FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ersig, AL Hadley, DW Koehly, LM AF Ersig, Anne L. Hadley, Donald W. Koehly, Laura M. TI Colon Cancer Screening Practices and Disclosure After Receipt of Positive or Inconclusive Genetic Test Results for Hereditary Nonpolyposis Colorectal Cancer SO CANCER LA English DT Article DE hereditary nonpolyposis colorectal cancer; health behavior; cancer screening ID FOLLOW-UP CARE; LYNCH-SYNDROME; INHERITED PREDISPOSITION; ENDOMETRIAL CANCER; INDIVIDUALS; RECOMMENDATIONS; COMMUNICATION; RELATIVES; BEHAVIOR; PARTICIPATION AB BACKGROUND: Patients who receive conclusive genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) tend to adopt appropriate colorectal cancer screening behaviors and disclose their test results. However, little is known about the disclosure processes or screening behaviors of individuals who receive inconclusive genetic test results. This study compared endoscopy use and disclosure between individuals with positive and inconclusive genetic test results, within a year after results were received. METHODS: Individuals with a personal history of cancer and suspected of having HNPCC participated in genetics education and counseling, underwent HNPCC testing, and received genetic test results (GCT) within a prospective cohort study. Demographic, psychosocial, and behavioral data were obtained from questionnaires and interviews completed before and after GCT. RESULTS: Index cases with inconclusive genetic test results were less likely to screen within 12 months. Index cases who disclosed test results to children within 6 months were more likely to screen within 12 months, controlling for mutation status. Index cases with inconclusive genetic test results were less likely to share results with a healthcare provider within 6 months. Index cases who disclosed genetic test results to healthcare providers within 6 months were more likely to have endoscopy within 12 months. CONCLUSIONS: Genetic test results and disclosure significantly affected colon cancer screening at 12-month follow-up. Interventions to improve adherence to colorectal cancer screening should consider increased education of those receiving inconclusive results and encourage disclosure to healthcare providers and family members. Cancer 2009;115:4071-9. Published 2009 by the American Cancer Society.* C1 [Ersig, Anne L.; Hadley, Donald W.; Koehly, Laura M.] NHGRI, SBRB, NIH, Bethesda, MD 20892 USA. [Ersig, Anne L.] Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. [Ersig, Anne L.] NINR, NIH, Bethesda, MD 20892 USA. RP Hadley, DW (reprint author), NHGRI, SBRB, NIH, Bldg 31,Room B1B37F,31 Ctr Dr,MSC 2073, Bethesda, MD 20892 USA. EM dhadley@mail.nih.gov FU National Human Genome Research Institute; National Cancer Institute at the National Institutes of Health, Bethesda, Maryland; National Institute of Nursing Research, National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Cancer Institute at the National Institutes of Health, Bethesda, Maryland. Dr. Ersig was supported by a Graduate Partnerships Program fellowship from the National Institute of Nursing Research, National Institutes of Health. NR 36 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4071 EP 4079 DI 10.1002/cncr.24478 PG 9 WC Oncology SC Oncology GA 493BY UT WOS:000269709300008 PM 19536903 ER PT J AU Anderson, WF Pfeiffer, RM Tucker, MA Rosenberg, PS AF Anderson, William F. Pfeiffer, Ruth M. Tucker, Margaret A. Rosenberg, Philip S. TI Divergent Cancer Pathways for Early-Onset and Late-Onset Cutaneous Malignant Melanoma SO CANCER LA English DT Article DE superficial spreading melanoma; lentigo maligna melanoma; Poisson regression models; 2-component mixture models; age-period-cohort models; Surveillance; Epidemiology; End Results ID BRAF MUTATIONS; UNITED-STATES; SUN EXPOSURE; RISK-FACTORS; SKIN CANCER; AGE; CLASSIFICATION; EPIDEMIOLOGY; SURVEILLANCE; MODELS AB BACKGROUND: Emerging data suggest that cutaneous malignant melanomas (CMM) may arise through divergent cancer pathways that are linked to intermittent versus accumulated sun exposure. However, numerous questions remain regarding the timing and/or age of exposure. METHODS: The authors systematically examined the effect of aging on CMM incidence in data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Standard descriptive epidemiology was supplemented with mathematical models. The impact of advancing age on CMM incidence was assessed by sex, histopathologic classification (superficial spreading melanoma [SSM] or lentigo maligna melanoma [LMM]), and anatomic site (face, head, and neck [FHN] or lower extremity [LE]). RESULTS: Sex, histopathology, and anatomic site were age-specific effect modifiers for CMM that indicated divergent (bimodal) early-onset and late-onset cancer pathways. Early-onset melanomas were associated predominantly with women, SSM, and LE. Late-onset melanomas were correlated with men, LMM, and FHN. Early- and late-onset melanoma populations were confirmed with age-period-cohort models that were adjusted for period and cohort effects. Two-component mixture models also fit the data better than a single cancer population. CONCLUSIONS: The current results were consistent with a divergent and age-dependent solar hypothesis for CMM. Early-onset melanomas may represent gene-sun exposure interactions that occur early (and/or intermittently) in life among susceptible individuals. Late-onset melanomas may reflect accumulated, lifelong sun exposure in comparatively less susceptible individuals. Future analytical studies should be powered adequately to account for this age-dependent effect modification both for acknowledged melanoma risk factors (sex, histopathology, and anatomic site) and for suspected melanoma risk factors, such as constituent genetic variants. Cancer 2009;115:4176-85. Published 2009 by the American Cancer Society.* C1 [Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,Natl Inst Hlth,EPS, Bethesda, MD 20892 USA. [Tucker, Margaret A.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,Natl Inst Hlth, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,Natl Inst Hlth,EPS, Room 8036,6120 Execut Blvd, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Tucker, Margaret/B-4297-2015 FU National Institutes of Health/National Cancer Institute FX Supported in part by the Intramural Research Program of the National Institutes of Health/National Cancer Institute. NR 35 TC 37 Z9 37 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4176 EP 4185 DI 10.1002/cncr.24481 PG 10 WC Oncology SC Oncology GA 493BY UT WOS:000269709300020 PM 19536874 ER PT J AU Farley, JH Tian, CQ Rose, GS Brown, CL Birrer, M Maxwell, GL AF Farley, John H. Tian, Chunqiao Rose, G. Scott Brown, Carol L. Birrer, Michael Maxwell, G. Larry TI Race Does Not Impact Outcome for Advanced Ovarian Cancer Patients Treated With Cisplatin/Paclitaxel An Analysis of Gynecologic Oncology Group Trials SO CANCER LA English DT Article DE ovarian cancer; chemotherapy; Gynecologic Oncology Group; racial disparity ID INTRAVENOUS CISPLATIN PLUS; PHASE-III TRIAL; STAGE-III; UNITED-STATES; INTRAPERITONEAL CISPLATIN; SURGICAL CYTOREDUCTION; RACIAL DISPARITIES; PROGNOSTIC-FACTORS; AFRICAN-AMERICAN; PACLITAXEL AB BACKGROUND: The objectives of this study were to confirm whether racial disparity exists with regard to outcome between black women and white women with ovarian cancer and to identify factors associated with the administration of adjuvant treatment that had an impact on survival. METHODS: A retrospective review of 97 black women and 1392 white women with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma was performed. All patients received paclitaxel combined with cisplatin while participating in 1 of 7 Gynecologic Oncology Group clinical trials. The treatment parameters that were reviewed included relative dose, relative time, and relative dose intensity. The treatment parameters and outcomes were compared between black patients and white patients. RESULTS: There were no differences in relative dose (0.90 vs 0.89), relative time (1.02 vs 0.99), or relative dose intensity (0.90 vs 0.91) received between black patients and white patients. Black women had less grade 3 and 4 leukopenia (53% vs 63%; P < .05) and gastrointestinal toxicity (10% vs 19%; P < .05) than white women. Performance status >0, age >= 70 years, and mucinous histology were associated with not completing treatment (P < .001). The median progression-free survival was 16.2 months for black patients and 16.1 months for white patients, and the median overall survival was 37.9 months and 39.7 months, respectively (P > .05 for all). CONCLUSIONS: When they received similar treatment, there was no difference in clinical outcome between black women and white women with advanced stage epithelial ovarian cancer when they received similar treatment as participants in Gynecologic Oncology Group clinical trials. Black patients may experience less severe gastrointestinal toxicity or leukopenia compared with whites when treated with platinum-based chemotherapy. Cancer 2009;115:4210-7. Published 2009 by the American Cancer Society.* C1 [Farley, John H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynaecol, Bethesda, MD 20832 USA. [Tian, Chunqiao] Roswell Pk Canc Inst, Gynecol Oncol Grp, Stat & Data Ctr, Buffalo, NY 14263 USA. [Rose, G. Scott; Maxwell, G. Larry] Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Washington, DC 20307 USA. [Rose, G. Scott; Maxwell, G. Larry] Walter Reed Army Med Ctr, US Mil Canc Inst, Washington, DC 20307 USA. [Brown, Carol L.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Birrer, Michael] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Farley, JH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynaecol, 4301 Jones Bridge Rd, Bethesda, MD 20832 USA. EM john.farley@us.army.mil FU American Board of Obstetrics and Gynecology/American Association of Obstetricians and Gynecologists Foundation; National Cancer Institute [CA 27469]; Gynecologic Oncology Group Statistical and Data Center [CA 37517] FX Supported by a grant from the American Board of Obstetrics and Gynecology/American Association of Obstetricians and Gynecologists Foundation and by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). NR 25 TC 20 Z9 20 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4210 EP 4217 DI 10.1002/cncr.24482 PG 8 WC Oncology SC Oncology GA 493BY UT WOS:000269709300023 PM 19536873 ER PT J AU Jain, N Brouwers, P Okcu, MF Cirino, PT Krull, KR AF Jain, Neelam Brouwers, Pim Okcu, M. Fatih Cirino, Paul T. Krull, Kevin R. TI Sex-Specific Attention Problems in Long-Term Survivors of Pediatric Acute Lymphoblastic Leukemia SO CANCER LA English DT Article DE acute lymphoblastic leukemia; long-term survivors; attention problems; sex ID ACUTE LYMPHOCYTIC-LEUKEMIA; HIGH-DOSE METHOTREXATE; WHITE-MATTER; CHILDHOOD; CHILDREN; CHEMOTHERAPY; ADOLESCENCE; PERFORMANCE; DIAGNOSIS; CIRCUITS AB BACKGROUND: Neurocognitive problems are a frequent outcome of chemotherapy for pediatric leukemia, although individual differences exist in patient outcome. Sex of the patient and age at diagnosis are 2 characteristics that have been associated with differential outcomes. The relation between these patient characteristics and specific attention deficits (ie, initiating, inhibiting, shifting, focusing, sustaining attention, and working memory) has not been well researched. The purpose of this study was to evaluate the pattern of attention problems in male and female long-term survivors of pediatric acute lymphoblastic leukemia (ALL). METHODS: One hundred three long-term survivors (ie, >= 5 years from diagnosis; 51% boys, mean age at diagnosis of 3.9 years, and mean time since diagnosis 7.5 years) completed standardized measures of basic and complex attention skills related to anterior (ie, inhibition, shifting attention, working memory), posterior (ie, focusing), and subcortical brain systems (ie, sustaining). RESULTS: Treatment intensity was related to sustained attention, with those patients treated on high-risk protocols displaying significantly lower performance. Girls performed worse than boys on measures related to the anterior attention system (ie, shifting attention, P < .042) and the subcortical attention system (ie, sustained attention, P < .001), whereas boys performed worse than girls on different measures of anterior control (ie, inhibition, P < .039; working memory, P < .003). CONCLUSIONS: The results of this study suggest that children diagnosed with and treated for pediatric ALL perform poorly on select measures of attention and executive control, and that this performance is influenced by sex and treatment intensity. Cancer 2009;115:4238-45. (C) 2009 American Cancer Society. C1 [Jain, Neelam; Krull, Kevin R.] St Jude Childrens Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Jain, Neelam; Cirino, Paul T.; Krull, Kevin R.] Univ Houston, Dept Psychol, Houston, TX USA. [Jain, Neelam; Krull, Kevin R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Brouwers, Pim; Okcu, M. Fatih; Krull, Kevin R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Brouwers, Pim; Okcu, M. Fatih] Texas Childrens Canc Ctr, Houston, TX USA. [Brouwers, Pim] NIMH, Div AIDS & Hlth & Behav Res, Rockville, MD 20857 USA. RP Jain, N (reprint author), St Jude Childrens Hosp, Dept Epidemiol & Canc Control, 262 Danny Thomas Pl,MS 735, Memphis, TN 38105 USA. EM neelam.jain@stjude.org OI Cirino, Paul T./0000-0002-9587-0388 NR 44 TC 23 Z9 23 U1 2 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4238 EP 4245 DI 10.1002/cncr.24464 PG 8 WC Oncology SC Oncology GA 493BY UT WOS:000269709300026 PM 19536898 ER PT J AU Pollack, LA Rowland, JH Crammer, C Stefanek, M AF Pollack, Lori A. Rowland, Julia H. Crammer, Corinne Stefanek, Michael TI Introduction: Charting the Landscape of Cancer Survivors' Health-Related Outcomes and Care SO CANCER LA English DT Editorial Material AB The field of cancer survivorship is characterized by a complex and rapidly evolving landscape. This supplement presents a series of data-driven articles selected to highlight the breadth of new knowledge in this area of the cancer control continuum that were presented at the Fourth Biennial Cancer Survivorship Research Conference in Atlanta, Georgia, June 2008. Included in the volume is research on the biobehavioral impact of cancer; studies on quality-of-life and economic outcomes; and work focused on caregivers, understudied populations, and healthcare providers. Cancer 2009;115(18 suppl):4265-9. Published 2009 by the American Cancer Society. C1 [Pollack, Lori A.] Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, Dept Hlth & Human Serv, Atlanta, GA 30341 USA. [Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Crammer, Corinne; Stefanek, Michael] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30329 USA. RP Pollack, LA (reprint author), Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, Dept Hlth & Human Serv, 4770 Buford Hwy NE,Mailstop K55, Atlanta, GA 30341 USA. EM lpollack@cdc.gov NR 19 TC 11 Z9 13 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4265 EP 4269 DI 10.1002/cncr.24579 PG 5 WC Oncology SC Oncology GA 493CA UT WOS:000269709500001 PM 19731347 ER PT J AU Yabroff, KR Kim, Y AF Yabroff, K. Robin Kim, Youngmee TI Time Costs Associated With Informal Caregiving for Cancer Survivors SO CANCER LA English DT Article; Proceedings Paper CT 4th Biennial Cancer Survivorship Research Conference CY JUN 18-20, 2008 CL Atlanta, GA SP Amer Canc Soc, NCI, Lance Armstrong Fdn DE informal caregiving; cancer; burden of illness; time cost; economic ID CARE; FAMILIES; MANAGEMENT; DEMENTIA; DISEASE; GENDER AB BACKGROUND: To the authors' knowledge, little work has been done to estimate the time costs associated with informal caregiving for cancer survivors. METHODS: Data from a national survey of caregivers of cancer patients in 2003 to 2006 were used to estimate the time associated with informal caregiving in the 2 years after patient diagnosis with bladder, breast, colorectal, kidney, lung, melanoma of the skin, ovarian, prostate, or uterine cancer, or non-Hodgkins lymphoma (NHL). Caregivers reported the duration and daily intensity of caregiving as well as the types and frequency of support provided. The median wage rate in 2006 ($16.28) was used to value caregiver time, and other methods to value time were evaluated with sensitivity analyses. RESULTS: On average, caregivers provided care for 8.3 hours per day for 13.7 months. The number of months and daily hours spent caregiving were the highest for cancer survivors diagnosed with distant disease compared with survivors with regional or localized disease (P <.05). Approximately half of caregivers provided emotional, instrumental, tangible, or medical support, although the frequency varied dramatically. Informal caregiver time costs over the 2-year period after diagnosis were the highest for caregivers of patients diagnosed with lung ($72,702; 95% confidence interval [95% CI], $56,814-$88,590) and ovarian ($66,210; 95% CI, $40,750-$91,670) cancers and NHL ($59,613; 95% CI, $43,423-$75,803) and the lowest for caregivers of patients with breast cancer ($38,334; 95% CI, $31,442-$45,226). CONCLUSIONS: Time spent by informal caregivers was substantial and was an important component of the burden of cancer care. Incorporation of the value of informal caregiver time will be important when evaluating the costs and benefits of cancer control interventions. Cancer 2009;115(18 suppl):4362-73. (C) 2009 American Cancer Society. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kim, Youngmee] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30329 USA. [Kim, Youngmee] Univ Miami, Dept Psychol, Miami, FL USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572; Kim, Youngmee/0000-0002-3109-6362 NR 35 TC 83 Z9 87 U1 1 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4362 EP 4373 DI 10.1002/cncr.24588 PG 12 WC Oncology SC Oncology GA 493CA UT WOS:000269709500009 PM 19731345 ER PT J AU Ji, JF Wang, XW AF Ji, Junfang Wang, Xin Wei TI New kids on the block Diagnostic and prognostic microRNAs in hepatocellular carcinoma SO CANCER BIOLOGY & THERAPY LA English DT Review DE hepatocellular carcinoma; microRNA; diagnosis; prognosis; miR-181; miR-21; miR-126 ID NON-TUMOROUS TISSUES; CAENORHABDITIS-ELEGANS; GENE-EXPRESSION; DOWN-REGULATION; ALPHA-FETOPROTEIN; SUPPRESSOR GENE; NUCLEAR EXPORT; UNITED-STATES; UP-REGULATION; HEPATITIS-B AB Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer and the third leading cause of cancer death worldwide. Molecular profiling of changes in gene expression has improved our understanding of the HCC mechanism, allowing the identification of biomarkers for HCC diagnosis and HCC patient stratification for prognosis and therapy. Recently, a new group of molecules, microRNAs, has been discovered to be aberrantly expressed in HCC and some of them are functionally involved in HCC carcinogenesis and progression. Further, certain microRNAs are associated with HCC or related to HCC subtypes, implying the potential of microRNAs for HCC patient stratification of diagnosis and prognosis. Some of these HCC-associated microRNAs have been validated in independent cohorts, paving the way for developing clinically useful platforms to assess HCC risk, aiding HCC diagnosis and assisting in HCC patient stratification with the potential for personalized adjuvant therapy. Here, we mainly focus on the diagnostic and prognostic roles of miRNAs as a group of new biomarkers for HCC. C1 [Ji, Junfang; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, 37 Convent Dr,Bldg 37,Room 3044A, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU National Cancer Institute [Z01 BC 010313] FX We wish to thank Dr. Timothy Schulz and the NIH Fellows Editorial Board for editing the manuscript. This work was supported by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute (Z01 BC 010313). NR 73 TC 7 Z9 7 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP 15 PY 2009 VL 8 IS 18 BP 1683 EP 1690 DI 10.4161/cbt.8.18.8898 PG 8 WC Oncology SC Oncology GA 514VS UT WOS:000271424700003 ER PT J AU Kadota, M Sato, M Duncan, B Ooshima, A Yang, HH Diaz-Meyer, N Gere, S Kageyama, SI Fukuoka, J Nagata, T Tsukada, K Dunn, BK Wakefield, LM Lee, MP AF Kadota, Mitsutaka Sato, Misako Duncan, Beverly Ooshima, Akira Yang, Howard H. Diaz-Meyer, Natacha Gere, Sheryl Kageyama, Shun-Ichiro Fukuoka, Junya Nagata, Takuya Tsukada, Kazuhiro Dunn, Barbara K. Wakefield, Lalage M. Lee, Maxwell P. TI Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; COPY-NUMBER; COLORECTAL CANCERS; EXPRESSION; PATTERNS; SURVIVAL; SUBTYPES; TARGET AB To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the "mountain-and-hill" view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression. [Cancer Res 2009;69(18):7357-65] C1 [Kadota, Mitsutaka; Duncan, Beverly; Yang, Howard H.; Diaz-Meyer, Natacha; Gere, Sheryl; Lee, Maxwell P.] NCI, Ctr Canc Res, Lab Populat Genet, Bethesda, MD 20892 USA. [Sato, Misako; Ooshima, Akira; Wakefield, Lalage M.] NCI, Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Dunn, Barbara K.] NCI, Canc Prevent Div, Basic Prevent Sci Res Grp, Bethesda, MD 20892 USA. [Kageyama, Shun-Ichiro; Fukuoka, Junya] Toyama Univ Hosp, Pathol Lab, Toyama, Japan. [Nagata, Takuya; Tsukada, Kazuhiro] Toyama Univ, Dept Surg, Toyama 930, Japan. RP Lee, MP (reprint author), NCI, Ctr Canc Res, Lab Populat Genet, Bldg 41,Room D702,41 Lib Dr, Bethesda, MD 20892 USA. EM leemax@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute FX Grant support: Intramural Research Program of the NIH and the National Cancer Institute. The costs of publication of this article were defrayed in part by the payment of page charges, This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely, to indicate this fact.; We thank the Cooperative Human Tissue Network for providing tumor tissues, Drs. Kent Hunter and Daoud Meerzaman for critical reading of the manuscript, Dr. Robert Clifford for providing bioinformatics support, and Dr. Stephen Hewitt for providing TMA slides. NR 30 TC 60 Z9 63 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2009 VL 69 IS 18 BP 7357 EP 7365 DI 10.1158/0008-5472.CAN-09-0064 PG 9 WC Oncology SC Oncology GA 496FC UT WOS:000269954000030 PM 19706770 ER PT J AU Brems, H Park, C Maertens, O Pemov, A Messia, L Upadhyaya, M Claes, K Beert, E Peeters, K Mautner, V Sloan, JL Yao, L Lee, CCR Sciot, R De Smet, L Legius, E Stewart, DR AF Brems, Hilde Park, Caroline Maertens, Ophelia Pemov, Alexander Messia, Ludwine Upadhyaya, Meena Claes, Kathleen Beert, Eline Peeters, Kristel Mautner, Victor Sloan, Jennifer L. Yao, Lawrence Lee, Chyi-Chia Richard Sciot, Raf De Smet, Luc Legius, Eric Stewart, Douglas R. TI Glomus Tumors in Neurofibromatosis Type 1: Genetic, Functional, and Clinical Evidence of a Novel Association SO CANCER RESEARCH LA English DT Article ID METHYLATION-SPECIFIC PCR; NF1 GENE; HEREDITARY CANCER; IDENTIFICATION; MUTATIONS; REPEAT; PATHOGENESIS; POLYMORPHISM; SUPPRESSOR; MODEL AB Neurofibromatosis type 1 (NF1) is a common disorder that arises secondary to mutations in the tumor suppressor gene NF1 Glomus tumors are small, benign but painful tumors that originate from the glomus body, a thermo regulatory shunt concentrated in the fingers and toes. We report 11 individuals with NF1 who harbored 20 glomus tumors of the fingers and 1 in the toe; 5 individuals had multiple glomus tumors. We hypothesized that biallelic inactivation of NF1 underlies the pathogenesis of these tumors. In 12 NF1-associated glomus tumors, we used cell culture and laser capture microdissection to isolate DNA. We also analyzed two sporadic (not NF1-associated) glomus tumors. Genetic analysis showed germ line and somatic NF1 mutations in seven tumors. RAS mitogen-activated protein kinase hyperactivation was observed in cultured NF1(-/-) glomus cells, reflecting a lack of inhibition of the pathway by functional neurofibromin, the protein product of NFI. No abnormalities in NF1 or RAS mitogen-activated protein kinase activation were found in sporadic glomus tumors. By comparative genomic hybridization, we observed amplification of the 3'-end of CRTAC1 and a deletion of the 5'-end of WASF1 in two NF1-associated glomus tumors. For the first time, we show that loss of neurofibromin function is crucial in the pathogenesis of glomus tumors in NF1. Glomus tumors of the fingers or toes should be considered as part of the tumor spectrum of NF1. [Cancer Res 2009;69(18):7393-401] C1 [Stewart, Douglas R.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Brems, Hilde; Beert, Eline; Peeters, Kristel; Legius, Eric] Catholic Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium. [Sciot, Raf] Catholic Univ Louvain, Dept Pathol, B-3000 Louvain, Belgium. [Park, Caroline] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Maertens, Ophelia] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Maertens, Ophelia] Harvard Univ, Sch Med, Boston, MA USA. [Sloan, Jennifer L.