruses are nonturreted Reoviridae members. The rotavirus VP3 protein is a multifunctional capping enzyme and antagonist of the interferon-induced cellular oligoadenylate synthetase-RNase L pathway. Despite mediating important processes, VP3 is the sole protein component of the rotavirus virion whose structure remains unknown. In the current study, we used sequence alignment and homology modeling to identify features common to nonturreted Reoviridae capping enzymes and to predict the domain organization, structure, and active sites of rotavirus VP3. Our results suggest that orbivirus and rotavirus capping enzymes share a domain arrangement similar to that of the bluetongue virus capping enzyme. Sequence alignments revealed conserved motifs and suggested that rotavirus and orbivirus capping enzymes contain a variable N-terminal domain, a central guanine-N7-methyltransferase domain that contains an additional inserted domain, and a C-terminal guanylyltransferase and RNA 5'-triphosphatase domain. Sequence conservation and homology modeling suggested that the insertion in the guanine-N7-methyltransferase domain is a ribose-2'-O-methyltransferase domain for most rotavirus species. Our analyses permitted putative identification of rotavirus VP3 active-site residues, including those that form the ribose-2'-O-methyltransferase catalytic tetrad, interact with S-adenosyl-L-methionine, and contribute to autoguanylation. Previous reports have indicated that group A rotavirus VP3 contains a C-terminal 2H-phosphodiesterase domain that can cleave 2'-5' oligoadenylates, thereby preventing RNase L activation. Our results suggest that a C-terminal phosphodiesterase domain is present in the capping enzymes from two additional rotavirus species. Together, these findings provide insight into a poorly understood area of rotavirus biology and are a springboard for future biochemical and structural studies of VP3. C1 [Ogden, Kristen M.; Snyder, Matthew J.; Dennis, Allison F.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Ogden, KM (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM guglielmikm@niaid.nih.gov RI Patton, John/P-1390-2014 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. NR 60 TC 9 Z9 10 U1 0 U2 5 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 AUG PY 2014 VL 88 IS 16 BP 9072 EP 9085 DI 10.1128/JVI.00923-14 PG 14 WC Virology SC Virology GA AM7HP UT WOS:000340036800030 PM 24899176 ER PT J AU van Doremalen, N Miazgowicz, KL Milne-Price, S Bushmaker, T Robertson, S Scott, D Kinne, J McLellan, JS Zhu, J Munster, VJ AF van Doremalen, Neeltje Miazgowicz, Kerri L. Milne-Price, Shauna Bushmaker, Trenton Robertson, Shelly Scott, Dana Kinne, Joerg McLellan, Jason S. Zhu, Jiang Munster, Vincent J. TI Host Species Restriction of Middle East Respiratory Syndrome Coronavirus through Its Receptor, Dipeptidyl Peptidase 4 SO JOURNAL OF VIROLOGY LA English DT Article ID MERS-COV; NEUTRALIZING ANTIBODIES; FUNCTIONAL RECEPTOR; CLINICAL-FEATURES; DROMEDARY CAMELS; RHESUS MACAQUES; BINDING DOMAIN; SPIKE PROTEIN; SAUDI-ARABIA; INFECTION AB Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012. Recently, the MERS-CoV receptor dipeptidyl peptidase 4 (DPP4) was identified and the specific interaction of the receptor-binding domain (RBD) of MERS-CoV spike protein and DPP4 was determined by crystallography. Animal studies identified rhesus macaques but not hamsters, ferrets, or mice to be susceptible for MERS-CoV. Here, we investigated the role of DPP4 in this observed species tropism. Cell lines of human and nonhuman primate origin were permissive of MERS-CoV, whereas hamster, ferret, or mouse cell lines were not, despite the presence of DPP4. Expression of human DPP4 in nonsusceptible BHK and ferret cells enabled MERS-CoV replication, whereas expression of hamster or ferret DPP4 did not. Modeling the binding energies of MERS-CoV spike protein RBD to DPP4 of human (susceptible) or hamster (nonsusceptible) identified five amino acid residues involved in the DPP4-RBD interaction. Expression of hamster DPP4 containing the five human DPP4 amino acids rendered BHK cells susceptible to MERS-CoV, whereas expression of human DPP4 containing the five hamster DPP4 amino acids did not. Using the same approach, the potential of MERS-CoV to utilize the DPP4s of common Middle Eastern livestock was investigated. Modeling of the DPP4 and MERS-CoV RBD interaction predicted the ability of MERS-CoV to bind the DPP4s of camel, goat, cow, and sheep. Expression of the DPP4s of these species on BHK cells supported MERS-CoV replication. This suggests, together with the abundant DPP4 presence in the respiratory tract, that these species might be able to function as a MERS-CoV intermediate reservoir. C1 [van Doremalen, Neeltje; Miazgowicz, Kerri L.; Milne-Price, Shauna; Bushmaker, Trenton; Robertson, Shelly; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Scott, Dana] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Kinne, Joerg] Cent Vet Res Labs, Dubai, U Arab Emirates. [McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA. [Zhu, Jiang] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Zhu, Jiang] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. RP Munster, VJ (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 44 TC 41 Z9 41 U1 0 U2 31 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 AUG PY 2014 VL 88 IS 16 BP 9220 EP 9232 DI 10.1128/JVI.00676-14 PG 13 WC Virology SC Virology GA AM7HP UT WOS:000340036800041 PM 24899185 ER PT J AU Althabe, F Belizan, JM Buekens, P McClure, EM Koso-Thomas, M AF Althabe, Fernando Belizan, Jose M. Buekens, Pierre McClure, Elizabeth M. Koso-Thomas, Marion CA NICHD's Global Network For Women's TI Antenatal corticosteroids to reduce preterm deaths in low-income settings SO LANCET GLOBAL HEALTH LA English DT Letter C1 [Althabe, Fernando; Belizan, Jose M.] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Buekens, Pierre] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Althabe, F (reprint author), Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. FU NICHD NIH HHS [U01 HD042372, U10 HD076474] NR 3 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD AUG PY 2014 VL 2 IS 8 BP E444 EP E444 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM6UB UT WOS:000339999600008 PM 25103510 ER EF