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Yao, Lawrence] Ctr Clin, Dept Radiol, Bethesda, MD USA. [Messia, Ludwine] Univ Alabama Birmingham, Dept Genet, Med Genom Lab, Birmingham, AL USA. [Upadhyaya, Meena] Cardiff Univ, Inst Med Genet, Cardiff, S Glam, Wales. [Maertens, Ophelia; Claes, Kathleen] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Mautner, Victor] Univ Hosp Eppendorf, Dept Maxillofacial Surg, Lab Tumor Biol & Dev Disorders, Hamburg, Germany. [De Smet, Luc] Univ Hosp Pellenberg, Dept Orthopaed Surg, Lubbeck, Belgium. RP Stewart, DR (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr,Bldg 49,Room 4A62, Bethesda, MD 20892 USA. EM drstewart@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU Division of Intramural Research of the National Human Genome Research Institute; U.S. National Cancer Institute of the NIH; Institute for the Promotion of Innovation through Science and Technology in Flanders; Fonds voor Wetenschappelijk Onderzock Vlaanderen [G.0578.06, G.0551.08]; Federal Office for Scientific, Technical, and Cultural Affairs, Belgium [P5/25]; K.U. Leuven; Research Foundation Flanders (FWO Vlaanderen) FX Grant support: Division of Intramural Research of the National Human Genome Research Institute (D.H, Stewart) and the U.S. National Cancer Institute of the NIH (D.R. Stewart and Brigitte Widemann). Additional support was provided by the Institute for the Promotion of Innovation through Science and Technology in Flanders (H. Brems), research grants from the Fonds voor Wetenschappelijk Onderzock Vlaanderen (G.0578.06 and G.0551.08; E. Legius), the Interuniversity Attraction Poles granted by the Federal Office for Scientific, Technical, and Cultural Affairs, Belgium (IAP, 2007-2011; P5/25; E. Legius), and by a Concerted Action grant from the K.U. Leuven (E. Legius). O. Maertens is a postdoctoral researcher with the Research Foundation Flanders (FWO Vlaanderen).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; The authors thank Dena Hernandez and Andrew Singleton (National Institute on Aging of the U.S. NIH) for their help with microarray processing; Julia Fekecs and Les Biesecker (both from the National Human Genome Research Institute) for figure preparation and discussions, respectively. NR 42 TC 45 Z9 46 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2009 VL 69 IS 18 BP 7393 EP 7401 DI 10.1158/0008-5472.CAN-09-1752 PG 9 WC Oncology SC Oncology GA 496FC UT WOS:000269954000034 PM 19738042 ER PT J AU Semsey, S Benjamin, JAM Mitarai, N Krishna, S Csiszovszki, Z Sneppen, K Masse, E AF Semsey, Szabolcs Benjamin, Julie-Anna M. Mitarai, Namiko Krishna, Sandeep Csiszovszki, Zsolt Sneppen, Kim Masse, Eric TI Dynamics of the recovery from sRNA-mediated gene silencing SO CELL CYCLE LA English DT Editorial Material DE small RNA; iron; mRNA silencing; galactose; RyhB; Spot42 ID ESCHERICHIA-COLI; DEGRADATION C1 [Semsey, Szabolcs] Eotvos Lorand Univ, Dept Genet, Budapest, Hungary. [Benjamin, Julie-Anna M.; Masse, Eric] Univ Sherbrooke, Dept Biochim, RNA Grp, Sherbrooke, PQ J1K 2R1, Canada. [Mitarai, Namiko] Kyushu Univ 33, Dept Phys, Fukuoka 812, Japan. [Krishna, Sandeep; Sneppen, Kim] Niels Bohr Inst, DK-2100 Copenhagen, Denmark. [Csiszovszki, Zsolt] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Semsey, S (reprint author), Eotvos Lorand Univ, Dept Genet, Budapest, Hungary. EM semseys@yahoo.com; eric.masse@usherbrooke.ca RI Semsey, Szabolcs/L-6329-2013; Mitarai, Namiko/M-4575-2014; OI Mitarai, Namiko/0000-0003-0116-7606; Semsey, Szabolcs/0000-0002-4522-5495; Sneppen, Kim/0000-0001-9820-3567 NR 12 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2009 VL 8 IS 18 BP 2863 EP 2864 DI 10.4161/cc.8.18.9400 PG 2 WC Cell Biology SC Cell Biology GA 494FL UT WOS:000269796000005 PM 19729996 ER PT J AU Starz-Gaiano, M Melani, M Meinhardt, H Montell, D AF Starz-Gaiano, Michelle Melani, Mariana Meinhardt, Hans Montell, Denise TI Interpretation of the UPD/JAK/STAT morphogen gradient in Drosophila follicle cells SO CELL CYCLE LA English DT Article DE cell motility; mathematical modeling; JAK/STAT; morphogens; drosophila ID BIOLOGICAL PATTERN-FORMATION; POSITIONAL INFORMATION; JAK/STAT PATHWAY; NEGATIVE FEEDBACK; STAT ACTIVATION; BICOID PROTEIN; SELF-RENEWAL; OOGENESIS; EMBRYO; MIGRATION C1 [Starz-Gaiano, Michelle; Melani, Mariana; Montell, Denise] Johns Hopkins Sch Med, Dept Biol Chem, Baltimore, MD 21218 USA. [Starz-Gaiano, Michelle] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21228 USA. [Melani, Mariana] NICHD, Mol Genet Lab, NIH, Bethesda, MD USA. [Meinhardt, Hans] Max Planck Inst Entwicklungsbiol, D-72076 Tubingen, Germany. RP Montell, D (reprint author), Johns Hopkins Sch Med, Dept Biol Chem, Baltimore, MD 21218 USA. EM dmontell@jhmi.edu FU NIGMS NIH HHS [R01 GM046425, R01 GM046425-18A1] NR 68 TC 16 Z9 16 U1 0 U2 1 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 SEP 15 PY 2009 VL 8 IS 18 BP 2917 EP 2925 PG 9 WC Cell Biology SC Cell Biology GA 494FL UT WOS:000269796000019 PM 19729999 ER PT J AU Samet, JM Avila-Tang, E Boffetta, P Hannan, LM Olivo-Marston, S Thun, MJ Rudin, CM AF Samet, Jonathan M. Avila-Tang, Erika Boffetta, Paolo Hannan, Lindsay M. Olivo-Marston, Susan Thun, Michael J. Rudin, Charles M. TI Lung Cancer in Never Smokers: Clinical Epidemiology and Environmental Risk Factors SO CLINICAL CANCER RESEARCH LA English DT Review ID INDOOR AIR-POLLUTION; CHLAMYDIA-PNEUMONIAE INFECTION; IDIOPATHIC PULMONARY-FIBROSIS; HORMONE REPLACEMENT THERAPY; NONSMOKING URANIUM MINERS; NEEDLE ASPIRATION BIOPSY; TOBACCO-SMOKE; PASSIVE SMOKING; CIGARETTE-SMOKING; UNITED-STATES AB More than 161,000 lung cancer deaths are projected to occur in the United States in 2008. Of these, an estimated 10 to 15% will be caused by factors other than active smoking, corresponding to 16,000 to 24,000 deaths annually. Thus lung cancer in never smokers would rank among the most common causes of cancer mortality in the United States if considered as a separate category. Slightly more than half of the lung cancers caused by factors other than active smoking occur in never smokers. As summarized in the accompanying article, lung cancers that occur in never smokers differ from those that occur in smokers in their molecular profile and response to targeted therapy. These recent laboratory and clinical observations highlight the importance of defining the genetic and environmental factors responsible for the development of lung cancer in never smokers. This article summarizes available data on the clinical epidemiology of lung cancer in never smokers, and several environmental risk factors that population-based research has implicated in the etiology of these cancers. Primary factors closely tied to lung cancer in never smokers include exposure to known and suspected carcinogens including radon, second-hand tobacco smoke, and other indoor air pollutants. Several other exposures have been implicated. However, a large fraction of lung cancers occurring in never smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area. (Clin Cancer Res 2009;15(18):5626-45) C1 [Rudin, Charles M.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA. [Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [Hannan, Lindsay M.; Thun, Michael J.] Amer Canc Soc, Atlanta, GA 30329 USA. [Olivo-Marston, Susan] NCI, Bethesda, MD 20892 USA. RP Rudin, CM (reprint author), Johns Hopkins Univ, Sch Med, David H Koch Canc Res Bldg,Room 544,1550 Orleans, Baltimore, MD 21231 USA. EM rudin@jhmi.edu FU NCI NIH HHS [P30 CA006973-44] NR 184 TC 151 Z9 157 U1 8 U2 30 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5626 EP 5645 DI 10.1158/1078-0432.CCR-09-0376 PG 20 WC Oncology SC Oncology GA 496OA UT WOS:000269982800007 PM 19755391 ER PT J AU Rudin, CM Avila-Tang, E Harris, CC Herman, JG Hirsch, FR Pao, W Schwartz, AG Vahakangas, KH Samet, JM AF Rudin, Charles M. Avila-Tang, Erika Harris, Curtis C. Herman, James G. Hirsch, Fred R. Pao, William Schwartz, Ann G. Vahakangas, Kirsi H. Samet, Jonathan M. TI Lung Cancer in Never Smokers: Molecular Profiles and Therapeutic Implications SO CLINICAL CANCER RESEARCH LA English DT Review ID GROWTH-FACTOR-RECEPTOR; ENVIRONMENTAL TOBACCO-SMOKE; PHASE-III TRIAL; PREVIOUSLY TREATED PATIENTS; COAL COMBUSTION EMISSIONS; P53 MUTATION HOTSPOT; REPAIR GENE XRCC1; S-TRANSFERASE M1; K-RAS GENES; DNA-REPAIR AB The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. Although a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years show that lung cancers in never smokers are much more likely to carry activating mutations of the epidermal growth factor receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anticancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never-smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers. (Clin Cancer Res 2009;15(18):5646-61) C1 [Rudin, Charles M.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA. [Harris, Curtis C.] NCI, Bethesda, MD 20892 USA. [Hirsch, Fred R.] Univ Colorado, Denver, CO 80202 USA. [Pao, William] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Schwartz, Ann G.] Wayne State Univ, Detroit, MI USA. [Vahakangas, Kirsi H.] Univ Kuopio, FIN-70211 Kuopio, Finland. RP Rudin, CM (reprint author), Johns Hopkins Univ, Sch Med, David H Koch Canc Res Bldg,Room 544,1550 Orleans, Baltimore, MD 21231 USA. EM rudin@jhmi.edu FU Flight Attendant Medical Research Institute (FAMRI) FX Flight Attendant Medical Research Institute (FAMRI). Note: Supplementary data for this article are available at Clinical Cancer NR 151 TC 72 Z9 76 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5646 EP 5661 DI 10.1158/1078-0432.CCR-09-0377 PG 16 WC Oncology SC Oncology GA 496OA UT WOS:000269982800008 PM 19755392 ER PT J AU Okunieff, P Kachnic, LA Constine, LS Fuller, CD Gaspar, LE Hayes, DF Hooks, J Ling, C Meyskens, FL Philip, PA Raben, D Smalley, SR Swanson, GP Teicher, BA Thomas, CR Vikram, B Zelefsky, MJ Baker, LH AF Okunieff, Paul Kachnic, Lisa A. Constine, Louis S. Fuller, Clifton D. Gaspar, Laurie E. Hayes, Daniel F. Hooks, Jean Ling, Clifton Meyskens, Frank L., Jr. Philip, Philip A. Raben, David Smalley, Stephen R. Swanson, Gregory P. Teicher, Beverly A. Thomas, Charles R., Jr. Vikram, Bhadrasain Zelefsky, Michael J. Baker, Laurence H. TI Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008 SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; LOCALIZED PROSTATE-CANCER; METASTATIC BREAST-CANCER; DOUBLE-STRAND BREAKS; TOPOISOMERASE-II; LYSYL OXIDASE; HOMOLOGOUS RECOMBINATION; RADIOFREQUENCY ABLATION; PROGNOSTIC FACTORS; GAMMA-RADIATION AB Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High-priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational end points that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans. (Clin Cancer Res 2009;15(18):5663-70) C1 [Okunieff, Paul] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Kachnic, Lisa A.] Boston Univ, Med Ctr, Boston, MA USA. [Fuller, Clifton D.; Swanson, Gregory P.] Univ Texas San Antonio, San Antonio, TX USA. [Gaspar, Laurie E.; Raben, David] Univ Colorado Denver, Aurora, CO USA. [Hayes, Daniel F.; Baker, Laurence H.] Univ Michigan, Ann Arbor, MI 48109 USA. [Hooks, Jean] BrainLab, Munich, Germany. [Ling, Clifton] Varian Med Syst Inc, Palo Alto, CA USA. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Orange, CA 92668 USA. [Philip, Philip A.] Karmanos Canc Inst, Detroit, MI USA. [Smalley, Stephen R.] Olathe Med Ctr, Olathe, KS USA. [Teicher, Beverly A.] Genzyme Corp, Framingham, MA 01701 USA. [Thomas, Charles R., Jr.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Vikram, Bhadrasain] NCI, Rockville, MD USA. [Zelefsky, Michael J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Okunieff, P (reprint author), Univ Rochester, Med Ctr, Dept Radiat Oncol, 601 Elmwood Ave,Box 647, Rochester, NY 14642 USA. EM paul_okunieff@urmc.rochester.edu OI Fuller, Clifton/0000-0002-5264-3994 FU NCI NIH HHS [CA14028, CA46113, CA58723, CA76448, U10 CA042777, CA42777, U10 CA038926, U10 CA032102-32, U10 CA032102, P30 CA062203, N01 CA027057, CA22433, U10 CA027057, U10 CA014028, U10 CA011083, N01 CA038926, N01 CA032102, CA11083] NR 96 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5663 EP 5670 DI 10.1158/1078-0432.CCR-09-0357 PG 8 WC Oncology SC Oncology GA 496OA UT WOS:000269982800009 PM 19723641 ER PT J AU Khanna, C London, C Vail, D Mazcko, C Hirschfeld, S AF Khanna, Chand London, Cheryl Vail, David Mazcko, Christina Hirschfeld, Steven TI Guiding the Optimal Translation of New Cancer Treatments From Canine to Human Cancer Patients SO CLINICAL CANCER RESEARCH LA English DT Review ID NON-HODGKINS-LYMPHOMA; HELICAL TOMOTHERAPY; COMPANION ANIMALS; DOMESTIC DOG; PET DOGS; MODELS; THERAPY; TUMORS; ONCOLOGY; GENOME AB On June 20, 2008, a meeting entitled "Translation of new cancer treatments from canine to human cancer patients," sponsored by the National Cancer Institute in Bethesda, Maryland, was convened to discuss the potential value, opportunity, risks, and rewards of an integrated and comparative drug development path for new cancer therapeutics that includes naturally occurring cancers in pet animals. A summary of this meeting and subsequent discussion are provided here to afford clarity on, the conduct of these studies so as to optimize the opportunities provided by this novel drug development and modeling strategy. (Clin Cancer Res 200915(18):5671-7) C1 [Vail, David] Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. [London, Cheryl] Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA. [Khanna, Chand; Mazcko, Christina] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, Bethesda, MD USA. RP Khanna, C (reprint author), Eunice Kennedy Shriver Natl Canc Inst, Head Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Comparat Oncol Program,Ctr Canc Res, 37 Convent Dr,Room 2144, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov RI London, Cheryl/E-6561-2012; Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 47 Z9 47 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5671 EP 5677 DI 10.1158/1078-0432.CCR-09-0719 PG 7 WC Oncology SC Oncology GA 496OA UT WOS:000269982800010 PM 19737961 ER PT J AU Schetter, AJ Nguyen, GH Bowman, ED Mathe, EA Yuen, ST Hawkes, JE Croce, CM Leung, SY Harris, CC AF Schetter, Aaron J. Nguyen, Giang Huong Bowman, Elise D. Mathe, Ewy A. Yuen, Siu Tsan Hawkes, Jason E. Croce, Carlo M. Leung, Suet Yi Harris, Curtis C. TI Association of Inflammation-Related and microRNA Gene Expression with Cancer-Specific Mortality of Colon Adenocarcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER; LUNG-CANCER; IMMUNE CELLS; PROGNOSIS; SIGNATURE; CYTOKINE; TARGETS; TUMOR; CARCINOMA; SURVIVAL AB Purpose: Inflammatory genes and microRNAs have roles in colon carcinogenesis; therefore, they may provide useful biomarkers for colon cancer. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression. Experimental Design: Quantitative reverse transcriptase-PCR. was used to measure the expression of 23 inflammatory genes in colon adenocarcinomas and adjacent noncancerous tissues from 196 patients. These data were used to develop models for cancer-specific mortality on a training cohort (n = 57), and this model was tested in both a test (n = 56) and a validation (n = 83) cohort. Expression data for miR-21 were available for these patients and were compared and combined with inflammatory gene expression. Results: PRG1, IL-10, CD68, IL-23a, and IL-12a expression in noncancerous tissue, and PRG1, ANXA1, IL-23a, IL-17a, FOXP3, and HLA-DRA expression in tumor tissues were associated with poor prognosis based on Cox regression (|Z-score| > 1.5) and were used to generate the inflammatory risk score (IRS). IRS was associated with cancer-specific mortality in the training, test (P = 0.01), and validation (P = 0.02) cohorts. This association was strong for stage 11 cases (P = 0.002). Expression of miR-21 was associated with IL-6, IL-8, IL-10, IL-12a, and NOS2a, providing evidence that the function of this microRNA and these inflammatory genes are linked. Both IRS and miR-21 expression were independently associated with cancer-specific mortality, including stage II patients alone. Conclusion: IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients. (Clin Cancer Res 2009;15(18):5878-87) C1 [Schetter, Aaron J.; Nguyen, Giang Huong; Bowman, Elise D.; Mathe, Ewy A.; Hawkes, Jason E.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nguyen, Giang Huong; Hawkes, Jason E.] Howard Hughes Med Inst, NIH Res Scholar, Chevy Chase, MD USA. [Yuen, Siu Tsan; Leung, Suet Yi] Univ Hong Kong, Queen Mary Hosp, Dept Pathol, Pokfulam, Hong Kong, Peoples R China. [Croce, Carlo M.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 2068A, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Yuen , Siu /K-6311-2014; Leung, Suet Yi/C-4340-2009; OI Hawkes, Jason E./0000-0001-5870-181X FU Intramural Research Program of the National Cancer Institute; Center for Cancer Research, NIH; Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, NIH; Howard Hughes Medical Institute FX Grant support: Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. A.J. Schetter was supported by the Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, NIH. G.H. Nguyen and J.E. Hawkes were supported by the Howard Hughes Medical Institute Grant for Graduate Medical Education. NR 50 TC 112 Z9 118 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5878 EP 5887 DI 10.1158/1078-0432.CCR-09-0627 PG 10 WC Oncology SC Oncology GA 496OA UT WOS:000269982800032 PM 19737943 ER PT J AU Bekaii-Saab, T Markowitz, J Prescott, N Sadee, W Heerema, N Wei, L Dai, ZY Papp, A Campbell, A Culler, K Balint, C O'Neil, B Lee, RM Zalupski, M Dancey, J Chen, H Grever, M Eng, C Villalona-Calero, M AF Bekaii-Saab, Tanios Markowitz, Joseph Prescott, Nichole Sadee, Wolfgang Heerema, Nyla Wei, Lai Dai, Zunyan Papp, Audrey Campbell, Angela Culler, Kristy Balint, Catherine O'Neil, Bert Lee, Ruey-min Zalupski, Mark Dancey, Janet Chen, Helen Grever, Michael Eng, Charis Villalona-Calero, Miguel TI A Multi-Institutional Phase II Study of the Efficacy and Tolerability of Lapatinib in Patients with Advanced Hepatocellular Carcinomas SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; ALPHA-FETOPROTEIN LEVELS; CLINICAL-TRIALS; PTEN EXPRESSION; CANCER; SORAFENIB; ERLOTINIB; ADRIAMYCIN; THERAPY AB Background: Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC. Methods: A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of >= 30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins. Results: Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting > 120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on > 90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival. Conclusions: Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined. (Clin Cancer Res 2009;15(18):5895-901) C1 [Bekaii-Saab, Tanios; Markowitz, Joseph; Heerema, Nyla; Campbell, Angela; Culler, Kristy; Balint, Catherine; Grever, Michael; Villalona-Calero, Miguel] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Bekaii-Saab, Tanios; Sadee, Wolfgang; Dai, Zunyan; Papp, Audrey; Grever, Michael; Villalona-Calero, Miguel] Ohio State Univ, Dept Pharmacol, Columbus, OH 43210 USA. [Wei, Lai] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Prescott, Nichole; Eng, Charis] Cleveland Clin, Genom Med Inst, Cleveland, OH 44106 USA. [Prescott, Nichole; Eng, Charis] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Eng, Charis] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. [Eng, Charis] Case Western Reserve Univ, Sch Med, CASE Comprehens Canc Ctr, Cleveland, OH 44106 USA. [O'Neil, Bert] Univ N Carolina, Chapel Hill, NC USA. [Lee, Ruey-min] Virginia Commonwealth Univ, Richmond, VA USA. [Zalupski, Mark] Univ Michigan, Ann Arbor, MI 48109 USA. [Dancey, Janet; Chen, Helen] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Bekaii-Saab, T (reprint author), Ohio State Univ, Ctr Comprehens Canc, B421 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM Tanios.Bekaii-Saab@osumc.edu RI Bekaii-Saab, Tanios/E-2733-2011; OI Eng, Charis/0000-0002-3693-5145 FU TRF SAIC BOA [24XS106]; [U01-CA76576]; [NO1-CM62207] FX Grant support: U01-CA76576, NO1-CM62207, and TRF SAIC BOA 24XS106. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 50 TC 57 Z9 60 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 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5895 EP 5901 DI 10.1158/1078-0432.CCR-09-0465 PG 7 WC Oncology SC Oncology GA 496OA UT WOS:000269982800034 PM 19737952 ER PT J AU Brumme, Z Wang, BX Nair, K Brumme, C de Pierres, C Reddy, S Julg, B Moodley, E Thobakgale, C Lu, Z van der Stok, M Bishop, K Mncube, Z Chonco, F Yuki, Y Frahm, N Brander, C Carrington, M Freedberg, K Kiepiela, P Goulder, P Walker, B Ndung'u, T Losina, E AF Brumme, Zabrina Wang, Bingxia Nair, Kriebashne Brumme, Chanson de Pierres, Chantal Reddy, Shabashini Julg, Boris Moodley, Eshia Thobakgale, Christina Lu, Zhigang van der Stok, Mary Bishop, Karen Mncube, Zenele Chonco, Fundisiwe Yuki, Yuko Frahm, Nicole Brander, Christian Carrington, Mary Freedberg, Kenneth Kiepiela, Photini Goulder, Philip Walker, Bruce Ndung'u, Thumbi Losina, Elena TI Impact of Select Immunologic and Virologic Biomarkers on CD4 Cell Count Decrease in Patients with Chronic HIV-1 Subtype C Infection: Results from Sinikithemba Cohort, Durban, South Africa SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD8(+) T-CELLS; PLASMA VIRAL LOAD; CLASS-I ALLELES; SET-POINT; LYMPHOCYTE RESPONSES; DISEASE PROGRESSION; GAG; AIDS; HLA AB Background. The extent to which immunologic and clinical biomarkers influence human immunodeficiency virus type 1 (HIV-1) infection outcomes remains incompletely characterized, particularly for non-B subtypes. On the basis of data supporting in vitro HIV-1 protein-specific CD8 T lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV-1 biomarkers, with rates of CD4 cell count decrease in individuals infected with HIV-1 subtype C. Methods. Bivariate and multivariate mixed-effects models were used to assess the relationship of baseline CD4 cell count, plasma viral load, human leukocyte antigen (HLA) class I alleles, and HIV-1 protein-specific CD8 T cell responses with the rate of CD4 cell count decrease in a longitudinal population-based cohort of 300 therapy-naive, chronically infected adults with baseline CD4 cell counts >200 cells/mm(3) and plasma viral loads > 500 copies/mL over a median of 25 months of follow-up. Results. In bivariate analyses, baseline CD4 cell count, plasma viral load, and possession of a protective HLA allele correlated significantly with the rate of CD4 cell count decrease. No relationship was observed between HIV-1 protein - specific CD8 T cell responses and CD4 cell count decrease. Results from multivariate models incorporating baseline CD4 cell counts (201-350 vs >350 cells/mm(3)), plasma viral load (<= 100,000 vs >100,000 copies/mL), and HLA (protective vs not protective) yielded the ability to discriminate CD4 cell count decreases over a 10- fold range. The fastest decrease was observed among individuals with CD4 cell counts >350 cells/mm(3) and plasma viral loads >100,000 copies/mL with no protective HLA alleles (-59 cells/mm(3) per year), whereas the slowest decrease was observed among individuals with CD4 cell counts 201-350 cells/mm(3), plasma viral loads <= 100,000 copies/ mL, and a protective HLA allele (-6 cells/mm(3) per year). Conclusions. The combination of plasma viral load and HLA class I type, but not in vitro HIV-1 protein specific CD8 T cell responses, differentiates rates of CD4 cell count decrease in patients with chronic subtype-C infection better than either marker alone. C1 [Wang, Bingxia; Lu, Zhigang; Freedberg, Kenneth; Losina, Elena] Massachusetts Gen Hosp, Program HIV Outcomes Res, Boston, MA 02114 USA. [Brumme, Zabrina; Brumme, Chanson; Julg, Boris; Frahm, Nicole; Brander, Christian; Goulder, Philip; Walker, Bruce; Ndung'u, Thumbi] Harvard Univ, Boston, MA 02115 USA. [Brumme, Zabrina; Brumme, Chanson; Julg, Boris; Frahm, Nicole; Brander, Christian; Goulder, Philip; Walker, Bruce; Ndung'u, Thumbi] Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Nair, Kriebashne; de Pierres, Chantal; Reddy, Shabashini; Julg, Boris; Moodley, Eshia; Thobakgale, Christina; van der Stok, Mary; Bishop, Karen; Mncube, Zenele; Chonco, Fundisiwe; Kiepiela, Photini; Goulder, Philip; Walker, Bruce; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Durban, South Africa. [Goulder, Philip] Nuffield Dept Med, Dept Paediat, Oxford, England. [Yuki, Yuko; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21701 USA. [Walker, Bruce] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Losina, E (reprint author), Massachusetts Gen Hosp, Program HIV Epidemiol & Outcomes Res, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM elosina@partners.org OI Brander, Christian/0000-0002-0548-5778; Ndung'u, Thumbi/0000-0003-2962-3992; Brumme, Chanson/0000-0003-2722-5288 FU Canadian Institutes of Health Research; South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS; Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative; South African AIDS Vaccine Initiative; Center for AIDS Research at Harvard University; National Institutes of Health [R01-AI067073, N01-AI-15422, R01-AI46995]; Wellcome Trust; National Cancer Institute and National Institutes of Health [HHSN261200800001E]; Intramural Research Program FX Canadian Institutes of Health Research (postdoctoral fellowship to Z.L.B.); the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS (T.N.); Bill and Melinda Gates Foundation; the International AIDS Vaccine Initiative; the South African AIDS Vaccine Initiative; Center for AIDS Research at Harvard University; National Institutes of Health (grant R01-AI067073 and contract N01-AI-15422 to B. D. W. and grant R01-AI46995 to P. G.); the Wellcome Trust (P. G.); National Cancer Institute and National Institutes of Health (contract HHSN261200800001E and the Intramural Research Program). NR 39 TC 14 Z9 14 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2009 VL 49 IS 6 BP 956 EP 964 DI 10.1086/605503 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 485ST UT WOS:000269145100021 PM 19663693 ER PT J AU Vinh, DC Masannat, F Dzioba, RB Galgiani, JN Holland, SM AF Vinh, Donald C. Masannat, Fares Dzioba, Robert B. Galgiani, John N. Holland, Steven M. TI Refractory Disseminated Coccidioidomycosis and Mycobacteriosis in Interferon-gamma Receptor 1 Deficiency SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IFN-GAMMA; AUTOANTIBODIES; SUSCEPTIBILITY; TUBERCULOSIS; PATIENT; POLYMORPHISMS; ASSOCIATION; INFECTIONS; RESISTANCE; IMMITIS AB Severe coccidioidomycosis is rare, and specific genetic susceptibility to the disease remains unidentified. We describe a patient with disseminated recalcitrant coccidioidomycosis with autosomal dominant interferon-gamma receptor 1 deficiency caused by a heterozygous IFNGR1 818del4 mutation. Therefore, the interleukin-12/interferon-gamma axis appears to be critical for control of coccidioidomycosis. C1 [Vinh, Donald C.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Masannat, Fares; Galgiani, John N.] Univ Arizona, Coll Med, Valley Fever Ctr Excellence, Tucson, AZ USA. [Masannat, Fares; Galgiani, John N.] So Arizona Vet Adm Hlth Care Syst, Tucson, AZ USA. [Dzioba, Robert B.] Univ Med Ctr, Tucson, AZ USA. RP Holland, SM (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bldg 10CRC,Rm B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov OI VINH, DONALD/0000-0003-1347-7767 FU Canadian Institutes of Health Research (CIHR); Division of Intramural Research; National Institute of Allergy and Infectious Diseases; NIH; US Department of Veterans Affairs FX Canadian Institutes of Health Research (CIHR fellowship for D.C.V.); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; US Department of Veterans Affairs. NR 22 TC 34 Z9 35 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2009 VL 49 IS 6 BP E62 EP E65 DI 10.1086/605532 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 485ST UT WOS:000269145100034 PM 19681704 ER PT J AU Shnyrova, AV Frolov, VA Zimmerberg, J AF Shnyrova, Anna V. Frolov, Vadim A. Zimmerberg, Joshua TI Domain-Driven Morphogenesis of Cellular Membranes SO CURRENT BIOLOGY LA English DT Review ID CLATHRIN-COATED PITS; ENDOPLASMIC-RETICULUM; SELF-ORGANIZATION; PHOSPHOLIPID-MEMBRANES; SPONTANEOUS CURVATURE; MEDIATED ENDOCYTOSIS; ACTIN POLYMERIZATION; BIOLOGICAL-MEMBRANES; TUBULAR CARRIERS; PLASMA-MEMBRANE AB Cellular membrane systems delimit and organize the intracellular space. Most of the morphological rearrangements in cells involve the coordinated remodeling of the lipid bilayer, the core of the membranes. This process is generally thought to be initiated and coordinated by specialized protein machineries. Nevertheless, it has become increasingly evident that the most essential part of the geometric information and energy required for membrane remodeling is supplied via the cooperative and synergistic action of proteins and lipids, as cellular shapes are constructed using the intrinsic dynamics, plasticity and self-organizing capabilities provided by the lipid bilayer. Here, we analyze the essential role of proteo-lipid membrane domains in conducting and coordinating morphological remodeling in cells. C1 [Shnyrova, Anna V.; Frolov, Vadim A.; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular & Mol Biol Lab, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Shnyrova, AV (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular & Mol Biol Lab, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov OI Frolov, Vadim/0000-0002-0653-5669 FU NIH, NICHD FX We apologize that space limitations did not allow us to cover all of the newly emerging paradigms in the rapidly changing fields of cellular morphogenesis and membrane dynamics or include many of the important references to original experimental findings. Work in Zimmerberg's lab is supported by the Intramural Research Program of the NIH, NICHD. NR 122 TC 21 Z9 21 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD SEP 15 PY 2009 VL 19 IS 17 SI SI BP R772 EP R780 DI 10.1016/j.cub.2009.07.063 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 495UM UT WOS:000269920500023 PM 19906579 ER PT J AU Kwon, D Mucci, D Langlais, KK Americo, JL DeVido, SK Cheng, YZ Kassis, JA AF Kwon, Deborah Mucci, Diane Langlais, Kristofor K. Americo, Jeffrey L. DeVido, Sarah K. Cheng, Yuzhong Kassis, Judith A. TI Enhancer-promoter communication at the Drosophila engrailed locus SO DEVELOPMENT LA English DT Article DE Promoter specificity; Regulatory DNA; Transcriptional control; Drosophila ID II CORE PROMOTER; RESPONSE ELEMENTS; GENE-EXPRESSION; BITHORAX COMPLEX; REGULATORY DNA; TATA-BOX; MELANOGASTER; SPECIFICITY; TRANSCRIPTION; PATTERN AB Enhancers are often located many tens of kilobases away from the promoter they regulate, sometimes residing closer to the promoter of a neighboring gene. How do they know which gene to activate? We have used homing P[en] constructs to study the enhancer-promoter communication at the engrailed locus. Here we show that engrailed enhancers can act over large distances, even skipping over other transcription units, choosing the engrailed promoter over those of neighboring genes. This specificity is achieved in at least three ways. First, early acting engrailed stripe enhancers exhibit promoter specificity. Second, a proximal promoter-tethering element is required for the action of the imaginal disc enhancer(s). Our data suggest that there are two partially redundant promoter-tethering elements. Third, the long-distance action of engrailed enhancers requires a combination of the engrailed promoter and sequences within or closely linked to the promoter proximal Polycomb-group response elements. These data show that multiple mechanisms ensure proper enhancer-promoter communication at the Drosophila engrailed locus. C1 [Kwon, Deborah; Langlais, Kristofor K.; Americo, Jeffrey L.; DeVido, Sarah K.; Cheng, Yuzhong; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Mucci, Diane] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Kassis, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov OI Kassis, Judith/0000-0001-9268-3213 FU Cystic Fibrosis Foundation; Food and Drug Administration; NIH, NICHD FX We thank Renato Paro for the pUZ vector; Pat O'Farrell and Nikita Yakubovich for the anti-En antibody; Miki Fujioka, Jim Jaynes, Karl Pfeifer, Mark Mortin and the Kassis lab members for comments on this manuscript. Diane Mucci was supported by a grant from the Cystic Fibrosis Foundation and by internal funds from the Food and Drug Administration. This research was supported by the Intramural Research Program of the NIH, NICHD. Deposited in PMC for release after 12 months. NR 44 TC 31 Z9 31 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 15 PY 2009 VL 136 IS 18 BP 3067 EP 3075 DI 10.1242/dev.036426 PG 9 WC Developmental Biology SC Developmental Biology GA 486AN UT WOS:000269167800004 PM 19675130 ER PT J AU Rhee, DY Zhao, XQ Francis, RJB Huang, GY Mably, JD Lo, CW AF Rhee, David Y. Zhao, Xiao-Qing Francis, Richard J. B. Huang, Guo Ying Mably, John D. Lo, Cecilia W. TI Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development SO DEVELOPMENT LA English DT Article DE Epicardium; Connexin 43; Heart development; Coronary vessels; Mouse ID GAP-JUNCTION PROTEIN; SMOOTH-MUSCLE-CELLS; MICROTUBULE-ORGANIZING CENTER; CARDIAC NEURAL CREST; ARTERY DEVELOPMENT; PLASMA-MEMBRANE; GOLGI-APPARATUS; CHICK-EMBRYO; NIH3T3 CELLS; AVIAN HEART AB Connexin 43 knockout (Cx43 KO) mice exhibit conotruncal malformations and coronary artery defects. We observed epicardial blisters in the Cx43 KO hearts that suggest defects in epicardial epithelial-mesenchymal transformation (EMT), a process that generates coronary vascular progenitors. Analysis using a three-dimensional collagen gel invasion assay showed that Cx43 KO epicardial cells are less invasive and that, unlike wild-type epicardial cells, they fail to organize into thin vessel-like projections. Examination of Cx43 KO hearts using Wt1 as an epicardial marker revealed a disorganized pattern of epicardial cell infiltration. Time-lapse imaging and motion analysis using epicardial explants showed a defect in directional cell migration. This was associated with changes in the actin/tubulin cytoskeleton. A defect in cell polarity was indicated by a failure of the microtubule-organizing center to align with the direction of cell migration. Forced expression of Cx43 constructs in epicardial explants showed the Cx43 tubulin-binding domain is required for Cx43 modulation of cell polarity and cell motility. Pecam staining revealed early defects in remodeling of the primitive coronary vascular plexuses in the Cx43 KO heart. Together, these findings suggest an early defect in coronary vascular development arising from a global perturbation of the cytoarchitecture of the cell. Consistent with this, we found aberrant myocardialization of the outflow tract, a process also known to be EMT dependent. Together, these findings suggest cardiac defects in the Cx43 KO mice arise from the disruption of cell polarity, a process that may be dependent on Cx43-tubulin interactions. C1 [Rhee, David Y.; Zhao, Xiao-Qing; Francis, Richard J. B.; Lo, Cecilia W.] NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Mably, John D.] Childrens Hosp Boston, Dept Cardiol, Boston, MA 02115 USA. [Mably, John D.] Harvard Univ, Dept Genet, Sch Med, Boston, MA USA. [Huang, Guo Ying] Fudan Univ, Childrens Hosp, Childrens Hosp Cardiovasc Ctr, Shanghai 200032, Peoples R China. RP Lo, CW (reprint author), NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM loc@nhlbi.nih.gov RI Francis, Richard/P-2524-2015 FU Ruth L. Kirschstein National Research Service Award; NIH [ZO1-HL005701] FX We thank Dr Raymond Runyan for helpful advice on the 3D collagen gel assay, Chris Combs (NHLBI Light Microscopy Core Facility) for help with confocal imaging and Peter Yang for critical reading of the manuscript. D. Y. R. was funded in part by a Ruth L. Kirschstein National Research Service Award. Supported by grants from NIH ZO1-HL005701 to C. W. L. Deposited in PMC for release after 12 months. NR 61 TC 45 Z9 46 U1 0 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 15 PY 2009 VL 136 IS 18 BP 3185 EP 3193 DI 10.1242/dev.032334 PG 9 WC Developmental Biology SC Developmental Biology GA 486AN UT WOS:000269167800015 PM 19700622 ER PT J AU del Castillo-Olivares, A Kulkarni, M Smith, HE AF del Castillo-Olivares, Antonio Kulkarni, Madhura Smith, Harold E. TI Regulation of sperm gene expression by the GATA factor ELT-1 SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Germ line; Spermatogenesis; GATA factor; Gene expression ID SEX-DETERMINING GENE; TRANSCRIPTION FACTOR GATA-1; NEMATODE CAENORHABDITIS-ELEGANS; ZINC-FINGER PROTEINS; ONE-HYBRID SYSTEM; C-ELEGANS; DNA-BINDING; DIFFERENTIATION GENE; MOUSE TESTIS; CELL FATE AB Cell fate specification is mediated primarily through the expression of cell-type-specific genes. The regulatory pathway that governs the sperm/egg decision in the hermaphrodite germ line of Caenorhabditis elegans has been well characterized, but the transcription factors that drive these developmental programs remain unknown. We report the identification of ELT-1, a GATA transcription factor that specifies hypodermal fate in the embryo, as a regulator of sperm-specific transcription in the germ line. Computational analysis identified a conserved bipartite sequence element that is found almost exclusively in the promoters of a number of sperm genes. ELT-1 was recovered in a yeast one-hybrid screen for factors that bind to that sperm consensus site. In vitro assays defined the sperm consensus sequence as an optimal binding site for ELT-1. We determined that expression of elt-1 is elevated in the sperm-producing germ line, and that ELT-1 is required for sperm function. Deletion of the ELT-1 binding site from a sperm promoter abrogates sperm-specific expression of a reporter transgene. This work demonstrates a role for the ELT-1 transcription factor in sperm, and provides a critical link between the germ line sex determination program and gamete-specific gene expression. (C) 2009 Elsevier Inc. All rights reserved. C1 [del Castillo-Olivares, Antonio; Smith, Harold E.] Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. [Kulkarni, Madhura] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Kulkarni, Madhura] Harvard Univ, Sch Med, Dept Cell Biol, Charlestown, MA 02129 USA. [Kulkarni, Madhura] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA. [Smith, Harold E.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Smith, HE (reprint author), 8 Ctr Dr, Bethesda, MD 20892 USA. EM smithhe2@niddk.nih.gov FU National Science Foundation [0445684] FX We wish to thank the Caenorhabditis Genetics Center and the C. elegans Gene Knockout Consortium for providing strains and plasmids, Bronessa Fernandes for assistance with the yeast one-hybrid assays, one anonymous reviewer for suggesting the mosaic/GFP experiment, and members of the lab and the Baltimore/Washington worm community for fruitful discussions. This work was supported in part by National Science Foundation grant number 0445684 to H. E. S. NR 79 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 2009 VL 333 IS 2 BP 397 EP 408 DI 10.1016/j.ydbio.2009.06.044 PG 12 WC Developmental Biology SC Developmental Biology GA 526AQ UT WOS:000272260300015 PM 19591818 ER PT J AU Panduri, V Liu, G Surapureddi, S Kondapalli, J Soberanes, S de Souza-Pinto, NC Bohr, VA Budinger, GRS Schumacker, PT Weitzman, SA Kamp, DW AF Panduri, V. Liu, G. Surapureddi, S. Kondapalli, J. Soberanes, S. de Souza-Pinto, N. C. Bohr, V. A. Budinger, G. R. S. Schumacker, P. T. Weitzman, S. A. Kamp, D. W. TI Role of mitochondrial hOGG1 and aconitase in oxidant-induced lung epithelial cell apoptosis SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE DNA repair; Aconitase; Ogg1; Free radicals; Asbestos; Mitochondria ID OXIDATIVE DNA-DAMAGE; FLUORESCENT PROTEIN INDICATORS; ENDOTHELIAL-CELLS; GLYCOSYLASE HOGG1; MAMMALIAN-CELLS; REPAIR ENZYME; LON PROTEASE; NUCLEAR-DNA; HUMAN OGG1; 8-OXOGUANINE AB 8-Oxoguanine DNA glycosylase (Ogg1) repairs 8-oxo-7,8-dihydroxyguanine (8-oxoG), one of the most abundant DNA adducts caused by oxidative stress. In the mitochondria, Ogg1 is thought to prevent activation of the intrinsic apoptotic pathway in response to oxidative stress by augmenting DNA repair. However, the predominance of the beta-Ogg1 isoform, which lacks 8-oxoG DNA glycosylase activity, suggests that mitochondrial Ogg1 functions in a role independent of DNA repair. We report here that overexpression of mitochondria-targeted human alpha-hOgg1 (mt-hOgg1) in human lung adenocarcinoma cells with some alveolar epithelial cell characteristics (A549 cells) prevents oxidant-induced mitochondrial dysfunction and apoptosis by preserving mitochondrial aconitase. Importantly, mitochondrial alpha-hOgg1 mutants lacking 8-oxoG DNA repair activity were as effective as wild-type mt-hOgg1 in preventing oxidant-induced caspase-9 activation, reductions in mitochondrial aconitase, and apoptosis, suggesting that the protective effects of mt-hOgg1 occur independent of DNA repair. Notably, wild-type and mutant mt-hOgg1 coprecipitate with mitochondrial aconitase. Furthermore, overexpression of mitochondrial aconitase abolishes oxidant-induced apoptosis whereas hOgg1 silencing using shRNA reduces mitochondrial aconitase and augments apoptosis. These findings suggest a novel mechanism that mt-hOgg1 acts as a mitochondrial aconitase chaperone protein to prevent oxidant-mediated mitochondrial dysfunction and apoptosis that might be important in the molecular events underlying oxidant-induced toxicity. (C) 2009 Elsevier Inc. All rights reserved. C1 [Panduri, V.; Liu, G.; Soberanes, S.; Budinger, G. R. S.; Weitzman, S. A.; Kamp, D. W.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Panduri, V.; Liu, G.; Soberanes, S.; Budinger, G. R. S.; Weitzman, S. A.; Kamp, D. W.] Jesse Brown VA Med Ctr, Chicago, IL 60611 USA. [Surapureddi, S.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Kondapalli, J.; Schumacker, P. T.] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [de Souza-Pinto, N. C.; Bohr, V. A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Kamp, DW (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, 240 E Huron,McGaw M-330, Chicago, IL 60611 USA. EM d-kamp@northwestern.edu RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; liu, gang/M-4073-2014 OI Souza-Pinto, Nadja/0000-0003-4206-964X; liu, gang/0000-0002-4536-8453 FU Department of Veterans Affairs; National Institutes of Health [HL67835-01, HL35440] FX The authors appreciate the kind gift of adenoviral vectors containing hOgg1 and empty vector controls provided by Dr. Glenn Wilson (University of South Alabama) and mitochondrial aconitase polyclonal antibody provided by Dr Luke Szweda (Case Western Reserve University). The authors acknowledge the technical efforts provided by Neil Bruce. This work was supported by a Merit Review grant from the Department of Veterans Affairs (D. W. K.), the National Institutes of Health Grants HL67835-01 (G. R. S. B.), and HL35440 (P. T. S). NR 47 TC 30 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP 15 PY 2009 VL 47 IS 6 BP 750 EP 759 DI 10.1016/j.freeradbiomed.2009.06.010 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 542LH UT WOS:000273494300008 PM 19524665 ER PT J AU Abdelmegeed, MA Moon, KH Hardwick, JP Gonzalez, FJ Song, BJ AF Abdelmegeed, Mohamed A. Moon, Kwan-Hoon Hardwick, James P. Gonzalez, Frank J. Song, Byoung-Joon TI Role of peroxisome proliferator-activated receptor-alpha in fasting-mediated oxidative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE PPAR-alpha; Null mice; Fasting; Steatosis; Liver; Oxidative stress; Lipid peroxidation; Protein nitration; Protein oxidation; Superoxide dismutase; Aldehyde dehydrogenase ID FATTY-ACID OXIDATION; MITOCHONDRIAL ALDEHYDE DEHYDROGENASE; MANGANESE-SUPEROXIDE-DISMUTASE; GLUTATHIONE-S-TRANSFERASE; PPAR-ALPHA; RAT-LIVER; NITRIC-OXIDE; DIFFERENTIAL EXPRESSION; LIPID-PEROXIDATION; HEPATIC STEATOSIS AB The peroxisome proliferator-activated receptor-alpha (PPAR alpha) regulates lipid homeostasis, particularly in the liver. This study was aimed at elucidating the relationship between hepatosteatosis and oxidative stress during fasting. Fasted Ppara-null mice exhibited marked hepatosteatosis, which was associated with elevated levels of lipid peroxidation, nitric oxide synthase activity, and hydrogen peroxide accumulation. Total glutathione (GSH), mitochondrial GSH, and the activities of major antioxidant enzymes were also lower in the fasted Ppara-null mice. Consequently, the number and extent of nitrated proteins were markedly increased in the fasted Ppara-null mice, although high levels of protein nitration were still detected in the fed Ppara-null mice while many oxidatively modified proteins were only found in the fasted Ppara-null mice. However, the role of inflammation in increased oxidative stress in the fasted Ppara-null mice was minimal based on the similar levels of tumor necrosis factor-alpha change in all groups. These results with increased oxidative stress observed in the fasted Ppara-null mice compared with other groups demonstrate a role for PPAR alpha in fasting-mediated oxidative stress and that inhibition of PPAR alpha functions may increase the susceptibility to oxidative damage in the presence of another toxic agent. Published by Elsevier Inc. C1 [Abdelmegeed, Mohamed A.; Moon, Kwan-Hoon; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. [Hardwick, James P.] Northeastern Ohio Univ Coll Med & Pharm, Dept Integrat Med Sci, Rootstown, OH 44272 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bjs@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism. We are thankful to Dr. Klaus Gawrisch for supporting this study. NR 64 TC 36 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP 15 PY 2009 VL 47 IS 6 BP 767 EP 778 DI 10.1016/j.freeradbiomed.2009.06.017 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 542LH UT WOS:000273494300010 PM 19539749 ER PT J AU Olson, P Lu, J Zhang, H Shai, A Chun, MG Wang, YC Libutti, SK Nakakura, EK Golub, TR Hanahan, D AF Olson, Peter Lu, Jun Zhang, Hao Shai, Anny Chun, Matthew G. Wang, Yucheng Libutti, Steven K. Nakakura, Eric K. Golub, Todd R. Hanahan, Douglas TI MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer SO GENES & DEVELOPMENT LA English DT Article DE MicroRNA; pancreatic neuroendocrine tumor (PNET); cancer; transgenic mouse; mouse model of human cancer; miR-200 ID PANCREATIC-ISLET TUMORIGENESIS; CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR ANGIOGENESIS; TRANSGENIC MICE; MIR-200 FAMILY; MOUSE MODEL; EXPRESSION SIGNATURE; VASCULAR INTEGRITY; BREAST-CANCER; LUNG-CANCER AB While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality. C1 [Olson, Peter; Shai, Anny; Chun, Matthew G.; Hanahan, Douglas] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Olson, Peter; Shai, Anny; Chun, Matthew G.; Wang, Yucheng; Nakakura, Eric K.; Hanahan, Douglas] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Lu, Jun; Zhang, Hao; Golub, Todd R.] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Lu, Jun] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Lu, Jun] Yale Univ, Stem Cell Ctr, New Haven, CT 06520 USA. [Libutti, Steven K.] NCI, Tumor Angiogenesis Sect, Surg Branch, Bethesda, MD 20892 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hanahan, D (reprint author), Swiss Fed Inst Technol EPFL, Swiss Inst Expt Canc Res, ISREC, CH-1015 Lausanne, Switzerland. EM dh@ucsf.edu FU National Cancer Institute [T32 CA09043]; NSF FX We thank Bob Horvitz for encouraging this project and our collaboration, and for comments on the manuscript. We thank Gary Ruvkun and Michael McManus for critical reading of the manuscript and James Christensen (Pfizer, Inc.) for providing sunitinib. We thank Marina Vayner, Susan Cacacho, and Ehud Drori for excellent technical assistance. We acknowledge access to the University of California at San Francisco Diabetes Center's Microscopy and Islet Isolation Cores. Q-PCR was performed at the Genome Analysis Core, Helen Diller Family Comprehensive Cancer Center, UCSF. The research at UCSF was supported by a grant from the National Cancer Institute. D. H. is an American Cancer Society Research Professor. P. O. and A. S. acknowledge salary support from NCI Training Grant T32 CA09043 ( Director J. Michael Bishop), Molecular Analysis of Tumor Viruses. M. G. C. was supported by a fellowship from the NSF. NR 78 TC 148 Z9 162 U1 0 U2 18 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD SEP 15 PY 2009 VL 23 IS 18 BP 2152 EP 2165 DI 10.1101/gad.1820109 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 494RI UT WOS:000269832600005 PM 19759263 ER PT J AU Jordan, P Copsey, A Newnham, L Kolar, E Lichten, M Hoffmann, E AF Jordan, Philip Copsey, Alice Newnham, Louise Kolar, Elizabeth Lichten, Michael Hoffmann, Eva TI Ipl1/Aurora B kinase coordinates synaptonemal complex disassembly with cell cycle progression and crossover formation in budding yeast meiosis SO GENES & DEVELOPMENT LA English DT Article DE Meiosis; synaptonemal complex; chromosome structure; Ipl1/Aurora B kinase; Cdc5/Polo-like kinase ID MEIOTIC CHROMOSOME SYNAPSIS; SACCHAROMYCES-CEREVISIAE; HISTONE H3; CENTROMERIC LOCALIZATION; SUMO MODIFICATIONS; DNA-REPLICATION; PROTEIN-KINASE; AURORA-B; SEGREGATION; PHOSPHORYLATION AB Several protein kinases collaborate to orchestrate and integrate cellular and chromosomal events at the G2/M transition in both mitotic and meiotic cells. During the G2/M transition in meiosis, this includes the completion of crossover recombination, spindle formation, and synaptonemal complex (SC) breakdown. We identified Ipl1/Aurora B kinase as the main regulator of SC disassembly. Mutants lacking Ipl1 or its kinase activity assemble SCs with normal timing, but fail to dissociate the central element component Zip1, as well as its binding partner, Smt3/SUMO, from chromosomes in a timely fashion. Moreover, lack of Ipl1 activity causes delayed SC disassembly in a cdc5 as well as a CDC5-inducible ndt80 mutant. Crossover levels in the ipl1 mutant are similar to those observed in wild type, indicating that full SC disassembly is not a prerequisite for joint molecule resolution and subsequent crossover formation. Moreover, expression of meiosis I and meiosis II-specific B-type cyclins occur normally in ipl1 mutants, despite delayed formation of anaphase I spindles. These observations suggest that Ipl1 coordinates changes to meiotic chromosome structure with resolution of crossovers and cell cycle progression at the end of meiotic prophase. C1 [Jordan, Philip; Copsey, Alice; Newnham, Louise; Hoffmann, Eva] Univ Sussex, MRC, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. [Kolar, Elizabeth; Lichten, Michael] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hoffmann, E (reprint author), Univ Sussex, MRC, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. EM eh58@sussex.ac.uk RI Lichten, Michael/C-5795-2013; OI Lichten, Michael/0000-0001-9707-2956; Newnham, Louise/0000-0002-1627-5530; hoffmann, eva/0000-0002-2588-0652 FU Medical Research Council; National Cancer Institute, NIH; Royal Society Dorothy Hodgkin Fellowship FX We thank Angelika Amon, Min-Hao Kuo, Franz Klein, and G. Shirleen Roeder for antibodies and strains, and members of the Hoffmann and Lichten laboratories for discussion and comments on this work. The Hoffmann laboratory was funded by a grant from the Medical Research Council and the Lichten laboratory was funded by an Intramural Research Program of the National Cancer Institute, NIH. E. H. was funded by a Royal Society Dorothy Hodgkin Fellowship. NR 62 TC 16 Z9 16 U1 2 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD SEP 15 PY 2009 VL 23 IS 18 BP 2237 EP 2251 DI 10.1101/gad.536109 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 494RI UT WOS:000269832600012 PM 19759266 ER PT J AU Schurman, SH Hedayati, M Wang, ZM Singh, DK Speina, E Zhang, YQ Becker, K Macris, M Sung, P Wilson, DM Croteau, DL Bohr, VA AF Schurman, Shepherd H. Hedayati, Mohammad Wang, ZhengMing Singh, Dharmendra K. Speina, Elzbieta Zhang, Yongqing Becker, Kevin Macris, Margaret Sung, Patrick Wilson, David M., III Croteau, Deborah L. Bohr, Vilhelm A. TI Direct and indirect roles of RECQL4 in modulating base excision repair capacity SO HUMAN MOLECULAR GENETICS LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; FORMAMIDOPYRIMIDINE-DNA GLYCOSYLASE; STRAND BREAK REPAIR; WERNER-SYNDROME; SYNDROME PROTEIN; FLAP ENDONUCLEASE-1; POLYMERASE-BETA; HELICASE ACTIVITY; GENOTOXIC AGENTS; GENOME STABILITY AB RECQL4 is a human RecQ helicase which is mutated in approximately two-thirds of individuals with Rothmund-Thomson syndrome (RTS), a disease characterized at the cellular level by chromosomal instability. BLM and WRN are also human RecQ helicases, which are mutated in Bloom and Werner's syndrome, respectively, and associated with chromosomal instability as well as premature aging. Here we show that primary RTS and RECQL4 siRNA knockdown human fibroblasts accumulate more H(2)O(2)-induced DNA strand breaks than control cells, suggesting that RECQL4 may stimulate repair of H(2)O(2)-induced DNA damage. RTS primary fibroblasts also accumulate more XRCC1 foci than control cells in response to endogenous or induced oxidative stress and have a high basal level of endogenous formamidopyrimidines. In cells treated with H(2)O(2), RECQL4 co-localizes with APE1, and FEN1, key participants in base excision repair. Biochemical experiments indicate that RECQL4 specifically stimulates the apurinic endonuclease activity of APE1, the DNA strand displacement activity of DNA polymerase beta, and incision of a 1- or 10-nucleotide flap DNA substrate by Flap Endonuclease I. Additionally, RTS cells display an upregulation of BER pathway genes and fail to respond like normal cells to oxidative stress. The data herein support a model in which RECQL4 regulates both directly and indirectly base excision repair capacity. C1 [Schurman, Shepherd H.; Hedayati, Mohammad; Wang, ZhengMing; Singh, Dharmendra K.; Speina, Elzbieta; Wilson, David M., III; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing; Becker, Kevin] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Macris, Margaret; Sung, Patrick] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Speina, Elzbieta] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Suite 100,Rm 06B133, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Becker, Kevin/0000-0002-6794-6656; Schurman, Shepherd/0000-0002-9133-7906 FU National Institute of Health; National Institute on Aging; National Institute of Health Research [RO1ES-015632]; Polish Ministry of Science and Higher Education [N303 391436]; [Z01 AG000726-16]; [Z01 AG000727] FX This work was supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging and by National Institute of Health Research Grant RO1ES-015632. Annual reports Z01 AG000726-16 and Z01 AG000727. E. S. was supported, in part, by a grant from the Polish Ministry of Science and Higher Education N303 391436. NR 71 TC 48 Z9 48 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2009 VL 18 IS 18 BP 3470 EP 3483 DI 10.1093/hmg/ddp291 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 486NF UT WOS:000269203000012 PM 19567405 ER PT J AU Tolstov, YL Pastrana, DV Feng, HC Becker, JC Jenkins, FJ Moschos, S Chang, Y Buck, CB Moore, PS AF Tolstov, Yanis L. Pastrana, Diana V. Feng, Huichen Becker, Juergen C. Jenkins, Frank J. Moschos, Stergios Chang, Yuan Buck, Christopher B. Moore, Patrick S. TI Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Merkel cell polyomavirus; Merkel cell carcinoma; virus-like particles; enzyme-linked immunosorbent assay; serologic assay ID CARCINOMA; IDENTIFICATION; REACTIVITY; CANCER; VIRUS; VP1; DNA AB Merkel cell polyomavirus (MCV) is a newly-discovered human tumor virus found in similar to 80% of Merkel cell carcinoma (MCC). The rate of MCV infection among persons without MCC is unknown. We developed a MCV virus-like particle (VLP) enzyme-linked immunoassay (EIA) that does not cross-react with human BK or murine polyomaviruses. Peptide mapping of the MCV VP1 gene and immunoblotting with denatured MCV VLP are less sensitive than the MCV EIA in detecting MCV antibodies suggesting antibody reactivity in this assay primarily targets conformational but not linear epitopes. Among MCC patients, all 21 (100%) patients tested with MCV-positive tumors had high serum MCV IgG but not high MCV IgM levels. Only 3 of 6 (50%) MCC patients with MCV-negative tumors were positive for MCV antibodies. Sera from most adults, including 107 of 166 (64%) blood donors, 63 of 100 (63%) commercial donors and 37 of 50 (74%) systemic lupus erythematosus patients, show evidence for prior MCV exposure. Age-specific MCV prevalence was determined by examining a cross-sectional distribution of 150 Langerhans cell histiocytosis (an unrelated neoplasm) patient sera. MCV prevalence increases from 50% among children age 15 years or younger to 80% among persons older than 50 years. We did not find evidence for vertical transmission among infants. Although past exposure to MCV is common among all adult groups, MCC patients have a markedly elevated MCV IgG response compared with control patients. Our study demonstrates that MCV is a widespread but previously unrecognized human infection. (C) 2009 UICC C1 [Tolstov, Yanis L.; Feng, Huichen; Chang, Yuan; Moore, Patrick S.] Univ Pittsburgh, Inst Canc, Mol Virol Program, Pittsburgh, PA 15213 USA. [Pastrana, Diana V.; Buck, Christopher B.] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Becker, Juergen C.] Univ Clin Wurzburg, Dept Dermatol Venerol & Allergy, Wurzburg, Germany. [Jenkins, Frank J.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Moschos, Stergios] Univ Pittsburgh, Dept Internal Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. RP Chang, Y (reprint author), Univ Pittsburgh, Inst Canc, Mol Virol Program, 5117 Ctr Ave,Suite 1-8, Pittsburgh, PA 15213 USA. EM yc70@pitt.edu; buckc@nih.gov; psm9@pitt.edu RI Chang, Yuan/F-4146-2011; Feng, Huichen/F-5502-2011; Moore, Patrick/F-3960-2011; OI Feng, Huichen/0000-0003-3069-8174; Moore, Patrick/0000-0002-8132-858X; Buck, Christopher/0000-0003-3165-8094 FU NIH [CA136363, CA120726]; Al Copeland Foundation; University of Pittsburgh FX Grant sponsor: NIH; Grant numbers: CA136363, CA120726; Grant sponsors: The Al Copeland Foundation, University of Pittsburgh EXPLORER Award, University of Pittsburgh Clinical and Translational Science Institute Catalyst Training Program. NR 27 TC 155 Z9 155 U1 1 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2009 VL 125 IS 6 BP 1250 EP 1256 DI 10.1002/ijc.24509 PG 7 WC Oncology SC Oncology GA 489AU UT WOS:000269392700002 PM 19499548 ER PT J AU Stockwin, LH Han, BN Yu, SX Hollingshead, MG ElSohly, MA Gul, W Slade, D Galal, AM Newton, DL AF Stockwin, Luke H. Han, Bingnan Yu, Sherry X. Hollingshead, Melinda G. ElSohly, Mahmoud A. Gul, Waseem Slade, Desmond Galal, Ahmed M. Newton, Dianne L. TI Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE artemisinin dimer; reactive oxygen species (ROS); UPR; thapsigargin; SERCA ID UNFOLDED-PROTEIN RESPONSE; ENDOTHELIAL-GROWTH-FACTOR; CANCER-CELLS; TRANSCRIPTIONAL INDUCTION; INTRACELLULAR CALCIUM; QINGHAOSU ARTEMISININ; PLASMA-MEMBRANE; TUMOR PROMOTER; IN-VITRO; ANTIMALARIAL AB Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anticancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were > 1,000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the antioxidant L-NAC, the iron chelator desferroxamine and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity, whereas inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage, iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA). A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity. (C) 2009 UICC C1 [Stockwin, Luke H.; Han, Bingnan; Yu, Sherry X.; Newton, Dianne L.] NCI, Dev Therapeut Program, SAIC Frederick, Frederick, MD 21702 USA. [Hollingshead, Melinda G.] NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Frederick, MD 21702 USA. [ElSohly, Mahmoud A.; Gul, Waseem] ElSohly Labs, Oxford, MS USA. [ElSohly, Mahmoud A.; Slade, Desmond; Galal, Ahmed M.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. RP Newton, DL (reprint author), NCI, Dev Therapeut Program, SAIC Frederick, Bldg 320,Room 6, Frederick, MD 21702 USA. EM 12506dnewton@ncifcrf.gov FU National Institutes of Health [NO1-CO-12400]; National Cancer Institute FX Grant sponsor: National Institutes of Health; Grant number: NO1-CO-12400; Grant sponsors: National Cancer Institute, Developmental Therapeutics Program (Division of Cancer Treatment and Diagnosis of the National Cancer Institute). NR 48 TC 49 Z9 53 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2009 VL 125 IS 6 BP 1266 EP 1275 DI 10.1002/ijc.24496 PG 10 WC Oncology SC Oncology GA 489AU UT WOS:000269392700004 PM 19533749 ER PT J AU Kumamoto, K Fujita, K Kurotani, R Saito, M Unoki, M Hagiwara, N Shiga, H Bowman, ED Yanaihara, N Okamura, S Nagashima, M Miyamoto, K Takenoshita, S Yokota, J Harris, CC AF Kumamoto, Kensuke Fujita, Kaori Kurotani, Reiko Saito, Motonobu Unoki, Motoko Hagiwara, Nobutoshi Shiga, Hideaki Bowman, Elise D. Yanaihara, Nozomu Okamura, Shu Nagashima, Makoto Miyamoto, Kotaro Takenoshita, Seiichi Yokota, Jun Harris, Curtis C. TI ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ING2; MMP13; chromatin remodeling; colon cancer; metastasis; NF-kappa B ID NF-KAPPA-B; CANDIDATE TUMOR-SUPPRESSOR; COLLAGENASE-3 MATRIX METALLOPROTEINASE-13; COLORECTAL-CANCER; TRANSCRIPTIONAL REPRESSION; PLANT HOMEODOMAIN; GENE; P53; ACETYLATION; PROTEINS AB Inhibitor of growth 2 (ING2) is associated with chromatin remodeling and regulation of gene expression by binding to a methylated histone H3K4 residue and recruiting HDAC complexes to the region. The aim of our study is to investigate the regulation of ING2 expression and the clinical significance of upregulated ING2 in colon cancer. Here, we show that the ING2 mRNA level in colon cancer tissue increased to more than twice than that in normal mucosa in the 45% of colorectal cancer cases that we examined. A putative NF-kappa B binding site was found in the ING2 promoter region. We confirmed that NF-kappa B could bind to the ING2 promoter by EMSA and luciferase assays. Subsequent microarray analyses revealed that ING2 upregulates expression of matrix metalloproteinase 13 (MMP13), which enhances cancer invasion and metastasis. ING2 regulation of MMP13 expression was confirmed in both ING2 overexpression and knock down experiments. MMP13 expression was further induced by coexpression of ING2 with HDAC1 or with mSin3A, suggesting that the ING2-HDAC1-mSin3A complex members regulates expression of MMP13. In vitro invasion assay was performed to determine functional significance of ING2 upregulation. ING2 overexpressed cells exhibited greater invasive potential. Taken together, upregulation of ING2 was associated with colon cancer and MMP13-dependent cellular invasion, indicating that ING2 expression might be involved with cancer invasion and metastasis. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America. C1 [Kumamoto, Kensuke; Fujita, Kaori; Saito, Motonobu; Unoki, Motoko; Hagiwara, Nobutoshi; Shiga, Hideaki; Bowman, Elise D.; Yanaihara, Nozomu; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kumamoto, Kensuke; Saito, Motonobu; Miyamoto, Kotaro; Takenoshita, Seiichi] Fukushima Med Univ, Sch Med, Dept Surg 2, Fukushima, Japan. [Kurotani, Reiko] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Unoki, Motoko] RIKEN, Inst Phys & Chem Res, Lab Biomarker, Tokyo, Japan. [Nagashima, Makoto] Toho Univ, Sakura Med Ctr, Dept Surg, Chiba 2748510, Japan. [Yokota, Jun] Natl Canc Ctr, Res Inst, Div Biol, Tokyo 104, Japan. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov OI Shiga, Hideaki/0000-0001-7218-154X FU NIH; NCI; CCR FX Grant sponsors: NIH, NCI, CCR. NR 63 TC 24 Z9 24 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2009 VL 125 IS 6 BP 1306 EP 1315 DI 10.1002/ijc.24437 PG 10 WC Oncology SC Oncology GA 489AU UT WOS:000269392700008 PM 19437536 ER PT J AU Hernandez-Ramirez, RU Galvan-Portillo, MV Ward, MH Agudo, A Gonzalez, CA Onate-Ocana, LF Herrera-Goepfert, R Palma-Coca, O Lopez-Carrillo, L AF Hernandez-Ramirez, Raul U. Galvan-Portillo, Marcia V. Ward, Mary H. Agudo, Antonio Gonzalez, Carlos A. Onate-Ocana, Luis F. Herrera-Goepfert, Roberto Palma-Coca, Oswaldo Lopez-Carrillo, Lizbeth TI Dietary intake of polyphenols, nitrate and nitrite and gastric cancer risk in Mexico City SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE nitrate; nitrite; diet; polyphenols; gastric cancer ID N-NITROSO COMPOUNDS; FOOD FREQUENCY QUESTIONNAIRE; NUTRIENT INTAKE; PHYTOESTROGEN INTAKE; STOMACH-CANCER; LUNG-CANCER; VITAMIN-C; FLAVONOIDS; ESOPHAGEAL; WOMEN AB N-Nitroso compounds (NOC) are potent animal carcinogens and potential human carcinogens. The primary source of exposure for most individuals may be endogenous formation, a process that can be inhibited by dietary polyphenols. To estimate the risk of gastric cancer (GC) in relation to the individual and combined consumption of polyphenols and NOC precursors (nitrate and nitrite), a population-based case-control study was carried out in Mexico City from 2004 to 2005 including 257 histologically confirmed GC cases and 478 controls. Intake of polyphenols, nitrate and nitrite were estimated using a food frequency questionnaire. High intakes of cinnamic acids, secoisolariciresinol and coumestrol were associated with an similar to 50% reduction in GC risk. A high intake of total nitrite as well as nitrate and nitrite from animal sources doubled the GC risk. Odds ratios around 2-fold were observed among individuals with both low intake of cinnamic acids, secoisolariciresinol or coumestrol and high intake of animal-derived nitrate or nitrite, compared to high intake of the polyphenols and low animal nitrate or nitrite intake, respectively. Results were similar for both the intestinal and diffuse types of GC. Our results show, for the first time, a protective effect for GC because of higher intake of cinnamic acids, secoisolariciresinol and coumestrol, and suggest that these polyphenols reduce GC risk through inhibition of endogenous nitrosation. The main sources of these polyphenols were pears, mangos and beans for cinnamic acids; beans, carrots and squash for secoisolariciresinol and legumes for coumestrol. (C) 2009 UICC C1 [Hernandez-Ramirez, Raul U.; Galvan-Portillo, Marcia V.; Palma-Coca, Oswaldo; Lopez-Carrillo, Lizbeth] Natl Inst Publ Hlth, Ctr Populat Hlth Res, Cuernavaca 62508, Morelos, Mexico. [Ward, Mary H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Agudo, Antonio; Gonzalez, Carlos A.] Catalan Inst Oncol, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona, Spain. [Onate-Ocana, Luis F.] Natl Canc Inst, Gastr Neoplasia Clin, Dept Gastroenterol, Mexico City, DF, Mexico. [Herrera-Goepfert, Roberto] Natl Canc Inst, Dept Pathol, Mexico City, DF, Mexico. RP Lopez-Carrillo, L (reprint author), Natl Inst Publ Hlth, Ctr Populat Hlth Res, Av Univ 655, Cuernavaca 62508, Morelos, Mexico. EM lizbeth@insp.mx RI Gonzalez, Carlos A/O-4651-2014; OI Gonzalez, Carlos A/0000-0003-2822-9715; Agudo, Antonio/0000-0001-9900-5677 FU CONACYT [Salud-2002-001-7107] FX Grant sponsor: CONACYT: Grant number Salud-2002-001-7107. NR 50 TC 38 Z9 39 U1 0 U2 13 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2009 VL 125 IS 6 BP 1424 EP 1430 DI 10.1002/ijc.24454 PG 7 WC Oncology SC Oncology GA 489AU UT WOS:000269392700022 PM 19449378 ER PT J AU Wang, SS Carreon, JD Hanchard, B Chanock, S Hisada, M AF Wang, Sophia S. Carreon, J. Daniel Hanchard, Barrie Chanock, Stephen Hisada, Michie TI Common genetic variants and risk for non-Hodgkin lymphoma and adult T-cell lymphoma/leukemia in Jamaica SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE NHL; ATL; Jamaica; HTLV-I; SNP ID VIRUS TYPE-I; TYPE-1 CARRIERS; LEUKEMIA; LEUKEMIA/LYMPHOMA; POLYMORPHISM; SUSCEPTIBILITY; PROGRESSION AB We evaluated whether risk of non-Hodgkin lymphoma (NHL), particularly adult T-cell leukemia/lymphoma (ATL) related to human T-lymphotropic virus (HTLV) infection was associated with 63 single nucleotide polymorphisms (SNPs) from 38 candidate genes. The 395 NHL cases registered in Jamaica were matched by age, sex, calendar-year and HTLV serostatus to 309 controls from the same population. Interleukin 13 (IL13) Ex4+98A>G SNP (rs20541) was associated with decreased NHL risk (OR(AG/AA) = 0.62,95% CI = 0.44-0.87, p = 0.006), as was vascular cell adhesion molecule-1, VCAM1 Ex9+149G>A SNP (rs1041163) (OR(CT), = 0.77, 95% CI = 0.54-1.10, OR(CC)=0.35, 95% CI = 0.16-0.76, p-trend = 0.007). Both results were stronger in analyses restricted to ATL cases and HTLV-positive controls, suggesting a role for these genes in ATL etiology (IL13 OR(AG/AA) = 0.54, 95% CI = 0.36-0.84, p = 0.005; VCAM1 OR(CT) = 0.65, 95% CI = 0.42-1.01, OR(CT) = 0.20, 95% CI = 0.08-0.54, p-trend = 0.001). Confirmation of these results in Caribbean and other populations is needed. (C) 2009 UICC C1 [Wang, Sophia S.; Carreon, J. Daniel; Chanock, Stephen; Hisada, Michie] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. [Hanchard, Barrie] Univ W Indies, Dept Pathol, Kingston 7, Jamaica. RP Wang, SS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 7070, Rockville, MD 20852 USA. EM wangso@mail.nih.gov FU HTLV FX The authors gratefully acknowledge Drs. James J. Goedert and Hong-Chuan Li from the National Cancer Institute; Ms. Amali Amarasinghe, Violet Devairakkam, and Mr. Danny Ringer from the Research Triangle Institute; and Dr. Beverly Cranston and the HTLV program team at the University of the West Indies, Jamaica for making this study possible. They also thank Dr. Charles Rabkin of the NCI for his careful review of the manuscript. NR 16 TC 7 Z9 7 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2009 VL 125 IS 6 BP 1479 EP 1482 DI 10.1002/ijc.24489 PG 4 WC Oncology SC Oncology GA 489AU UT WOS:000269392700029 PM 19533685 ER PT J AU Zhang, QM Gao, F Peng, H Cheng, H Liu, YW Tang, JQ Thompson, J Wei, GH Zhang, JR Du, YG Yan, JH Gao, GF AF Zhang, Qiangmin Gao, Feng Peng, Hao Cheng, Hao Liu, Yiwei Tang, Jiaqi Thompson, John Wei, Guohua Zhang, Jingren Du, Yuguo Yan, Jinghua Gao, George F. TI Crystal Structures of Streptococcus suis Mannonate Dehydratase (ManD) and Its Complex with Substrate: Genetic and Biochemical Evidence for a Catalytic Mechanism SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ENZYMATIC-ACTIVITIES; ENOLASE SUPERFAMILY; ACTIVE-SITE; EVOLUTION; ISOMERASE AB Mannonate dehydratase (ManD) is found only in certain bacterial species, where it participates in the dissimilation of glucuronate. ManD catalyzes the dehydration of D-mannonate to yield 2-keto-3-deoxygluconate (2-KDG), the carbon and energy source for growth. Selective inactivation of ManD by drug targeting is of therapeutic interest in the treatment of human Streptococcus suis infections. Here, we report the overexpression, purification, functional characterization, and crystallographic structure of ManD from S. suis. Importantly, by Fourier transform mass spectrometry, we show that 2-KDG is formed when the chemically synthesized substrate (D-mannonate) is incubated with ManD. Inductively coupled plasma-mass spectrometry revealed the presence of Mn(2+) in the purified protein, and in the solution state catalytically active ManD exists as a homodimer of two 41-kDa subunits. The crystal structures of S. suis ManD in native form and in complex with its substrate and Mn(2+) ion have been solved at a resolution of 2.9 angstrom. The core structure of S. suis ManD is a TIM barrel similar to that of other members of the xylose isomerase-like superfamily. Structural analyses and comparative amino acid sequence alignments provide evidence for the importance of His311 and Tyr325 in ManD activity. The results of site-directed mutagenesis confirmed the functional role(s) of these residues in the dehydration reaction and a plausible mechanism for the ManD-catalyzed reaction is proposed. C1 [Zhang, Qiangmin; Gao, Feng; Peng, Hao; Cheng, Hao; Liu, Yiwei; Yan, Jinghua; Gao, George F.] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China. [Zhang, Qiangmin; Cheng, Hao; Gao, George F.] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. [Tang, Jiaqi] Res Inst Med Nanjing Command, Dept Epidemiol, Nanjing 210002, Peoples R China. [Thompson, John] Natl Inst Dent & Craniofacial Res, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Wei, Guohua; Du, Yuguo] Chinese Acad Sci, Ecoenvironm Sci Res Ctr, Beijing 100085, Peoples R China. [Zhang, Jingren] Albany Med Coll, Ctr Immunol & Microbial Dis, Albany, NY 12208 USA. [Gao, George F.] Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China. RP Gao, GF (reprint author), Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Datun Rd, Beijing 100101, Peoples R China. EM gaof@im.ac.cn FU Ministry of Science and Technology [2005CB523001, 2006BAD06A04, 2007DFC30240, 2006DFB32010]; National Natural Science Foundation of China [30770024, 30728014]; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD [20892]; NSFC [30525010] FX This work was supported by grants from the Ministry of Science and Technology (Project 973, grant 2005CB523001; National Key Technology R&D Program 2006BAD06A04; International Collaborative Projects 2007DFC30240 and 2006DFB32010) and the National Natural Science Foundation of China (grants 30770024 and 30728014). J.T. was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892. G. F. G is a Distinguished Young Investigator of the NSFC (grant no. 30525010). NR 26 TC 8 Z9 8 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP 15 PY 2009 VL 191 IS 18 BP 5832 EP 5837 DI 10.1128/JB.00599-09 PG 6 WC Microbiology SC Microbiology GA 488TI UT WOS:000269372600030 PM 19617363 ER PT J AU Jackson, SN Woods, AS AF Jackson, Shelley N. Woods, Amina S. TI Direct profiling of tissue lipids by MALDI-TOFMS SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Review DE Lipids; Direct profiling; Tissue; MALDI; MS/MS ID ASSISTED LASER-DESORPTION; FLIGHT MASS-SPECTROMETRY; ION MOBILITY-TOFMS; SITU STRUCTURAL-CHARACTERIZATION; INTERMEDIATE-PRESSURE MALDI; RAT-BRAIN TISSUE; PHOSPHOLIPID-COMPOSITION; LARGE BIOMOLECULES; SAMPLE PREPARATION; MATRIX DEPOSITION AB Advances in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) have allowed for the direct analysis of biological molecules from tissue. Although most of the early studies of direct tissue profiling by MALDI-TOFMS have focused on proteins and peptides, analysis of lipids has increased dramatically in recent years. This review gives an overview of the factors to consider when analyzing lipids directly from tissue and some recent examples of the use of MALDI-TOFMS for the direct profiling of lipids in tissue. Published by Elsevier B.V. C1 [Jackson, Shelley N.; Woods, Amina S.] NIDA IRP, NIH, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA IRP, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU National Institute on Drug Abuse; NIH; Office of National Drug Control Policy (ONDCP) FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors thank the Office of National Drug Control Policy (ONDCP)for instrumentation funding, without which this and other projects could not have been accomplished. NR 76 TC 47 Z9 48 U1 0 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD SEP 15 PY 2009 VL 877 IS 26 BP 2822 EP 2829 DI 10.1016/j.jchromb.2008.11.033 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 486UG UT WOS:000269224200015 PM 19095508 ER PT J AU Zhu, XY Marcus, WD Xu, WX Lee, HI Han, KP Egan, JO Yovandich, JL Rhode, PR Wong, HC AF Zhu, Xiaoyun Marcus, Warren D. Xu, Wenxin Lee, Hyung-il Han, Kaiping Egan, Jack O. Yovandich, Jason L. Rhode, Peter R. Wong, Hing C. TI Novel Human Interleukin-15 Agonists SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; TCR/IL-2 FUSION PROTEIN; ESTABLISHED TUMORS; CYTOKINE-RECEPTOR; CRYSTAL-STRUCTURE; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; SOLUBLE IL-15R-ALPHA; ANTITUMOR-ACTIVITY; IL-15 AB IL-15 is an immunostimulatory cytokine trans-presented with the IL-15 receptor a-chain to the shared IEL-2/EL-15R beta and common gamma-chains displayed on the surface of T cells and NK cells. To further define the functionally important regions of this cytokine, activity and binding studies were conducted on human IL-15 muteins generated by site-directed mutagenesis. Amino acid substitutions of the asparagine residue at position 72, which is located at the end of helix C, were found to provide both partial agonist and superagonist activity, with various nonconservative substitutions providing enhanced activity. Particularly, the N72D substitution provided a 4-5-fold increase in biological activity of the IL-15 mutein compared with the native molecule based on proliferation assays with cells bearing human IL-15R beta and common gamma-chains. The IL-15N72D mutein exhibited superagonist activity through improved binding ability to the human IL-15R beta-chain. However, the enhanced potency of IL-15N72D was not observed with cells expressing the mouse IL-15R alpha-IL-15R beta-gamma(c), complex, suggesting that this effect is specific to the human IL-15 receptor. The enhanced biological activity of IL-15N72D was associated with more intense phosphorylation of Jak1 and Stat5 and better anti-apoptotic activity compared with the wild-type IL-15. IL-15N72D superagonist activity was also preserved when linked to a single-chain TCR domain to generate a tumor-specific fusion protein. Thus, the human IL-15 superagonist muteins and fusions may create opportunities to construct more efficacious immunotherapeutic agents with clinical utility. The Journal of Immunology, 2009, 183: 3598-3607. C1 [Zhu, Xiaoyun; Marcus, Warren D.; Xu, Wenxin; Lee, Hyung-il; Han, Kaiping; Egan, Jack O.; Rhode, Peter R.; Wong, Hing C.] Altor Biosci Corp, Miramar, FL 33025 USA. [Yovandich, Jason L.] NCI, Biol Resources Branch, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Wong, HC (reprint author), Altor Biosci Corp, 2810 N Commerce Pkwy, Miramar, FL 33025 USA. EM hingwong@altorbioscience.com FU NCI NIH HHS [R43 CA139810, R43 CA139810-01] NR 43 TC 33 Z9 33 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2009 VL 183 IS 6 BP 3598 EP 3607 DI 10.4049/jimmunol.0901244 PG 10 WC Immunology SC Immunology GA 498XR UT WOS:000270179700010 PM 19710453 ER PT J AU Truong, P Heydari, S Garidou, L McGavern, DB AF Truong, Phi Heydari, Sara Garidou, Lucile McGavern, Dorian B. TI Persistent Viral Infection Elevates Central Nervous System MHC Class I through Chronic Production of Interferons SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; T-CELLS; MOLECULAR-MECHANISMS; ANTIGEN PRESENTATION; DENDRITIC CELLS; CARRIER MICE; LCM VIRUS; EXPRESSION; CLEARANCE; IMMUNOTHERAPY AB Persistence of even the stealthiest viruses can perturb immune function either to the benefit or detriment of the host. Lymphocytic choriomeningitis virus (LCMV) establishes lifelong, systemic persistence when introduced in utero or at birth. Despite a highly evolved host-pathogen relationship, LCMV cannot escape detection by the innate immune system, which results in chronic stimulation of the type 1 IFN pathway in adult carrier mice. In this study we demonstrate that IFN-beta is chronically up-regulated in peripheral lymphoid and nonlymphoid tissues (but not the CNS) of mice persistently infected from birth with LCMV and that dendritic cells (DCs) represent at least one source of IFN-beta. Interestingly, chronic stimulation of this innate pathway significantly elevated MHC class I expression in the CNS as well as the periphery. Elevated MHC I expression was dependent on IFN-alpha beta receptor but not MyD88-dependent signaling, as only genetic deletion of the former reduced MHC I to normal levels. An increase in circulating virus was also observed in the IFN-alpha beta receptor deficient carrier mice, signifying that type I IFN continually exerts anti-viral pressure during a LCMV carrier state. Finally, to determine whether heightened CNS MHC I could be therapeutically corrected, we purged LCMV carrier mice of their persistent infection using adoptive immunotherapy. This treatment significantly reduced CNS MHC I expression. Collectively, these data demonstrate that even a well adapted pathogen can chronically stimulate the innate immune system and consequently alter the expression of Ag presenting machinery in an immunologically specialized compartment like the CNS. The Journal of Immunology, 2009, 183: 3895-3905. C1 [Truong, Phi; Heydari, Sara; Garidou, Lucile; McGavern, Dorian B.] NINDS, NIH, Bethesda, MD 20892 USA. RP McGavern, DB (reprint author), NINDS, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mcgavernd@mail.nih.gov OI McGavern, Dorian/0000-0001-9568-545X FU National Institutes of Health Intramural program [AI070967-01, MH062261-06]; The Burroughs Wellcome Fund; The Ray Thomas Edwards Foundation; Association pour la recherche sur la sclerose en plaques FX This work was supported by National Institutes of Health Intramural program as well as Grants AI070967-01, MH062261-06, a grant from The Burroughs Wellcome Fund, and The Ray Thomas Edwards Foundation (all to D.B.M.). L.G. was supported by a fellowship from Association pour la recherche sur la sclerose en plaques. NR 43 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2009 VL 183 IS 6 BP 3895 EP 3905 DI 10.4049/jimmunol.0803085 PG 11 WC Immunology SC Immunology GA 498XR UT WOS:000270179700041 PM 19717517 ER PT J AU Chatterjee, S Lardinois, O Bonini, MG Bhattacharjee, S Stadler, K Corbett, J Deterding, LJ Tomer, KB Kadiiska, M Mason, RP AF Chatterjee, Saurabh Lardinois, Olivier Bonini, Marcelo G. Bhattacharjee, Suchandra Stadler, Krisztian Corbett, Jean Deterding, Leesa J. Tomer, Kenneth B. Kadiiska, Maria Mason, Ronald P. TI Site-Specific Carboxypeptidase B1 Tyrosine Nitration and Pathophysiological Implications following Its Physical Association with Nitric Oxide Synthase-3 in Experimental Sepsis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVATABLE FIBRINOLYSIS INHIBITOR; CARBONATE RADICAL-ANION; ENDOTHELIAL-CELLS; NITROGEN-DIOXIDE; SEPTIC SHOCK; PEROXYNITRITE; METALLOCARBOXYPEPTIDASES; INFLAMMATION; PROTEINS; SYSTEMS AB LPS-induced sepsis results in oxidative modification and inactivation of carboxypeptidase B1 (CPB1). In this study, immunoprecipitated CPB1 was probed for tyrosine nitration using monoclonal nitrotyrosine-specific Abs in a murine model of LPS-induced sepsis. Tyrosine nitration of CPB1 was significantly reduced in the presence of NO synthase (NOS) inhibitors and the xanthine oxidase (XO) inhibitor allopurinol and in NOS-3 knockout (KO) mice. CPB1 tyrosine nitration and loss of activity by the concerted action of NOS-3 and XO were also confirmed in vitro using both the NO donor 3-morpholinosydnonimine and peroxynitrite. Liquid chromatography/tandem mass spectrometry data indicated five sites of tyrosine nitration in vitro including Tyr(248), the tyrosine at the catalytic site. The site- and protein-specific nitration of CPB1 and the possible high nitration yield to inactivate it were elucidated by confocal microscopy. The studies indicated that CPB1 colocalized with NOS-3 in the cytosol of sinus-lining cells in the red pulp of the spleen. Further analysis of CPB1-immunoprecipitated samples indicated immunoreactivity to a monoclonal NOS-3 Ab, suggesting protein complex formation with CPB1. XO and NOS inhibitors and NOS-3 KO mice injected with LPS had decreased levels of C5a in spleens of septic mice, indicating peroxynitrite as a possible cause for CPBI functional alteration. Thus, CPB1 colocalization, coupling, and proximity to NOS-3 in the sinus-lining cells of spleen red pulp could explain the site-specific tyrosine nitration and inactivation of CPB1. These results open up new avenues for the investigation of several enzymes involved in inflammation and their site-specific oxidative modifications by protein-protein interactions as well as their role in sepsis. The Journal of Immunology, 2009, 183: 4055-4066. C1 [Chatterjee, Saurabh; Lardinois, Olivier; Bonini, Marcelo G.; Bhattacharjee, Suchandra; Stadler, Krisztian; Corbett, Jean; Kadiiska, Maria; Mason, Ronald P.] NIEHS, Free Rad Metab Grp, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Deterding, Leesa J.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Chatterjee, S (reprint author), NIEHS, Free Rad Metab Grp, Pharmacol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM chatterjees2@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01 ES050139-13] FX This work has been supported by the Intramural Research Program of the National Institutes of Health and by National Institute of Environmental Health Sciences Grant Z01 ES050139-13. NR 40 TC 16 Z9 16 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2009 VL 183 IS 6 BP 4055 EP 4066 DI 10.4049/jimmunol.0900593 PG 12 WC Immunology SC Immunology GA 498XR UT WOS:000270179700060 PM 19717511 ER PT J AU Pereyra, F Palmer, S Miura, T Block, BL Wiegand, A Rothchild, AC Baker, B Rosenberg, R Cutrell, E Seaman, MS Coffin, JM Walker, BD AF Pereyra, Florencia Palmer, Sarah Miura, Toshiyuki Block, Brian L. Wiegand, Ann Rothchild, Alissa C. Baker, Brett Rosenberg, Rachel Cutrell, Emily Seaman, Michael S. Coffin, John M. Walker, Bruce D. TI Persistent Low-Level Viremia in HIV-1 Elite Controllers and Relationship to Immunologic Parameters SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 15th Conference on Retroviruses and Opportunistic Infections CY FEB 03-06, 2008 CL Boston, MA ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; ANTIRETROVIRAL THERAPY; VIRAL REPLICATION; INFECTION; TYPE-1; ABSENCE; INDIVIDUALS; PLASMA; RNA AB Background. Human immunodeficiency virus type 1 (HIV-1) elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here, we quantify plasma HIV-1 RNA in elite controllers and correlate this with specific immunologic parameters. Methods. Plasma HIV-1 RNA levels were quantified in 90 elite controllers with use of a real time reverse-transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV-1-specific immune responses and longitudinal CD4(+) T cell counts were examined. Results. The median plasma HIV-1 RNA level was 2 copies/mL (interquartile range, 0.2-14 copies/mL). A longitudinal analysis of 31 elite controllers demonstrated 2-5-fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV-1-specific neutralizing antibodies and Western blot reactivity but not with CD8(+) T cell responses. Absolute CD4(+) T cell decrease was more common among individuals with detectable viremia (P = .04). Conclusions. Low-level viremia is present in the majority of elite controllers and is associated with higher HIV-1-specific antibody responses. Absolute CD4(+) T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time. C1 [Pereyra, Florencia; Miura, Toshiyuki; Block, Brian L.; Rothchild, Alissa C.; Baker, Brett; Rosenberg, Rachel; Cutrell, Emily; Walker, Bruce D.] Massachusetts Gen Hosp, Ragon Inst, MIT, Charlestown, MA 02129 USA. [Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Palmer, Sarah; Wiegand, Ann] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Miura, Toshiyuki; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Palmer, Sarah] Swedish Inst Infect Dis Control, Dept Virol, Solna, Sweden. [Palmer, Sarah] Karolinska Inst, Solna, Sweden. RP Pereyra, F (reprint author), Massachusetts Gen Hosp, Ragon Inst, MIT, 149 13th St, Charlestown, MA 02129 USA. EM fpereyra@partners.org OI Rothchild, Alissa/0000-0001-7484-1193 FU NIAID NIH HHS [AI30914, P30 AI060354, AI28568, R37 AI028568, R01 AI028568, R01 AI030914] NR 27 TC 108 Z9 110 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2009 VL 200 IS 6 BP 984 EP 990 DI 10.1086/605446 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 484HF UT WOS:000269034200019 PM 19656066 ER PT J AU Yang, J Johnson, C Shen, J AF Yang, Jehoon Johnson, Christopher Shen, Jun TI Detection of reduced GABA synthesis following inhibition of GABA transaminase using in vivo magnetic resonance signal of [C-13]GABA C1 SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE GABA; C-13; Magnetic resonance spectroscopy; Proton decoupling; Glucose metabolism ID GAMMA-AMINOBUTYRIC-ACID; RAT CEREBRAL-CORTEX; CORTICAL GABA; HUMAN BRAIN; C-13 MRS; GLUTAMATE-DECARBOXYLASE; SINGLE-SHOT; VINYL-GABA; 11.7 TESLA; TURNOVER AB Previous in vivo magnetic resonance spectroscopy (MRS) studies of gamma-aminobutyric acid (GABA) synthesis have relied on C-13 label incorporation into GABA C2 from [1-C-13] or [1,6-C-13(2)]glucose. In this study, the [C-13]GABA C1 signal at 182.3 ppm in the carboxylic/amide spectral region of localized in vivo C-13 spectra was detected. GABA-transaminase of rat brain was inhibited by administration of gabaculine after pre-labeling of GABA C1 and its metabolic precursors with exogenous [2,5-C-13(2)]glucose. A subsequent isotope chase experiment was performed by infusing unlabeled glucose, which revealed a markedly slow change in the labeling of GABA C1 accompanying the blockade of the GABA shunt. This slow labeling of GABA at elevated GABA concentration was attributed to the relatively small intercompartmental GABA-glutamine cycling flux that constitutes the main route of C-13 label loss during the isotope chase. Because this study showed that using low RF power broadband stochastic proton decoupling is feasible at very high field strength, it has important implications for the development of carboxylic/amide C-13 MRS methods to study brain metabolism and neurotransmission in human subjects at high magnetic fields. Published by Elsevier B.V. C1 [Yang, Jehoon; Johnson, Christopher; Shen, Jun] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Yang, Jehoon] Samsung Biomed Res Inst, Seoul, South Korea. RP Shen, J (reprint author), Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU NIH; NIMH FX The authors thank Dr. Steve Li for constructing the 13C{1H} RF coils/animal holder system, Dr. Steve Fox for performing the mass spectrometry analysis, Dr. Su Xu for preparing the figures, and Ms. loline Henter for editing the manuscript. This work was supported by the Intramural Program of NIH, NIMH. NR 47 TC 7 Z9 7 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 15 PY 2009 VL 182 IS 2 BP 236 EP 243 DI 10.1016/j.jneumeth.2009.06.015 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 491MA UT WOS:000269581800012 PM 19540876 ER PT J AU Ho, TM Pelkey, KA Pelletier, JG Huganir, RL Lacaille, JC McBain, CJ AF Ho, T. M. Pelkey, K. A. Pelletier, J. G. Huganir, R. L. Lacaille, J. -C. McBain, C. J. TI Burst firing induces postsynaptic LTD at developing mossy fibre-CA3 pyramid synapses SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM DEPRESSION; EXCITATORY SYNAPTIC-INTERACTIONS; RECEPTOR SUBUNIT COMPOSITION; RETINOTOPIC MAP REFINEMENT; GABA-MEDIATED INHIBITION; CA3 HIPPOCAMPAL-NEURONS; AMPA RECEPTORS; EXTRACELLULAR POTASSIUM; EPILEPTIFORM ACTIVITY; VISUAL-CORTEX AB Synaptic development is an activity-dependent process utilizing coordinated network activity to drive synaptogenesis and subsequent refinement of immature connections. Hippocampal CA3 pyramidal neurons (PYRs) exhibit intense burst firing (BF) early in development, concomitant with the period of mossy fibre (MF) development. However, whether developing MF-PYR synapses utilize PYR BF to promote MF synapse maturation remains unknown. Recently, we demonstrated that transient tonic depolarization of postsynaptic PYRs induces a persistent postsynaptic form of long-term depression (depolarization-induced long-term depression, DiLTD) at immature MF-PYR synapses. DiLTD induction is NMDAR independent but does require postsynaptic Ca=2D(eff)t, t -> infinity, where D(eff) is the effective diffusion coefficient, which is smaller than the particle diffusion coefficient in the tube with no partitions, D(0). The latter characterizes the short-time behavior of the mean squared displacement, =2D(0)t, t -> 0. Thus, the particle diffusion coefficient decreases from D(0) to D(eff) as time goes from zero to infinity. We derive analytical solutions for the Laplace transforms of the time-dependent diffusion coefficient and the mean squared displacement that show how these functions depend on the geometric parameters of the tube. To obtain these solutions we replace nonuniform partitions with apertures by effective partitions that are uniformly permeable for diffusing particles. Our choice of the partition permeability is based on the recent result for the corresponding effective trapping rate obtained by means of boundary homogenization. To establish the range of applicability of our approximate theory we compare its predictions with the results found in Brownian dynamics simulations. Comparison shows excellent agreement between the two at arbitrary value of the aperture radius when the tube radius does not exceed the interpartition distance. (C) 2009 American Institute of Physics. [doi: 10.1063/1.3224954] C1 [Makhnovskii, Yu A.] Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. [Berezhkovskii, A. M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zitserman, V. Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. RP Makhnovskii, YA (reprint author), Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Leninskii Pr 29, Moscow 117912, Russia. EM berezh@helix.nih.gov RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU NIH, Center for Information Technology FX A. M. B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 31 TC 34 Z9 34 U1 0 U2 4 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 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 14 PY 2009 VL 131 IS 10 AR 104705 DI 10.1063/1.3224954 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 494LP UT WOS:000269814800043 ER PT J AU Amaral, AFS Cantor, KP Silverman, DT Malats, N AF Amaral, Andre F. S. Cantor, Kenneth P. Silverman, Debra T. Malats, Nuria TI Selenium and risk of bladder cancer: A meta-analysis of epidemiological studies SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 46th Congress of the European-Societies-of-Toxicology CY SEP 13-16, 2009 CL Dreden, GERMANY SP European Soc Toxicol C1 [Amaral, Andre F. S.; Malats, Nuria] CNIO Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid, Spain. [Cantor, Kenneth P.; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Amaral, Andre/A-7662-2008 OI Amaral, Andre/0000-0002-0369-9449 NR 0 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 13 PY 2009 VL 189 BP S117 EP S117 DI 10.1016/j.toxlet.2009.06.406 PG 1 WC Toxicology SC Toxicology GA 493ZM UT WOS:000269778800342 ER PT J AU Goshorn, J AF Goshorn, Jeanne TI Information resources for disaster response from the US National Library of Medicine SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 46th Congress of the European-Societies-of-Toxicology CY SEP 13-16, 2009 CL Dreden, GERMANY SP European Soc Toxicol C1 [Goshorn, Jeanne] Natl Lib Med, NIH, HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 13 PY 2009 VL 189 BP S267 EP S267 DI 10.1016/j.toxlet.2009.06.831 PG 1 WC Toxicology SC Toxicology GA 493ZM UT WOS:000269778800791 ER PT J AU Zeng, XK Xiao, RP AF Zeng, Xiaokun Xiao, Rui-Ping TI Oxidative stress-induced cytotoxicity is mediated by beta arrestins SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 46th Congress of the European-Societies-of-Toxicology CY SEP 13-16, 2009 CL Dreden, GERMANY SP European Soc Toxicol C1 [Zeng, Xiaokun] Medstar Res Inst, Baltimore, MD USA. [Xiao, Rui-Ping] NIA, LCS, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 13 PY 2009 VL 189 BP S121 EP S121 DI 10.1016/j.toxlet.2009.06.418 PG 1 WC Toxicology SC Toxicology GA 493ZM UT WOS:000269778800354 ER PT J AU Allikmets, R Dean, M Hageman, GS Baird, PN Klaver, CC Bergen, AA Weber, BH AF Allikmets, Rando Dean, Michael Hageman, Gregory S. Baird, Paul N. Klaver, Caroline C. Bergen, Arthur A. Weber, Bernhard H. CA Int AMD Genetics Consortium TI The SERPING1 gene and age-related macular degeneration SO LANCET LA English DT Letter ID FACTOR-H POLYMORPHISM; RISK; VARIANT C1 [Allikmets, Rando] Columbia Univ, Dept Ophthalmol & Pathol, New York, NY 10032 USA. [Allikmets, Rando] Columbia Univ, Dept Cell Biol, New York, NY 10032 USA. [Dean, Michael] NCI, NIH, Frederick, MD 21701 USA. [Hageman, Gregory S.] Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. [Baird, Paul N.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Klaver, Caroline C.] Erasmus Univ, Rotterdam, Netherlands. [Bergen, Arthur A.] Royal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Amsterdam, Netherlands. [Weber, Bernhard H.] Univ Regensburg, Inst Human Genet, Regensburg, Germany. RP Allikmets, R (reprint author), Columbia Univ, Dept Ophthalmol & Pathol, New York, NY 10032 USA. EM rla22@columbia.edu RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Baird, Paul/0000-0002-1305-3502 FU NEI NIH HHS [R24 EY017404] NR 10 TC 17 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 12 PY 2009 VL 374 IS 9693 BP 875 EP 876 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 496BN UT WOS:000269943100016 PM 19748388 ER PT J AU Lagziel, A Overlack, N Bernstein, SL Morell, RJ Wolfrum, U Friedman, TB AF Lagziel, Ayala Overlack, Nora Bernstein, Steven L. Morell, Robert J. Wolfrum, Uwe Friedman, Thomas B. TI Expression of cadherin 23 isoforms is not conserved: implications for a mouse model of Usher syndrome type 1D SO MOLECULAR VISION LA English DT Article ID SENSORY HAIR-CELLS; TIP-LINK; INNER-EAR; PHOTORECEPTOR CELLS; NONSYNDROMIC DEAFNESS; RETINAL DEGENERATION; PROTEIN NETWORK; MUTANT ALLELES; WALTZER MICE; MUTATIONS AB Purpose: We compared cadherin 23 (Cdh23) mRNA and protein variants in the inner ear and retina of wild-type and mutant mice and primates to better understand the pleiotropic effects of Cdh23 mutations, and specifically to understand the absence of retinal degeneration in Cdh23 mutant mice. Methods: Semiquantitative real-time PCR was used to compare the level of expression of Cdh23 alternative transcripts in the inner ear and retina of wild-type and homozygous Cdh23(v-6J) (waltzer) mice. Antibodies generated against CDH23 isoforms were used in immunohistochemistry, immunohistology, electron microscopy, and western blot analyses of mouse and primate inner ear and retina to study the distribution of these isoforms in various cellular compartments. Results: Cdh23 mRNA alternative splice variants were temporally and spatially regulated in the inner ear and retina. In the mature mouse retina, CDH23 isoforms were broadly expressed in various cellular compartments of the photoreceptor layer. The wild-type CDH23_V3 protein isoform, which has PDZ binding motifs but neither extracellular domains nor a transmembrane domain, localized exclusively to the outer plexiform layer of the retina containing photoreceptor cell synapses and to the synaptic region of auditory and vestibular hair cells. The longest CDH23 protein isoform, CDH23_V1, appeared by western blotting to be the only one affected by the Cdh23(v-6J) mutation; it was expressed in the wild-type mouse inner ear, but not in the mouse retina. However, CDH23_V1 was detected in western blot analyses of monkey and human retinas. Conclusions: The time-and tissue-dependent expression patterns that we have shown for Cdh23 alternative transcripts suggest developmental roles and tissue-specific functions for the various transcripts. Many of these isoforms continue to be expressed in waltzer mice. The longest CDH23 isoform (CDH23_V1), however, is not expressed in mutant mice and is necessary for normal inner ear function. The longest isoform is expressed in the retinas of primates, but not detected in the mouse retina. This species difference suggests that the mouse may not be a suitable model for studying the retinitis pigmentosa phenotype of human Usher syndrome type 1D. C1 [Lagziel, Ayala; Morell, Robert J.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Overlack, Nora; Wolfrum, Uwe] Johannes Gutenberg Univ Mainz, Inst Zool, Dept Cell & Matrix Biol, D-6500 Mainz, Germany. [Bernstein, Steven L.] Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, 5 Res Court,2A-19, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov OI Morell, Robert/0000-0003-1537-7356 FU National Institute on Deafness and Other Communication Disorders [1 Z01 DC000039-12 LMG]; FAUN-foundation, German Research Council [GRK 1044/2] FX We thank Ronna Hertzano and Doris Wu for their critical reading of the manuscript. We also thank Zubair Ahmed for generating the Cdh23_v3 expression construct and Elisabeth Sehn for skilful technical assistance in electron microscopy. This work was supported by intramural research funds from the National Institute on Deafness and Other Communication Disorders to T. B. F. (1 Z01 DC000039-12 LMG) and the FAUN-foundation, German Research Council to U. W. (DFG, GRK 1044/2). NR 62 TC 14 Z9 14 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 12 PY 2009 VL 15 IS 196-99 BP 1843 EP 1857 PG 15 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 517MF UT WOS:000271617800001 PM 19756182 ER PT J AU Smith, JC Abdala, APL Rybak, IA Paton, JFR AF Smith, Jeffrey C. Abdala, Ana P. L. Rybak, Ilya A. Paton, Julian F. R. TI Structural and functional architecture of respiratory networks in the mammalian brainstem SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Royal-Society Discussion Meeting on Brainstem - Neural Networks Vital for Life CY 2008 CL Royal Soc, London, ENGLAND HO Royal Soc DE breathing; brainstem; respiratory rhythm and pattern generation; pons; pre-Botzinger complex; ventral respiratory column ID PRE-BOTZINGER COMPLEX; DECREMENTING EXPIRATORY NEURONS; PERSISTENT SODIUM CURRENT; INSPIRATORY OFF-SWITCH; RHYTHM GENERATION; IN-VITRO; PACEMAKER NEURONS; PATTERN GENERATOR; PREBOTZINGER COMPLEX; MEMBRANE-PROPERTIES AB Neural circuits controlling breathing in mammals are organized within serially arrayed and functionally interacting brainstem compartments extending from the pons to the lower medulla. The core circuit components that constitute the neural machinery for generating respiratory rhythm and shaping inspiratory and expiratory motor patterns are distributed among three adjacent structural compartments in the ventrolateral medulla: the Botzinger complex (BotC), pre-Botzinger complex (pre-BotC) and rostral ventral respiratory group (rVRG). The respiratory rhythm and inspiratory-expiratory patterns emerge from dynamic interactions between: (i) excitatory neuron populations in the pre-BotC and rVRG active during inspiration that form inspiratory motor output; (ii) inhibitory neuron populations in the pre-BotC that provide inspiratory inhibition within the network; and (iii) inhibitory populations in the BotC active during expiration that generate expiratory inhibition. Network interactions within these compartments along with intrinsic rhythmogenic properties of pre-BotC neurons form a hierarchy of multiple oscillatory mechanisms. The functional expression of these mechanisms is controlled by multiple drives from more rostral brainstem components, including the retrotrapezoid nucleus and pons, which regulate the dynamic behaviour of the core circuitry. The emerging view is that the brainstem respiratory network has rhythmogenic capabilities at multiple hierarchical levels, which allows flexible, state-dependent expression of different rhythmogenic mechanisms under different physiological and metabolic conditions and enables a wide repertoire of respiratory behaviours. C1 [Smith, Jeffrey C.] NINDS, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Abdala, Ana P. L.; Paton, Julian F. R.] Univ Bristol, Sch Med Sci, Dept Physiol & Pharmacol, Bristol Heart Inst, Bristol BS8 1TD, Avon, England. [Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. RP Smith, JC (reprint author), NINDS, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3C-917,35 Convent Dr, Bethesda, MD 20892 USA. EM jsmith@helix.nih.gov RI Abdala, Ana Paula/G-9104-2014; OI Abdala, Ana Paula/0000-0001-6051-2591; Paton, Julian/0000-0001-7410-2913 FU Intramural NIH HHS; NINDS NIH HHS [R01 NS057815] NR 75 TC 120 Z9 124 U1 1 U2 7 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD SEP 12 PY 2009 VL 364 IS 1529 BP 2577 EP 2587 DI 10.1098/rstb.2009.0081 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 478DW UT WOS:000268569000013 PM 19651658 ER PT J AU Cui, YX Freedman, JH AF Cui, Yuxia Freedman, Jonathan H. TI Cadmium Induces Retinoic Acid Signaling by Regulating Retinoic Acid Metabolic Gene Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAROTENE 15,15'-DIOXYGENASE ACTIVITY; INDUCED LIMB DEFECTS; BETA-CAROTENE; CAENORHABDITIS-ELEGANS; 15,15'-MONOOXYGENASE GENE; MATERNAL EXPOSURE; SPECIAL EMPHASIS; MOUSE EMBRYOS; PROVITAMIN-A; WISTAR RAT AB The transition metal cadmium is an environmental teratogen. In addition, cadmium and retinoic acid can act synergistically to induce forelimb malformations. The molecular mechanism underlying the teratogenicity of cadmium and the synergistic effect with retinoic acid has not been addressed. An evolutionarily conserved gene, beta,beta-carotene 15,15'-monooxygenase (BCMO), which is involved in retinoic acid biosynthesis, was studied in both Caenorhabditis elegans and murine Hepa 1-6 cells. In C. elegans, bcmo-1 was expressed in the intestine and was cadmium inducible. Similarly, in Hepa 1-6 cells, Bcmo1 was induced by cadmium. Retinoic acid-mediated signaling increased after 24-h exposures to 5 and 10 mu M cadmium in Hepa 1-6 cells. Examination of gene expression demonstrated that the induction of retinoic acid signaling by cadmium may be mediated by overexpression of Bcmo1. Furthermore, cadmium inhibited the expression of Cyp26a1 and Cyp26b1, which are involved in retinoic acid degradation. These results indicate that cadmium-induced teratogenicity may be due to the ability of the metal to increase the levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes. C1 [Cui, Yuxia; Freedman, Jonathan H.] NIEHS, Comparat Genom Grp, Mol Toxicol Lab, Natl Inst Hlth, Durham, NC 27709 USA. [Cui, Yuxia] Duke Univ, Nicholas Sch Environm & Earth Sci, Durham, NC 27708 USA. RP Freedman, JH (reprint author), NIEHS, Mol Toxicol Lab, NIH, Mail Drop E1-05,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM freedma1@niehs.nih.gov FU National Institutes of Health [U19ES011375, R01ES009949]; NIH; NIEHS [Z01ES102045] FX This work was supported, in whole or in part, by National Institutes of Health Grant U19ES011375 and R01ES009949 (to J. H. F.) and by the Intramural Research Program of NIH and NIEHS (Grant Z01ES102045). NR 63 TC 9 Z9 10 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 11 PY 2009 VL 284 IS 37 BP 24925 EP 24932 DI 10.1074/jbc.M109.026609 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 493JZ UT WOS:000269734000026 PM 19556237 ER PT J AU Shewmaker, F McGlinchey, RP Thurber, KR McPhie, P Dyda, F Tycko, R Wickner, RB AF Shewmaker, Frank McGlinchey, Ryan P. Thurber, Kent R. McPhie, Peter Dyda, Fred Tycko, Robert Wickner, Reed B. TI The Functional Curli Amyloid Is Not Based on In-register Parallel beta-Sheet Structure SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOLID-STATE NMR; HET-S PRION; NUCLEAR-MAGNETIC-RESONANCE; THIN AGGREGATIVE FIMBRIAE; ESCHERICHIA-COLI; EXPERIMENTAL CONSTRAINTS; SALMONELLA-ENTERITIDIS; SECONDARY STRUCTURE; FIBRILS; PROTEIN AB The extracellular curli proteins of Enterobacteriaceae form fibrous structures that are involved in biofilm formation and adhesion to host cells. These curli fibrils are considered a functional amyloid because they are not a consequence of misfolding, but they have many of the properties of protein amyloid. We confirm that fibrils formed by CsgA and CsgB, the primary curli proteins of Escherichia coli, possess many of the hallmarks typical of amyloid. Moreover we demonstrate that curli fibrils possess the cross-beta structure that distinguishes protein amyloid. However, solid state NMR experiments indicate that curli structure is not based on an in-register parallel beta-sheet architecture, which is common to many human disease-associated amyloids and the yeast prion amyloids. Solid state NMR and electron microscopy data are consistent with a beta-helix-like structure but are not sufficient to establish such a structure definitively. C1 [Wickner, Reed B.] NIDDK, Lab Biochem & Genet, Natl Inst Hlth, Bethesda, MD 20892 USA. [Thurber, Kent R.; Tycko, Robert] NIDDK, Labs Chem Phys, Natl Inst Hlth, Bethesda, MD 20892 USA. [Dyda, Fred] NIDDK, Labs Mol Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, Natl Inst Hlth, Bldg 8,Rm 207,8 Ctr Dr, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU NIDDK, National Institutes of Health FX This work was supported by the Intramural Program of the NIDDK, National Institutes of Health. NR 53 TC 53 Z9 54 U1 1 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 11 PY 2009 VL 284 IS 37 BP 25065 EP 25076 DI 10.1074/jbc.M109.007054 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 493JZ UT WOS:000269734000041 PM 19574225 ER PT J AU Lal, A Navarro, F Maher, CA Maliszewski, LE Yan, N O'Day, E Chowdhury, D Dykxhoorn, DM Tsai, P Hofmann, O Becker, KG Gorospe, M Hide, W Lieberman, J AF Lal, Ashish Navarro, Francisco Maher, Christopher A. Maliszewski, Laura E. Yan, Nan O'Day, Elizabeth Chowdhury, Dipanjan Dykxhoorn, Derek M. Tsai, Perry Hofmann, Oliver Becker, Kevin G. Gorospe, Myriam Hide, Winston Lieberman, Judy TI miR-24 Inhibits Cell Proliferation by Targeting E2F2, MYC, and Other Cell-Cycle Genes via Binding to "Seedless" 3 ' UTR MicroRNA Recognition Elements SO MOLECULAR CELL LA English DT Article ID C-MYC; PROTEIN-SYNTHESIS; EXPRESSION; IDENTIFICATION; MIRNA; DIFFERENTIATION; APOPTOSIS; ELEGANS; GROWTH; TRANSLATION AB miR-24, upregulated during terminal differentiation of multiple lineages, inhibits cell-cycle progression. Antagonizing miR-24 restores postmitotic cell proliferation and enhances fibroblast proliferation, whereas overexpressing miR-24 increases the G1 compartment. The 248 mRNAs downregulated upon miR-24 overexpression are highly enriched for DNA repair and cell-cycle regulatory genes that form a direct interaction network with prominent nodes at genes that enhance (MYC, E2F2, CCNB1, and CDC2) or inhibit (p27Kip1 and VHL) cell-cycle progression. miR-24 directly regulates MYC and E2F2 and some genes that they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 overexpression, is rescued by miR-24-insensitive E2F2. Therefore, E2F2 is a critical miR-24 target. The E2F2 3'UTR lacks a predicted miR-24 recognition element. In fact, miR-24 regulates expression of E2F2, MYC, AURKB, CCNA2, CDC2, CDK4, and FEN1 by recognizing seedless but highly complementary sequences. C1 [Lal, Ashish; Navarro, Francisco; Maliszewski, Laura E.; Yan, Nan; O'Day, Elizabeth; Chowdhury, Dipanjan; Dykxhoorn, Derek M.; Tsai, Perry; Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med,Immune Dis Inst, Boston, MA 02115 USA. [Lal, Ashish; Navarro, Francisco; Maliszewski, Laura E.; Yan, Nan; O'Day, Elizabeth; Chowdhury, Dipanjan; Dykxhoorn, Derek M.; Tsai, Perry; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Maher, Christopher A.] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA. [Becker, Kevin G.; Gorospe, Myriam] NIA, Res Resources Branch, IRP, NIH, Baltimore, MD 21224 USA. [Becker, Kevin G.; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. [Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hide, Winston] Univ Western Cape, S African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. [Dykxhoorn, Derek M.] Univ Miami, Miller Sch Med, John T Macdonald Fdn, Dept Human Genet, Miami, FL 33136 USA. [Dykxhoorn, Derek M.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. RP Lal, A (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med,Immune Dis Inst, Boston, MA 02115 USA. EM alal@idi.harvard.edu; lieberman@idi.harvard.edu RI Hide, Winston Hide/C-7217-2009; Hofmann, Oliver/F-1800-2013; Lieberman, Judy/A-2717-2015; Dykxhoorn, Derek/D-1357-2015; OI Hide, Winston Hide/0000-0002-8621-3271; Hofmann, Oliver/0000-0002-7738-1513; Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health (NIH) [A1070302]; GSK-IDI Alliance; the NIA-IRP; NIH; the Harry Oppenheimer Memorial Trust; GSK-IDI Alliance fellowship; Harvard Center for AIDS Research FX This work was supported, in part, by National Institutes of Health (NIH) A1070302 and a GSK-IDI Alliance grant (J.L.); the NIA-IRP, NIH (K.G.B., M.G.); the Harry Oppenheimer Memorial Trust (W.H.); a GSK-IDI Alliance fellowship (F.N.); and the Harvard Center for AIDS Research (N.Y.). We thank N. Dyson (Harvard Medical School) for the HA-E2F2 expression plasmid, Ray McGovern for programming support, and Lieberman laboratory members for useful discussions. NR 41 TC 327 Z9 343 U1 2 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 11 PY 2009 VL 35 IS 5 BP 610 EP 625 DI 10.1016/j.molcel.2009.08.020 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 495QP UT WOS:000269909400010 PM 19748357 ER PT J AU Rochman, M Postnikov, Y Correll, S Malicet, C Wincovitch, S Karpova, TS McNally, JG Wu, XL Bubunenko, NA Grigoryev, S Bustin, M AF Rochman, Mark Postnikov, Yuri Correll, Sarah Malicet, Cedric Wincovitch, Stephen Karpova, Tatiana S. McNally, James G. Wu, Xiaolin Bubunenko, Nina A. Grigoryev, Sergei Bustin, Michael TI The Interaction of NSBP1/HMGN5 with Nucleosomes in Euchromatin Counteracts Linker Histone-Mediated Chromatin Compaction and Modulates Transcription SO MOLECULAR CELL LA English DT Article ID CHROMOSOMAL-PROTEINS; GENE-REGULATION; IN-VIVO; BINDING-PROTEIN; H1; ACTIVATION; EXPRESSION; FIBER; DIFFERENTIATION; HETEROCHROMATIN AB Structural changes in specific chromatin domains are essential to the orderly progression of numerous nuclear processes, including transcription. We report that the nuclear protein NSBP1 (HMGN5), a recently discovered member of the HMGN nucleosome-binding protein family, is specifically targeted by its C-terminal domain to nucleosomes in euchromatin. We find that the interaction of NSBP1 with nucleosomes alters the compaction of cellular chromatin and that in living cells, NSBP1 interacts with linker histones. We demonstrate that the negatively charged C-terminal domain of NSBP1 interacts with the positively charged C-terminal domain of H5 and that NSBP1 counteracts the linker histone-mediated compaction of a nucleosomal array. Dysregulation of the cellular levels of NSBP1 alters the transcription level of numerous genes. We suggest that mouse NSBP1 is an architectural protein that binds preferentially to euchromatin and modulates the fidelity of the cellular transcription profile by counteracting the chromatin-condensing activity of linker histories. C1 [Rochman, Mark; Postnikov, Yuri; Malicet, Cedric; Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Wincovitch, Stephen] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Karpova, Tatiana S.; McNally, James G.] NCI, CCR Core Fluorescence Imaging Facil, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Correll, Sarah; Grigoryev, Sergei] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. [Wu, Xiaolin; Bubunenko, Nina A.] NCI, Lab Mol Technol, SAIC Frederick, Frederick, MD 21702 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Center for Cancer Research; NCI; NIH [N01-CO-12400]; NSF [MCB-0615536] FX We thank Valarie Barr for technical assistance with microscopy. We thank Doctor F. Catez for the initial observation that HMGN5 does not localize to heterochromatin. This project is supported by the Center for Cancer Research, intramural program of the NCI, NIH, by contract number N01-CO-12400 granted by NCI, NIH and by NSF grant MCB-0615536 to S.A.G. NR 50 TC 53 Z9 55 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 11 PY 2009 VL 35 IS 5 BP 642 EP 656 DI 10.1016/j.molcel.2009.07.002 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 495QP UT WOS:000269909400012 PM 19748358 ER PT J AU Shen, X Do, H Li, YJ Chung, WH Tomasz, M de Winter, JP Xia, B Elledge, SJ Wang, WD Li, L AF Shen, Xi Do, Huong Li, Yongjiang Chung, Woo-Hyun Tomasz, Maria de Winter, Johan P. Xia, Bing Elledge, Stephen J. Wang, Weidong Li, Lei TI Recruitment of Fanconi Anemia and Breast Cancer Proteins to DNA Damage Sites Is Differentially Governed by Replication SO MOLECULAR CELL LA English DT Article ID EPSTEIN-BARR-VIRUS; NUCLEOTIDE EXCISION-REPAIR; INTERSTRAND CROSS-LINKS; ORIGIN-BINDING-PROTEIN; HOMOLOGOUS RECOMBINATION; CORE COMPLEX; FANCD2; BRCA2; SUSCEPTIBILITY; PATHWAY AB Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear. We developed a chromatin-IP-based strategy termed eChIP and detected association of multiple FA proteins with DNA crosslinks in vivo. Interdependence analyses revealed that crosslink-specific enrichment of various FA proteins is controlled by distinct mechanisms. BRCA-related FA proteins (BRCA2, FANCJ/BACH1, and FANCN/PALB2), but not FA core and I/D2 complexes, require replication for their crosslink association. FANCD2, but not FANCJ and FANCN, requires the FA core complex for its recruitment. FA core complex requires nucleotide excision repair proteins XPA and XPC for its association. Consistent with the distinct recruitment mechanism, recombination-independent crosslink repair was inversely affected in cells deficient of FANC-core versus BRCA-related FA proteins. Thus, FA proteins participate in distinct DNA damage response mechanisms governed by DNA replication status. C1 [Shen, Xi; Do, Huong; Chung, Woo-Hyun; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Li, Yongjiang; Wang, Weidong] NIA, Genet Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Tomasz, Maria] CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA. [de Winter, Johan P.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. [Xia, Bing] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Radiat Oncol, Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Elledge, Stephen J.] Harvard Univ, Sch Med, Harvard Partners Ctr Genet & Genom, Howard Hughes Med Inst,Dept Genet, Boston, MA 02115 USA. RP Li, L (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM leili@mdanderson.org FU Intramural Research Program of the National Institute on Aging [AG000688-07]; National Institute of Health [CA97175, GM44664]; Fanconi Anemia Research Foundation FX The authors wish to thank Drs. John L Yates, Lee Zou, and Alan D'Andrea for helpful discussions and reagents. Dr. W. Zhou provided technical help in realtime PCR. J.F. Culajay and J. Liu (Core C PO1-CA97175) assisted in the largescale preparation of crosslinked DNA substrates. This work is supported, in part, by the Intramural Research Program of the National Institute on Aging (AG000688-07), National Institute of Health, and the Fanconi Anemia Research Foundation. This work was also supported by grants from the NIH (CA97175, Project 3 to L.L.; GM44664 to S.J.E.). S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 28 TC 60 Z9 60 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 11 PY 2009 VL 35 IS 5 BP 716 EP 723 DI 10.1016/j.molcel.2009.06.034 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 495QP UT WOS:000269909400018 PM 19748364 ER PT J AU Sotiriou, S Gibney, G Baxevanis, AD Nussbaum, RL AF Sotiriou, Sotiria Gibney, Gretchen Baxevanis, Andreas D. Nussbaum, Robert L. TI A single nucleotide polymorphism in the 3 ' UTR of the SNCA gene encoding alpha-synuclein is a new potential susceptibility locus for Parkinson disease SO NEUROSCIENCE LETTERS LA English DT Article DE Parkinson disease; alpha-Synuclein; SNCA 3 ' UTR; SNP; rs17016074 ID MESSENGER-RNA; DUPLICATION; DOWNSTREAM; SEQUENCE; ELEMENTS; TRIPLICATION; EXPRESSION; NEURONS; FAMILY AB In Parkinson disease, the second most common neurodegenerative disorder in humans, increased alpha-synuclein (SNCA) levels are pathogenic, as evidenced by gene copy number mutations and increased alpha-synuclein levels detected in some familial and sporadic PD cases, respectively. Gene expression can be regulated at the post-transcriptional level by elements in the 3' untranslated region (3'UTR) of mRNAs. The goal of this study was to determine whether the 3'UTR of human SNCA can affect gene expression. Comparative sequence analysis revealed very high conservation across the entire 3'UTR of human SNCA over millions of years, suggesting the presence of multiple functionally important domains. EST and RT-PCR analyses showed that four different polyadenylation events occur in the 3'UTR of human SNCA. Finally, using luciferase assays, we examined the effect of the minor allele of five naturally occurring single nucleotide polymorphisms (SNPs) in the 3'UTR of SNCA on gene expression. The minor allele of SNP rs17016074 increased luciferase expression by 32% in a transient transfection assay in SHSY5Y neuroblastoma cells. Understanding the role of the 3'UTR of human SNCA and identifying functionally important naturally occurring SNPs using reporter assays can complement disease association studies in humans, uncovering potential susceptibility or protective polymorphisms in Parkinson disease. Our findings demonstrate that the 3'UTR of human SNCA, as a whole, and rs17016074, in particular, are loci of potential clinical importance for Parkinson disease. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Sotiriou, Sotiria; Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Gibney, Gretchen; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Nussbaum, RL (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM Nussbaumr@medicine.ucsf.edu FU National Human Genome Research Institute; National Institutes of Health; Department of Medicine; UCSF School of Medicine FX We would like to thank Yien-Ming Kuo for help throughout this project and critical review of this manuscript and Lowell Umayam, Gabriel Renaud, and Anh-Dao Nguyen for bioinformatics support. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health and by the Department of Medicine, UCSF School of Medicine. NR 27 TC 30 Z9 31 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 11 PY 2009 VL 461 IS 2 BP 196 EP 201 DI 10.1016/j.neulet.2009.06.034 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 476HH UT WOS:000268429400029 PM 19540308 ER PT J AU Diaz-Ruiz, O Zapata, A Shan, LF Zhang, YJ Tomac, AC Malik, N de la Cruz, F Backman, CM AF Diaz-Ruiz, Oscar Zapata, Agustin Shan, Lufei Zhang, YaJun Tomac, Andreas C. Malik, Nasir de la Cruz, Fidel Backman, Cristina M. TI Selective Deletion of PTEN in Dopamine Neurons Leads to Trophic Effects and Adaptation of Striatal Medium Spiny Projecting Neurons SO PLOS ONE LA English DT Article AB The widespread distribution of the tumor suppressor PTEN in the nervous system suggests a role in a broad range of brain functions. PTEN negatively regulates the signaling pathways initiated by protein kinase B (Akt) thereby regulating signals for growth, proliferation and cell survival. Pten deletion in the mouse brain has revealed its role in controlling cell size and number. In this study, we used Cre-loxP technology to specifically inactivate Pten in dopamine (DA) neurons (Pten KO mice). The resulting mutant mice showed neuronal hypertrophy, and an increased number of dopaminergic neurons and fibers in the ventral mesencephalon. Interestingly, quantitative microdialysis studies in Pten KO mice revealed no alterations in basal DA extracellular levels or evoked DA release in the dorsal striatum, despite a significant increase in total DA tissue levels. Striatal dopamine receptor D1 (DRD1) and prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while dopamine receptor D2 (DRD2) and preproenkephalin (PPE) mRNA levels remained unchanged. In addition, PTEN inactivation protected DA neurons and significantly enhanced DA-dependent behavioral functions in KO mice after a progressive 6OHDA lesion. These results provide further evidence about the role of PTEN in the brain and suggest that manipulation of the PTEN/Akt signaling pathway during development may alter the basal state of dopaminergic neurotransmission and could provide a therapeutic strategy for the treatment of Parkinson's disease, and other neurodegenerative disorders. RP Diaz-Ruiz, O (reprint author), NIDA, Cellular Neurobiol Branch, Natl Inst Hlth, Baltimore, MD USA. EM cbackman@mail.nih.gov RI Diaz-Ruiz, Oscar/F-3162-2010; backman, cristina/C-1276-2013 FU Intramural NIH HHS NR 46 TC 22 Z9 22 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2009 VL 4 IS 9 AR e7027 DI 10.1371/journal.pone.0007027 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492XS UT WOS:000269696600019 PM 19750226 ER PT J AU Johnson, KE Sherman, ME Ssempiija, V Tobian, AAR Zenilman, JM Duggan, MA Kigozi, G Serwadda, D Wawer, MJ Quinn, TC Rabkin, CS Gray, RH AF Johnson, Kristine E. Sherman, Mark E. Ssempiija, Victor Tobian, Aaron A. R. Zenilman, Jonathan M. Duggan, Maire A. Kigozi, Godfrey Serwadda, David Wawer, Maria J. Quinn, Thomas C. Rabkin, Charles S. Gray, Ronald H. TI Foreskin inflammation is associated with HIV and herpes simplex virus type-2 infections in Rakai, Uganda SO AIDS LA English DT Article; Proceedings Paper CT 3rd Joint Conference of the British-Association-of-Sexual-Health-and-HIV/American-Sexually-Transmitt ed-Diseases-Association (BASHH-ASTDA) CY MAY 07-10, 2008 CL Brooklyn, NY SP British Assoc Sexual Hlth & HIV, Amer Sexually Transmitted Dis Assoc DE circumcision; foreskin; HIV; herpes simplex virus type 2; inflammation; Uganda ID SEXUALLY-TRANSMITTED-DISEASES; GENITAL ULCER DISEASE; MALE CIRCUMCISION; CERVICAL INFLAMMATION; LANGERHANS CELLS; TARGET-CELLS; MEN; WOMEN; RISK; TRANSMISSION AB Design: We assessed foreskin inflammation associated with HIV and herpes simplex virus type 2 (HSV-2) in circumcised men. Methods: Foreskin tissues were assessed in 97 HIV-infected and 135 HIV-uninfected men enrolled in randomized trials of circumcision in Rakai, Uganda. Inflammation was quantified using an ordinal score evaluating extent, intensity, and cellular composition of infiltrates in the epithelium and stroma. Prevalence rate ratios of inflammation were estimated by multivariate Poisson regression. Results: Foreskin inflammation was primarily focal. Epithelial inflammation was present in 4.2% of men with neither HIV nor HSV-2 infection; 7.8% of men with only HSV-2; 19.0% with HIV alone (P=0.04); and 31.6% in HIV/HSV-2 coinfected men [prevalence rate ratio (PRR) 7.5, 95% confidence interval (CI) 2.3-23.8, P<0.001]. Stromal inflammation was present in 14.1% of HIV/HSV-2 uninfected men, compared with 29.7% in men with HSV-2 alone (P=0.03), 33.3% in men with HIV alone (P=0.04), and 61.01% in men with HIV/HSV-2 coinfection (PRR 4.3, 95% CI 2.3-7.9, P<0.001). In HIV-infected men, epithelial inflammation was associated with higher HIV viral load. Epithelial inflammation was more frequent among men reporting recent genital ulceration. Both epithelial and stromal inflammation were more common among men with smegma on physical examination. Conclusion: Foreskin inflammation is increased with HIV and HSV-2 infections, higher HIV viral load and presence of smegma. Foreskin inflammation may have implications for HIV transmission and acquisition in uncircumcised men. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Johnson, Kristine E.; Zenilman, Jonathan M.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sherman, Mark E.; Rabkin, Charles S.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Ssempiija, Victor; Kigozi, Godfrey; Serwadda, David] Rakai Hlth Sci Program, Kalisizo, Uganda. [Ssempiija, Victor; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Duggan, Maire A.] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB T2N 1N4, Canada. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Johnson, KE (reprint author), Johns Hopkins Bayview Med Ctr, B-3N,4940 Eastern Ave, Baltimore, MD 21224 USA. EM kjohns87@jhmi.edu FU FIC NIH HHS [D43 TW001508, T22 TW000015]; Intramural NIH HHS [Z01 AI000361-25]; NIAID NIH HHS [U01 AI051171, U1AI51171] NR 41 TC 29 Z9 29 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP 10 PY 2009 VL 23 IS 14 BP 1807 EP 1815 DI 10.1097/QAD.0b013e32832efdf1 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 495QJ UT WOS:000269908800003 PM 19584700 ER PT J AU Gray, RR Tatem, AJ Lamers, S Hou, W Laeyendecker, O Serwadda, D Sewankambo, N Gray, RH Wawer, M Quinn, TC Goodenow, MM Salemi, M AF Gray, Rebecca R. Tatem, Andrew J. Lamers, Susanna Hou, Wei Laeyendecker, Oliver Serwadda, David Sewankambo, Nelson Gray, Ronald H. Wawer, Maria Quinn, Thomas C. Goodenow, Maureen M. Salemi, Marco TI Spatial phylodynamics of HIV-1 epidemic emergence in east Africa SO AIDS LA English DT Article DE Africa; epidemic; evolution; geographic information system; HIV-1; phylodynamics ID IMMUNODEFICIENCY-VIRUS TYPE-1; SUBTYPE-C; CONGO SUGGESTS; WOMEN; DIVERSITY; INFECTION; SEQUENCES; KINSHASA; UGANDA; EVOLUTION AB Design: We sought to investigate the evolutionary and historical reasons for the different epidemiological patterns of HIV-1 in the early epidemic. In order to characterize the demographic history of HIV-1 subtypes A and D in east Africa, we examined molecular epidemiology,geographical and historical data. Methodology: We employed high-resolution phylodynamics to investigate the introduction of HIV-1 A and D into east Africa, the geographic trends of viral spread, and the demographic growth of each subtype. We also used geographic information system data to investigate human migration trends, population growth, and human mobility. Results: HIV-1A and D were introduced into east Africa after 1950 and spread exponentially during the 1970s, concurrent with eastward expansion. Spatiotemporal data failed to explain the establishment and spread of HIV based on urban population growth and migration. The low prevalence of the virus in the Democratic Republic of Congo before and after the emergence of the pandemic was, however, consistent with regional accessibility data, highlighting the difficulty in travel between major population centers in central Africa. In contrast, the strong interconnectivity between population centers across the east African region since colonial times has likely fostered the rapid growth of the epidemic in this locale. Conclusion: This study illustrates how phylodynamic analysis of pathogens informed by geospatial data can provide a more holistic and evidence-based interpretation of past epidemics. We advocate that this 'landscape phylodynamics' approach has the potential to provide a framework both to understand epidemics' spread and to design optimal intervention strategies. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Salemi, Marco] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32610 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Tatem, Andrew J.] Ctr Geog Med, KEMRI Wellcome Trust Res Labs, Malaria Publ Hlth & Epidemiol Grp, Nairobi, Kenya. [Hou, Wei] Univ Florida, Dept Epidemiol & Hlth Policy Res, Div Biostat, Gainesville, FL 32610 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. [Serwadda, David; Sewankambo, Nelson] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Sewankambo, Nelson] Makerere Univ, Coll Hlth Sci, Fac Med, Kampala, Uganda. [Gray, Ronald H.; Wawer, Maria] Johns Hopkins Univ, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. RP Salemi, M (reprint author), Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, 1376 Mowry Rd, Gainesville, FL 32610 USA. EM salemi@pathology.ufl.edu RI Laeyendecker, Oliver/B-9331-2009; OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760 FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; NIH [00069244]; Experimental Pathogen Innovative FX This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. 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. M.S. was supported by NIH award number 00069244 and the Experimental Pathogen Innovative Grant (2008) awarded from UE NR 39 TC 56 Z9 56 U1 1 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2009 VL 23 IS 14 BP F9 EP F17 DI 10.1097/QAD.0b013e32832faf61 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 495QJ UT WOS:000269908800001 PM 19644346 ER PT J AU Calado, RT Yewdell, WT Wilkerson, KL Regal, JA Kajigaya, S Stratakis, CA Young, NS AF Calado, Rodrigo T. Yewdell, William T. Wilkerson, Keisha L. Regal, Joshua A. Kajigaya, Sachiko Stratakis, Constantine A. Young, Neal S. TI Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells SO BLOOD LA English DT Article ID RECESSIVE DYSKERATOSIS-CONGENITA; ACQUIRED APLASTIC-ANEMIA; BONE-MARROW FAILURE; REVERSE-TRANSCRIPTASE; HTERT EXPRESSION; RANDOMIZED TRIAL; MUTATIONS; ANDROGENS; RNA; COMPONENT AB Androgens have been used in the treatment of bone marrow failure syndromes without a clear understanding of their mechanism of action. Blood counts of patients with dyskeratosis congenita or aplastic anemia with mutations in telomerase genes can improve with androgen therapy. Here we observed that exposure in vitro of normal peripheral blood lymphocytes and human bone marrow-derived CD34(+) cells to androgens increased telomerase activity, coincident with higher TERT mRNA levels. Cells from patients who were heterozygous for telomerase mutations had low baseline telomerase activity, which was restored to normal levels by exposure to androgens. Estradiol had an effect similar to androgens on TERT gene expression and telomerase enzymatic activity. Tamoxifen abolished the effects of both estradiol and androgens on telomerase function, and letrozole, an aromatase inhibitor, blocked androgen effects on telomerase activity. Conversely, flutamide, an androgen receptor antagonist, did not affect androgen stimulation of telomerase. Down-regulation by siRNA of estrogen receptor-alpha (ER alpha), but not ER beta, inhibited estrogen-stimulated telomerase function. Our results provide a mechanism for androgen therapy in bone marrow failure: androgens appear to regulate telomerase expression and activity mainly by aromatization and through ER alpha. These findings have potential implications for the choice of current androgenic compounds and the development of future agents for clinical use. (Blood. 2009; 114: 2236-2243) C1 [Calado, Rodrigo T.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Calado, RT (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10-CRC,Rm 3E-5140, Bethesda, MD 20892 USA. EM calador@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 FU National Institutes of Health FX This work was supported by the National Institutes of Health Intramural Research Program. NR 43 TC 104 Z9 116 U1 0 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 10 PY 2009 VL 114 IS 11 BP 2236 EP 2243 DI 10.1182/blood-2008-09-178871 PG 8 WC Hematology SC Hematology GA 492YI UT WOS:000269698400008 PM 19561322 ER PT J AU Lee, JJ Rauter, I Garibyan, L Ozcan, E Sannikova, T Dillon, SR Cruz, AC Siegel, RM Bram, R Jabara, H Geha, RS AF Lee, John J. Rauter, Ingrid Garibyan, Lilit Ozcan, Esra Sannikova, Tatyana Dillon, Stacey R. Cruz, Anthony C. Siegel, Richard M. Bram, Richard Jabara, Haifa Geha, Raif S. TI The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function SO BLOOD LA English DT Article ID TRANSMEMBRANE ACTIVATOR; BLYS RECEPTOR; BAFF-R; APRIL; DOMAIN; BINDING; DIFFERENTIATION; SURVIVAL; MICE AB TNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NF kappa B signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI(-/-) background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that m TACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions. (Blood. 2009; 114: 2254-2262) C1 [Lee, John J.; Rauter, Ingrid; Garibyan, Lilit; Ozcan, Esra; Sannikova, Tatyana; Jabara, Haifa; Geha, Raif S.] Harvard Univ, Sch Med, Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Lee, John J.; Rauter, Ingrid; Garibyan, Lilit; Ozcan, Esra; Sannikova, Tatyana; Jabara, Haifa; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Dillon, Stacey R.] Zymogenet Inc, Dept Immunol, Seattle, WA 98105 USA. [Cruz, Anthony C.; Siegel, Richard M.] NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIAMS,NIH, Bethesda, MD 20892 USA. [Bram, Richard] Mayo Clin, Coll Med, Dept Immunol, Rochester, MN USA. RP Geha, RS (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Div Immunol, Karp 10,300 Longwood Ave, Boston, MA 02115 USA. EM raif.geha@childrens.harvard.edu FU NIH [P01-AI-031541, T32-AI-007512]; American Academy of Allergy, Asthma, and Immunology (AAAAI) GlaxoSmithKline (GSK); Austrian Science Fund [J2744-B12] FX This work was supported by NIH grants P01-AI-031541 and T32-AI-007512; American Academy of Allergy, Asthma, and Immunology (AAAAI) GlaxoSmithKline (GSK) Award; and Austrian Science Fund J2744-B12. NR 31 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 10 PY 2009 VL 114 IS 11 BP 2254 EP 2262 DI 10.1182/blood-2008-11-189720 PG 9 WC Hematology SC Hematology GA 492YI UT WOS:000269698400010 PM 19605846 ER PT J AU Sripichai, O Kiefer, CM Bhanu, NV Tanno, T Noh, SJ Goh, SH Russell, JE Rognerud, CL Ou, CN Oneal, PA Meier, ER Gantt, NM Byrnes, C Lee, YT Dean, A Miller, JL AF Sripichai, Orapan Kiefer, Christine M. Bhanu, Natarajan V. Tanno, Toshihiko Noh, Seung-Jae Goh, Sung-Ho Russell, J. Eric Rognerud, Cheryl L. Ou, Ching-Nan Oneal, Patricia A. Meier, Emily R. Gantt, Nicole M. Byrnes, Colleen Lee, Y. Terry Dean, Ann Miller, Jeffery L. TI Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming SO BLOOD LA English DT Article ID SICKLE-CELL-DISEASE; GAMMA-GLOBIN; BETA-THALASSEMIA; EXPRESSION; PROTEIN; KINASE; ERYTHROPOIESIS; DIFFERENTIATION; IDENTIFICATION; ACTIVATION AB Therapeutic regulation of globin genes is a primary goal of translational research aimed toward hemoglobinopathies. Signal transduction was used to identify chromatin modifications and transcription factor expression patterns that are associated with globin gene regulation. Histone modification and transcriptome profiling were performed using adult primary CD34(+) cells cultured with cytokine combinations that produced low versus high levels of gamma-globin mRNA and fetal hemoglobin (HbF). Embryonic, fetal, and adult globin transcript and protein expression patterns were determined for comparison. Chromatin immunoprecipitation assays revealed RNA polymerase II occupancy and histone tail modifications consistent with transcriptional activation only in the high-HbF culture condition. Transcriptome profiling studies demonstrated reproducible changes in expression of nuclear transcription factors associated with high HbF. Among the 13 genes that demonstrated differential transcript levels, 8 demonstrated nuclear protein expression levels that were significantly changed by cytokine signal transduction. Five of the 8 genes are recognized regulators of erythropoiesis or globin genes (MAFF, ID2, HHEX, SOX6, and EGR1). Thus, cytokine-mediated signal transduction in adult erythroid cells causes significant changes in the pattern of globin gene and protein expression that are associated with distinct histone modifications as well as nuclear reprogramming of erythroid transcription factors. (Blood. 2009; 114: 2299-2306) C1 [Sripichai, Orapan; Bhanu, Natarajan V.; Tanno, Toshihiko; Noh, Seung-Jae; Goh, Sung-Ho; Oneal, Patricia A.; Meier, Emily R.; Gantt, Nicole M.; Byrnes, Colleen; Lee, Y. Terry; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Kiefer, Christine M.; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Russell, J. Eric] Univ Penn, Sch Med, Dept Med Hematol Oncol, Philadelphia, PA 19104 USA. [Russell, J. Eric] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Rognerud, Cheryl L.; Ou, Ching-Nan] Texas Childrens Hosp, Dept Pathol, Houston, TX 77030 USA. [Rognerud, Cheryl L.; Ou, Ching-Nan] Baylor Coll Med, Houston, TX 77030 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, Bldg 10,Rm 9N311,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jm7f@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 42 TC 37 Z9 38 U1 3 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 10 PY 2009 VL 114 IS 11 BP 2299 EP 2306 DI 10.1182/blood-2009-05-219386 PG 8 WC Hematology SC Hematology GA 492YI UT WOS:000269698400015 PM 19597182 ER PT J AU Landgren, O Kyle, RA Rajkumar, V AF Landgren, Ola Kyle, Robert A. Rajkumar, Vincent TI Multiple myeloma is universally preceded by a prolonged premalignant stage: novel clinical insights and future directions Response SO BLOOD LA English DT Letter ID MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; LONG-TERM; RISK C1 [Landgren, Ola] Natl Canc Inst, NIH, Bethesda, MD 20892 USA. [Kyle, Robert A.; Rajkumar, Vincent] Mayo Clin, Rochester, MN USA. RP Landgren, O (reprint author), Natl Canc Inst, NIH, 9000 Rockville Pike,Bldg 10-Rm 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov NR 9 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 10 PY 2009 VL 114 IS 11 BP 2356 EP 2357 DI 10.1182/blood-2009-07-230441 PG 4 WC Hematology SC Hematology GA 492YI UT WOS:000269698400024 ER PT J AU Pusztai, L Jeong, JH Gong, Y Ross, JS Kim, C Paik, S Rouzier, R Andre, F Hortobagyi, GN Wolmark, N Symmans, WF AF Pusztai, Lajos Jeong, Jong-Hyeon Gong, Yun Ross, Jeffrey S. Kim, Chungyeul Paik, Soonmyung Rouzier, Roman Andre, Fabrice Hortobagyi, Gabriel N. Wolmark, Norman Symmans, W. Fraser TI Evaluation of Microtubule-Associated Protein-Tau Expression As a Prognostic and Predictive Marker in the NSABP-B 28 Randomized Clinical Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSITIVE BREAST-CANCER; PREOPERATIVE CHEMOTHERAPY; GENE-EXPRESSION; PACLITAXEL SENSITIVITY; ESTROGEN; DOXORUBICIN; CYCLOPHOSPHAMIDE; DOCETAXEL; RESISTANCE; SURVIVAL AB Purpose We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project (NSABP)-B 28 clinical trial. Expression levels were correlated with disease-free survival (DFS) and overall survival (OS). Interaction between this marker and paclitaxel efficacy was also examined. Methods Tissue microarrays were available for 1,942 patients (63% of all trial participants) who were randomly assigned to receive either four courses of doxorubicin and cyclophosphamide (AC) or AC followed by four courses of adjuvant paclitaxel chemotherapy. All patients who were hormone receptor positive received adjuvant endocrine therapy. Immunohistochemistry was used to measure Tau expression at M. D. Anderson Cancer Center blinded to clinical outcome. Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center. Results Forty-three percent of patients were Tau positive. Tau positivity correlated with estrogen receptor (ER) -positive status (P < .0001), lower histologic grade (P < .001), and lack of human epidermal growth factor receptor 2 (HER2) expression (P < .0001). In univariate analyses, Tau- and ER-positive status were both associated with better DFS and OS (P < .0001) whereas greater tumor size, high grade, lymph node- and HER2-positive status were each associated with worse DFS and OS (P < .0001). In multivariate analysis, the same variables except HER2 remained significant. There was no significant interaction between Tau expression and benefit from paclitaxel in the total population or among ER-positive or -negative patients. Conclusion High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy, but there was no significant interaction between Tau expression and paclitaxel benefit. C1 [Pusztai, Lajos] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77230 USA. Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77230 USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA. Albany Med Coll, Dept Pathol, Albany, NY 12208 USA. Hop Tenon, Dept Gynecol Oncol, F-75970 Paris, France. Inst Gustave Roussy, Translat Res Unit, Villejuif, France. RP Pusztai, L (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, POB 301439, Houston, TX 77230 USA. EM lpusztai@mdanderson.org OI kim, chungyeul/0000-0002-9636-5228; Jeong, Jong/0000-0003-0596-2201 FU Breast Cancer Research Foundation; Nellie B. Connally Breast Cancer Research Fund; National Cancer Institute, Department of Health and Human Services [U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974, U24-CA-114732] FX Supported by a grant from the Breast Cancer Research Foundation ( L. P.) and by the Nellie B. Connally Breast Cancer Research Fund. NSABP Trial B-28 was supported by Public Health Service Grants No. U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974, and U24-CA-114732 from the National Cancer Institute, Department of Health and Human Services. NR 28 TC 58 Z9 61 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2009 VL 27 IS 26 BP 4287 EP 4292 DI 10.1200/JCO.2008.21.6887 PG 6 WC Oncology SC Oncology GA 492JU UT WOS:000269652200011 PM 19667268 ER PT J AU Richey, EA Lyons, EA Nebeker, JR Shankaran, V McKoy, JM Luu, TH Nonzee, N Trifilio, S Sartor, O Benson, AB Carson, KR Edwards, BJ Gilchrist-Scott, D Kuzel, TM Raisch, DW Tallman, MS West, DP Hirschfeld, S Grillo-Lopez, AJ Bennett, CL AF Richey, Elizabeth A. Lyons, E. Alison Nebeker, Jonathan R. Shankaran, Veena McKoy, June M. Luu, Thanh Ha Nonzee, Narissa Trifilio, Steven Sartor, Oliver Benson, Al B., III Carson, Kenneth R. Edwards, Beatrice J. Gilchrist-Scott, Douglas Kuzel, Timothy M. Raisch, Dennis W. Tallman, Martin S. West, Dennis P. Hirschfeld, Steven Grillo-Lopez, Antonio J. Bennett, Charles L. TI Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-of-Hematology CY DEC 06-09, 2008 CL San Francisco, CA SP Amer Soc Hematol AB Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs. C1 [Bennett, Charles L.] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Div Geriatr Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NW Mem Hosp, Dept Pharm, Chicago, IL USA. Jesse Brown Vet Affairs Med Ctr, Vet Affairs Ctr Management Complex Chron Care, Chicago, IL USA. Vet Affairs Salt Lake City Geriatr Res Educ & Cli, Salt Lake City, UT USA. Tulane Med Sch, New Orleans, LA USA. Washington Univ, Sch Med, Siteman Comprehens Canc Ctr, St Louis, MO USA. Clin Res Pharm Coordinating Ctr, Vet Affairs Cooperat Studies Program, Albuquerque, NM USA. NICHHD, NIH, Bethesda, MD 20892 USA. Neoplast & Autoimmune Dis Res Inst, Rancho Santa Fe, CA USA. RP Bennett, CL (reprint author), Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, 303 E Chicago Ave,Olson Pavil Ste 8250, Chicago, IL 60611 USA. EM cbenne@northwestern.edu RI Hirschfeld, Steven/E-2987-2016; OI Hirschfeld, Steven/0000-0003-0627-7249; West, Dennis/0000-0002-9107-6697 FU NCI NIH HHS [1R01 CA102713-01, P30 CA60553, R01 CA102713, R01 CA125077] NR 14 TC 49 Z9 49 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2009 VL 27 IS 26 BP 4398 EP 4405 DI 10.1200/JCO.2008.21.1961 PG 8 WC Oncology SC Oncology GA 492JU UT WOS:000269652200028 PM 19636013 ER PT J AU Boyer, PL Vu, BC Ambrose, Z Julias, JG Warnecke, S Liao, CZ Meier, C Marquez, VE Hughes, SH AF Boyer, Paul L. Vu, B. Christie Ambrose, Zandrea Julias, John G. Warnecke, Svenja Liao, Chenzhong Meier, Chris Marquez, Victor E. Hughes, Stephen H. TI The Nucleoside Analogue D-carba T Blocks HIV-1 Reverse Transcription SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHEMICAL TROJAN HORSES; HERPES-SIMPLEX VIRUS; MULTIFUNCTIONAL ENZYME; THYMIDYLATE KINASE; DNA-SYNTHESIS; TYPE-1; NUCLEOTIDE; THYMIDINE; CRYSTAL; INHIBITOR AB A major pathway for HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs) involves reverse transcriptase (RT) Mutations that enhance ATP-dependent pyrophosphorolysis, which excises NRTIs from the end of viral DNA. We analyzed novel NRTIs for their ability to inhibit DNA synthesis of excision-proficient HIV-1 RT mutants, D-carba T is a carbocyclic nucleoside that has a 3' hydroxyl on the pseudosugar. The 3' hydroxyl group allows RT to incorporate additional dNTPs, which should protect D-carba TMP from excision. D-carba T can be converted to the triphosphate form by host cell kinases with moderate efficiency. D-carba T-TP is efficiently incorporated by HIV-1 RT; however, the next dNTP is added slowly to a D-carba TMP at the primer terminus. D-carba T effectively inhibits viral vectors that replicate using NRTI-resistant HIV-1 RTs, and there is no obvious toxicity in cultured cells. NRTIs based on the carbocyclic pseudosugar may offer an effective approach for the treatment of HIV-1 infections. C1 [Boyer, Paul L.; Vu, B. Christie; Ambrose, Zandrea; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Julias, John G.] SAIC Frederick, Frederick, MD 21702 USA. [Warnecke, Svenja; Meier, Chris] Univ Hamburg, Fac Sci, Dept Chem, D-20146 Hamburg, Germany. [Liao, Chenzhong; Marquez, Victor E.] NCI, Med Chem Lab, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B 539-130, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [NO1-CO-12400]; National Cancer Institute FX We thank Pat Clark for preparing purified enzymes, Tom Martin for cell sorting, At Kane with help with figures, and Teresa Burdette for help with the manuscript. This research has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400, and by the Intramural program (Center for Cancer Research) of the National Cancer Institute. NR 23 TC 8 Z9 8 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 10 PY 2009 VL 52 IS 17 BP 5356 EP 5364 DI 10.1021/jm801176e PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 492KU UT WOS:000269655500010 PM 19678643 ER PT J AU Derudas, M Carta, D Brancale, A Vanpouille, C Lisco, A Margolis, L Balzarini, J McGuigan, C AF Derudas, Marco Carta, Davide Brancale, Andrea Vanpouille, Christophe Lisco, Andrea Margolis, Leonid Balzarini, Jan McGuigan, Christopher TI The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHORYLATION; DERIVATIVES; CARBOXYPEPTIDASE; NUCLEOSIDE; PRODRUGS; POTENCY; KINASE; TRIAD; D4T AB Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated, ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types-1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive. C1 [Derudas, Marco; Carta, Davide; Brancale, Andrea; McGuigan, Christopher] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Vanpouille, Christophe; Lisco, Andrea; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. RP McGuigan, C (reprint author), Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. EM mcguigan@cardiff.ac.uk RI Brancale, Andrea/N-9445-2014; McGuigan, Chris/P-1580-2014 OI Brancale, Andrea/0000-0002-9728-3419; McGuigan, Chris/0000-0001-8409-710X FU KU Leuven (GOA) [05/19]; NICHD Intramural Program FX Marco Deruclas dedicates this work to the memory of Antonietta Derudas. We thank Frieda De Meyer, Leentje Persoons, Vicky Broeckx, Leen Ingels, and Ria Van Berwacr for excellent technical assistance with the antiviral and enzymatic assays. We acknowledge the excellent administrative support of Helen Murphy. Financial support by a grant of the KU Leuven (GOA no. 05/19) was provided. The work of A.L., C.V., and L.M. was supported by the NICHD Intramural Program. NR 18 TC 40 Z9 40 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 10 PY 2009 VL 52 IS 17 BP 5520 EP 5530 DI 10.1021/jm9007856 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 492KU UT WOS:000269655500024 PM 19645484 ER PT J AU Romagnoli, R Baraldi, PG Carrion, MD Cruz-Lopez, O Cara, CL Basso, G Viola, G Khedr, M Balzarini, J Mahboobi, S Sellmer, A Brancale, A Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Carrion, Maria Dora Cruz-Lopez, Olga Cara, Carlota Lopez Basso, Giuseppe Viola, Giampietro Khedr, Mohammed Balzarini, Jan Mahboobi, Siavosh Sellmer, Andreas Brancale, Andrea Hamel, Ernest TI 2-Arylamino-4-Amino-5-Aroylthiazoles. "One-Pot" Synthesis and Biological Evaluation of a New Class of Inhibitors of Tubulin Polymerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTINEOPLASTIC AGENTS; COLCHICINE; CANCER; COMBRETASTATIN-A-4; BINDING AB The essential role of microtubules in mitosis makes them a major target of compounds useful for cancer therapy. In our search for potent antitumor agents, a novel series of 2-anilino-4-amino-5-aroylthiazoles was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. SAR was elucidated with various substitutions on the phenylamino and aroyl moiety at the 2- and 5-positions, respectively, of the 4-aminothiazole skeleton. Tumor cell exposure to several of these compounds led to the arrest of HeLa cells in the G2/M phase of the cell cycle and induction of apoptosis. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cruz-Lopez, Olga; Cara, Carlota Lopez] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Pediat, Lab Oncoematol, I-35131 Padua, Italy. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Khedr, Mohammed; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Mahboobi, Siavosh; Sellmer, Andreas] Univ Regensburg, Fac Chem & Pharm, D-93040 Regensburg, Germany. [Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI Viola, Giampietro/I-4095-2012; Brancale, Andrea/N-9445-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017; OI BASSO, GIUSEPPE/0000-0002-2634-9302; Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Carrion, M. Dora/0000-0002-6794-3949; Khedr, Mohammed/0000-0002-5530-391X FU Intramural NIH HHS [Z99 CA999999] NR 12 TC 32 Z9 33 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 10 PY 2009 VL 52 IS 17 BP 5551 EP 5555 DI 10.1021/jm9001692 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 492KU UT WOS:000269655500027 PM 19663386 ER PT J AU Balboni, G Trapella, C Sasaki, Y Ambo, A Marczak, ED Lazarus, LH Salvadori, S AF Balboni, Gianfranco Trapella, Claudio Sasaki, Yusuke Ambo, Akihiro Marczak, Ewa D. Lazarus, Lawrence H. Salvadori, Severo TI Influence of the Side Chain Next to C-Terminal Benzimidazole in Opioid Pseudopeptides Containing the Dmt-Tic Pharmacophore SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AMINO-ACIDS; RECEPTOR; MU; POTENT; ANTAGONISTS; AGONISTS; ANALOGS; REQUIREMENTS; STIMULATION; TRAFFICKING AB To improve the structure-activity studies of the lead 6 opioid agonist H-Dmt-Tic-Asp*-Bid, we synthesized and pharmacologically characterized a series of analogues in which the side chain next to 1H-benzimidazole-2-yl (Bid) was substituted by those endowed with different chemical properties. Interesting results were obtained: (1) only Gly, Ala, and Asp resulted in delta agonism, (2) Phe yielded delta antagonism, (3) and all other residues except Glu (devoid of any activity) gave mu agonism. C1 [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. [Trapella, Claudio; Salvadori, Severo] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Trapella, Claudio; Salvadori, Severo] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. [Sasaki, Yusuke; Ambo, Akihiro] Tohoku Pharmaceut Univ, Dept Pharmacol, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Marczak, Ewa D.; Lazarus, Lawrence H.] NIEHS, Med Chem Grp, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. RP Balboni, G (reprint author), Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. EM gbalboni@unica.it; sal@unife.it RI Trapella, Claudio/I-2128-2012; OI Trapella, Claudio/0000-0002-6666-143X; SALVADORI, Severo/0000-0002-8224-2358 FU University of Cagliari; University of Ferrara; NIH; NIEHS FX This study was supported in part by the University of Cagliari (GB), the University of Ferrara (SS), and in part by the intramural Research Program of the NIH and NIEHS (L.H.L. and E.D.M.). NR 32 TC 6 Z9 6 U1 0 U2 2 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 SEP 10 PY 2009 VL 52 IS 17 BP 5556 EP 5559 DI 10.1021/jm900686q PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 492KU UT WOS:000269655500028 PM 19642675 ER PT J AU Schofield, PN Bubela, T Weaver, T Brown, SD Hancock, JM Einhorn, D Tocchini-Valentini, G de Angelis, MH Rosenthal, N AF Schofield, Paul N. Bubela, Tania Weaver, Thomas Brown, Stephen D. Hancock, John M. Einhorn, David Tocchini-Valentini, Glauco de Angelis, Martin Hrabe Rosenthal, Nadia CA Casimir Rome Meeting Participants TI Post-publication sharing of data and tools SO NATURE LA English DT Editorial Material C1 [Schofield, Paul N.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. [Bubela, Tania] Univ Alberta, Dept Publ Hlth Sci, Edmonton, AB T6G 2V2, Canada. [Weaver, Thomas] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Brown, Stephen D.; Hancock, John M.] MRC Harwell, Mammalian Genet Unit, Didcot OX11 0RD, Oxon, England. [Einhorn, David] Jackson Lab, Bar Harbor, ME 04609 USA. [Tocchini-Valentini, Glauco] Ist Biol Cellulare, I-00015 Rome, Italy. [de Angelis, Martin Hrabe] Inst Expt Genet, Munich, Germany. [Rosenthal, Nadia] EMBL Monterotondo, I-00015 Rome, Italy. RP Schofield, PN (reprint author), Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. EM PS@mole.bio.cam.ac.uk RI Rosenthal, Nadia/O-7009-2015; Hancock, John/A-2442-2009; Hrabe de Angelis, Martin/F-5531-2012; Wright, Dawn/A-4518-2011; Bubela, Tania/F-4860-2014; Hubbard, Tim/C-2567-2008 OI MATTEONI, RAFAELE/0000-0002-0314-5948; Rosenthal, Nadia/0000-0002-7599-7365; Hancock, John/0000-0003-2991-2217; Hrabe de Angelis, Martin/0000-0002-7898-2353; Wright, Dawn/0000-0002-2997-7611; Bubela, Tania/0000-0002-0807-2899; Hubbard, Tim/0000-0002-1767-9318 FU Medical Research Council [MC_U142684171]; Wellcome Trust [077198, 062023] NR 11 TC 72 Z9 74 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 10 PY 2009 VL 461 IS 7261 BP 171 EP 173 DI 10.1038/461171a PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492KN UT WOS:000269654600018 PM 19741686 ER PT J AU Sharon, I Alperovitch, A Rohwer, F Haynes, M Glaser, F Atamna-Ismaeel, N Pinter, RY Partensky, F Koonin, EV Wolf, YI Nelson, N Beja, O AF Sharon, Itai Alperovitch, Ariella Rohwer, Forest Haynes, Matthew Glaser, Fabian Atamna-Ismaeel, Nof Pinter, Ron Y. Partensky, Frederic Koonin, Eugene V. Wolf, Yuri I. Nelson, Nathan Beja, Oded TI Photosystem I gene cassettes are present in marine virus genomes SO NATURE LA English DT Article ID CYANOBACTERIUM SYNECHOCYSTIS SP; PHOTOSYNTHESIS GENES; TARGETED INACTIVATION; ELECTRON FLOW; PROCHLOROCOCCUS; SYNECHOCOCCUS; ORGANIZATION; ENVIRONMENT; PROKARYOTE; PACIFIC AB Cyanobacteria of the Synechococcus and Prochlorococcus genera are important contributors to photosynthetic productivity in the open oceans(1-3). Recently, core photosystem II (PSII) genes were identified in cyanophages and proposed to function in photosynthesis and in increasing viral fitness by supplementing the host production of these proteins(4-7). Here we show evidence for the presence of photosystem I (PSI) genes in the genomes of viruses that infect these marine cyanobacteria, using pre-existing meta-genomic data from the global ocean sampling expedition(8) as well as from viral biomes(9). The seven cyanobacterial core PSI genes identified in this study, psaA, B, C, D, E, K and a unique J and F fusion, form a cluster in cyanophage genomes, suggestive of selection for a distinct function in the virus life cycle. The existence of this PSI cluster was confirmed with overlapping and long polymerase chain reaction on environmental DNA from the Northern Line Islands. Potentially, the seven proteins encoded by the viral genes are sufficient to form an intact monomeric PSI complex. Projection of viral predicted peptides on the cyanobacterial PSI crystal structure(10) suggested that the viral-PSI components might provide a unique way of funnelling reducing power from respiratory and other electron transfer chains to the PSI. C1 [Sharon, Itai; Alperovitch, Ariella; Atamna-Ismaeel, Nof; Beja, Oded] Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel. [Sharon, Itai; Pinter, Ron Y.] Technion Israel Inst Technol, Fac Comp Sci, IL-32000 Haifa, Israel. [Glaser, Fabian] Technion Israel Inst Technol, Bioinformat Knowledge Unit, Lorry I Lokey Interdisciplinary Ctr Life Sci & En, IL-32000 Haifa, Israel. [Rohwer, Forest; Haynes, Matthew] San Diego State Univ, Dept Biol, San Diego, CA 92182 USA. [Rohwer, Forest] San Diego State Univ, Ctr Microbial Sci, San Diego, CA 92182 USA. [Partensky, Frederic] CNRS, F-29682 Roscoff, France. [Partensky, Frederic] UPMC, Biol Stn, UMR 7144, F-29682 Roscoff, France. [Koonin, Eugene V.; Wolf, Yuri I.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Nelson, Nathan] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Biochem, Daniella Rich Inst Struct Biol, IL-69978 Tel Aviv, Israel. RP Beja, O (reprint author), Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel. EM beja@tx.technion.ac.il OI Sharon, Itai/0000-0003-0705-2316; Partensky, Frederic/0000-0003-1274-4050 FU Israel Science Foundation [1203/06, 356/06]; Henry Taub Award for Academic Excellence; Technion V. P. R. Fund-Henri Gutwirth Promotion of Research Fund FX We would like to thank M. Rosenberg for technical support, D. Rusch, J. Zehr and S. Bench for sharing genomic data, D. Lindell and R. Sorek for encouragement and discussions, and U. Pick for the comments on cyclic photosynthesis. This work was supported in part by grants 1203/06 ( O. B.) and 356/06 ( N. N.) from the Israel Science Foundation, by the Henry Taub Award for Academic Excellence, and by the Technion V. P. R. Fund-Henri Gutwirth Promotion of Research Fund ( O. B.). NR 30 TC 113 Z9 124 U1 2 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 10 PY 2009 VL 461 IS 7261 BP 258 EP 262 DI 10.1038/nature08284 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492KN UT WOS:000269654600043 PM 19710652 ER PT J AU Major, EO AF Major, Eugene O. TI Reemergence of PML in Natalizumab-Treated Patients - New Cases, Same Concerns SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; ANTIBODY NATALIZUMAB; CELLS C1 NINDS, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 5 TC 61 Z9 61 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 10 PY 2009 VL 361 IS 11 BP 1041 EP 1043 DI 10.1056/NEJMp0906248 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 492LP UT WOS:000269659400004 PM 19741226 ER PT J AU Linda, H von Heijne, A Major, EO Ryschkewitsch, C Berg, J Olsson, T Martin, C AF Linda, Hans von Heijne, Anders Major, Eugene O. Ryschkewitsch, Caroline Berg, Johan Olsson, Tomas Martin, Claes TI Progressive Multifocal Leukoencephalopathy after Natalizumab Monotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID JC VIRUS-DNA; RELAPSING MULTIPLE-SCLEROSIS; CEREBROSPINAL-FLUID; CONTROLLED TRIAL; CROHNS-DISEASE; THERAPY; PCR AB We describe progressive multifocal leukoencephalopathy (PML) caused by infection with human polyomavirus JC virus in a patient with multiple sclerosis who was treated with natalizumab. The first PML symptoms appeared after 14 monthly infusions of the drug. Magnetic resonance imaging (MRI) showed a presumed multiple sclerosis lesion, and JC virus DNA was not detected on polymerase-chain-reaction (PCR) assay of cerebrospinal fluid. The patient's symptoms worsened, and the diagnosis of PML was established with a more sensitive quantitative PCR assay after 16 infusions of natalizumab. Plasma exchange was used to accelerate clearance of natalizumab. Approximately 3 weeks after plasma exchange, an immune-reconstitution inflammatory syndrome appeared. JC virus DNA was no longer detectable on quantitative PCR assay, and the patient's symptoms improved. C1 [Linda, Hans; Berg, Johan; Martin, Claes] Danderyd Hosp, Karolinska Inst, Neurol Unit, Div Internal Med, SE-18288 Stockholm, Sweden. [von Heijne, Anders] Danderyd Hosp, Karolinska Inst, Dept Radiol, SE-18288 Stockholm, Sweden. [Olsson, Tomas] Danderyd Hosp, Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, SE-18288 Stockholm, Sweden. [Major, Eugene O.; Ryschkewitsch, Caroline] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Linda, H (reprint author), Danderyd Hosp, Dept Internal Med, Div Neurol, SE-18288 Stockholm, Sweden. EM hans.linda@ki.se FU Swedish Research Council; European Union's Sixth Framework Program [LSHM-CT-2005-018637]; Bibbi and Niels Jensens Foundation; Sderberg Foundation FX Supported by grants from the Swedish Research Council, the European Union's Sixth Framework Program (Neuropromise project, LSHM-CT-2005-018637), the Bibbi and Niels Jensens Foundation, and the Sderberg Foundation. NR 22 TC 148 Z9 150 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 10 PY 2009 VL 361 IS 11 BP 1081 EP 1087 DI 10.1056/NEJMoa0810316 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 492LP UT WOS:000269659400011 PM 19741229 ER PT J AU Sha, QY Zhang, ZG Schymick, JC Traynor, BJ Zhang, SL AF Sha, Qiuying Zhang, Zhaogong Schymick, Jennifer C. Traynor, Bryan J. Zhang, Shuanglin TI Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis SO BMC MEDICAL GENETICS LA English DT Article ID MOTOR-NEURON DISEASE; SUSCEPTIBILITY GENES; COMPLEX TRAITS; BREAST-CANCER; ALS; POPULATION; MUTATIONS; LOCI; POLYMORPHISMS; PREVALENCE AB Background: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood. Methods: We proposed a two-stage approach based on seventeen biological plausible models to search for two-locus combinations that have significant joint effects to the disease in a genome-wide association study (GWAS). We used a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, all SNPs were screened using a single-marker test. In the second stage, all pairs made from the 1000 SNPs with the lowest p-values from the first stage were evaluated under each of the 17 two-locus models. Results: we performed the two-stage approach on a GWAS data set of sporadic ALS from the SNP Database at the NINDS Human Genetics Resource Center DNA and Cell Line Repository http://ccr.coriell.org/ninds/. Our two-locus analysis showed that two two-locus combinations--rs4363506 (SNP1) and rs3733242 (SNP2), and rs4363506 and rs16984239 (SNP3) -- were significantly associated with sporadic ALS. After adjusting for multiple tests and multiple models, the combination of SNP1 and SNP2 had a p-value of 0.032 under the Dom boolean AND Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom x Dom multiplicative model. Conclusion: The proposed two-stage analytical method can be used to search for joint effects of genes in GWAS. The two-stage strategy decreased the computational time and the multiple testing burdens associated with GWAS. We have also observed that the loci identified by our two-stage strategy can not be detected by single-locus tests. C1 [Sha, Qiuying; Zhang, Zhaogong; Zhang, Shuanglin] Michigan Technol Univ, Dept Math Sci, Houghton, MI 49931 USA. [Zhang, Zhaogong] Heilongjiang Univ, Sch Comp Sci & Technol, Harbin, Peoples R China. [Schymick, Jennifer C.; Traynor, Bryan J.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Schymick, Jennifer C.] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Zhang, Shuanglin] Heilongjiang Univ, Dept Math, Harbin, Peoples R China. RP Zhang, SL (reprint author), Michigan Technol Univ, Dept Math Sci, Houghton, MI 49931 USA. EM qsha@mtu.edu; zhaogong@mtu.edu; schymickj@mail.nih.gov; traynorb@mail.nih.gov; shuzhang@mtu.edu RI Traynor, Bryan/G-5690-2010 FU National Institute of Health (NIH) [R01 GM069940]; Overseas-Returned Scholars Foundation of Department of Education of Heilongjiang Province [1152HZ01]; National Institute on Aging [Z01 AG000949-02] FX This work was supported by the National Institute of Health (NIH) grants R01 GM069940 and the Overseas-Returned Scholars Foundation of Department of Education of Heilongjiang Province (1152HZ01). This work was supported in part by the Intramural Research Program of the National Institute on Aging (project Z01 AG000949-02). NR 40 TC 12 Z9 12 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD SEP 9 PY 2009 VL 10 AR 86 DI 10.1186/1471-2350-10-86 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 502UU UT WOS:000270486600001 PM 19740415 ER PT J AU Volkow, ND Wang, GJ Kollins, SH Wigal, TL Newcorn, JH Telang, F Fowler, JS Zhu, W Logan, J Ma, YM Pradhan, K Wong, C Swanson, JM AF Volkow, Nora D. Wang, Gene-Jack Kollins, Scott H. Wigal, Tim L. Newcorn, Jeffrey H. Telang, Frank Fowler, Joanna S. Zhu, Wei Logan, Jean Ma, Yeming Pradhan, Kith Wong, Christopher Swanson, James M. TI Evaluating Dopamine Reward Pathway in ADHD Clinical Implications SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY DISORDER; NUCLEUS-ACCUMBENS; COCAINE BINDING; BRAIN DOPAMINE; CHILDREN; REINFORCEMENT; PET; AVAILABILITY; ADOLESCENTS AB Context Attention-deficit/hyperactivity disorder (ADHD)-characterized by symptoms of inattention and hyperactivity-impulsivity-is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. Objective To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). Design, Setting, and Participants We used positron emission tomography to measure dopamine synaptic markers (transporters and D(2)/D(3) receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. Main Outcome Measures We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [(11)C] cocaine and for D(2)/D(3) receptors using [(11)C]raclopride, quantified as binding potential (distribution volume ratio -1). Results For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P=.004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD ( 95% CI, 0.03-0.12; P <=. 001); for D(2)/D(3) receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD( 95% CI, 0.06-0.30, P=.004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD ( 95% CI, 0.02-0.17, P=.01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD ( 95% CI, 0.04-0.22; P=. 003) and the mean D(2)/D(3) for controls was 2.80 vs 2.47 for those with ADHD ( 95% CI, 0.10-0.56; P=.005) and differences in D(2)/D(3) in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P=.004). Ratings of attention correlated with D(2)/D(3) in the accumbens (r=0.35; 95% CI, 0.15-0.52; P=.001), midbrain (r=0.35; 95% CI, 0.14-0.52; P=.001), caudate (r=0.32; 95% CI, 0.11-0.50; P=.003), and hypothalamic (r=0.31; CI, 0.10-0.49; P=.003) regions and with DAT in the midbrain (r=0.37; 95% CI, 0.16-0.53; P <= .001). Conclusion A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD. JAMA. 2009;302(10):1084-1091 www.jama.com C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Volkow, Nora D.; Telang, Frank; Ma, Yeming] NIAAA, Lab Neuroimaging, Bethesda, MD USA. [Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean; Pradhan, Kith; Wong, Christopher] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean; Pradhan, Kith; Wong, Christopher] Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. [Wang, Gene-Jack; Newcorn, Jeffrey H.; Fowler, Joanna S.] Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. [Kollins, Scott H.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Wigal, Tim L.; Swanson, James M.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA USA. [Zhu, Wei] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Kollins, Scott/G-2965-2012; OI Newcorn, Jeffrey /0000-0001-8993-9337 FU Brookhaven National Laboratory (BNL); Intramural Research Program of the National Institutes of Health (NIH) [MH66961-02]; Department of Energy FX This research was carried out at Brookhaven National Laboratory (BNL) and was supported in part by grant MH66961-02 from the Intramural Research Program of the National Institutes of Health (NIH), the National Institute of Mental Health and infrastructure support from the Department of Energy. NR 57 TC 228 Z9 229 U1 9 U2 45 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 9 PY 2009 VL 302 IS 10 BP 1084 EP 1091 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 491XH UT WOS:000269616200026 PM 19738093 ER PT J AU Daw, MI Tricoire, L Erdelyi, F Szabo, G McBain, CJ AF Daw, Michael I. Tricoire, Ludovic Erdelyi, Ferenc Szabo, Gabor McBain, Chris J. TI Asynchronous Transmitter Release from Cholecystokinin-Containing Inhibitory Interneurons Is Widespread and Target-Cell Independent SO JOURNAL OF NEUROSCIENCE LA English DT Article ID METABOTROPIC GLUTAMATE-RECEPTOR; FAST-SPIKING INTERNEURONS; PRINCIPAL NEURON SYNAPSE; HIPPOCAMPUS IN-VITRO; RAT HIPPOCAMPUS; FEEDFORWARD INHIBITION; GABA RELEASE; PERISOMATIC INHIBITION; NETWORK OSCILLATIONS; GABAERGIC NEURONS AB Neurotransmitter release at most central synapses is synchronized to the timing of presynaptic action potentials. Here, we show that three classes of depolarization-induced suppression of inhibition-expressing, cholecystokinin (CCK)-containing, hippocampal interneurons show highly asynchronous release in response to trains of action potentials. This asynchrony is correlated to the class of presynaptic interneuron but is unrelated to their postsynaptic cell target. Asynchronous and synchronous release from CCK-containing interneurons show a slightly different calcium dependence, such that the proportion of asynchronous release increases with external calcium concentration, possibly suggesting that the modes of release are mediated by different calcium sensors. Asynchronous IPSCs include very large (up to 500 pA/7nS) amplitude events, which persist in low extracellular calcium and strontium, showing that they result from quantal transmitter release at single release sites. Finally, we show that asynchronous release is prominent in response to trains of presynaptic spikes that mimic natural activity of CCK-containing interneurons. That asynchronous release from CCK-containing interneurons is a widespread phenomenon indicates a fundamental role for these cells within the hippocampal network that is distinct from the phasic inhibition provided by parvalbumin-containing interneurons. C1 [Daw, Michael I.; Tricoire, Ludovic; McBain, Chris J.] NICHHD, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Erdelyi, Ferenc; Szabo, Gabor] Inst Expt Med, Dept Gene Technol & Dev Neurobiol, H-1083 Budapest, Hungary. RP Daw, MI (reprint author), NICHHD, Program Dev Neurosci, NIH, Room 3C705,Bldg 35,35 Convent Dr,MSC 3715, Bethesda, MD 20892 USA. EM dawmicha@mail.nih.gov OI Daw, Michael/0000-0002-8374-5977 FU National Institute of Child Health and Human Development (NICHD) FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD). C. J. M. was supported by an NICHD intramural research award. Thanks to Josh Huang for the generous gift of the B13 PV-GFP mouse line. We thank Jeff Diamond, Ken Pelkey, and Christine Torborg for comments on this manuscript. We also thank Brian Jeffries for expert technical assistance and Jeff Diamond for assistance with deconvolution analysis. We thank Bruno Cauli and Helene Geoffroy for sharing primer sequences. NR 50 TC 78 Z9 78 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 9 PY 2009 VL 29 IS 36 BP 11112 EP 11122 DI 10.1523/JNEUROSCI.5760-08.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 492QS UT WOS:000269674700005 PM 19741117 ER PT J AU Labunskyy, VM Yoo, MH Hatfield, DL Gladyshev, VN AF Labunskyy, Vyacheslav M. Yoo, Min-Hyuk Hatfield, Dolph L. Gladyshev, Vadim N. TI Sep15, a Thioredoxin-like Selenoprotein, Is Involved in the Unfolded Protein Response and Differentially Regulated by Adaptive and Acute ER Stresses SO BIOCHEMISTRY LA English DT Article ID GLUCOSE-GLYCOPROTEIN GLUCOSYLTRANSFERASE; RETICULUM-ASSOCIATED DEGRADATION; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; UDP-GLUCOSE; MAMMALIAN-CELLS; GENE-EXPRESSION; MESSENGER-RNA; CALNEXIN; ERP57 AB The accumulation of misfolded proteins in the endoplasmic reticulum (ER) results in activation of signaling pathways collectively known as the unfolded protein response (UPR), The UPR promotes adaptation of cells to ER stress by transient inhibition of protein translation and transcriptional up-regulation of genes encoding chaperones, oxidoreductases, and ER-associated degradation components. However, it may also trigger appptosis in response to persistent ER stress. Recently, a novel selenocysteine-containing oxidoreductase, Sep15, has been reported to reside in the ER lumen. It has been proposed that this oxidoreductase may assist oxidative folding and structural maturation of N-glycosylated proteins targeted by UDP-glucose:glycoprotein glucosyltransferase, a chaperone implicated in quality control in the ER that forms a 1: 1 complex with Sep15. To address the role of Sep15 in protein folding, we analyzed changes in Sep15 expression in murine fibroblast NIH3T3 cells in response to tunicamycin, brefeldin A (brefA), thapsigargin, and DTT that lead to accumulation of unfolded proteins within the ER. We show that expression of this protein is transcriptionally up-regulated in response to adaptive UPR caused by tunicamycin and brefA, whereas acute ER stress caused by DTT and thapsigargin leads to rapid and specific degradation of Sep15 by proteasomes, However, Sep15 deficiency did not result in detectable ER stress, consistent with the idea that Sep15 assists in the maturation of a restricted group of N-glycosylated proteins and/or that its function may be compensated by other mechanisms. C1 [Labunskyy, Vyacheslav M.; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Labunskyy, Vyacheslav M.; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Yoo, Min-Hyuk; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013 FU National Institutes of Health [CA080946]; Intramural Research Program of the National Institutes of Health; National Cancer Institute, Center for Cancer Research FX This work was supported by a grant from the National Institutes of Health (CA080946) to V.N.G. and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, to D.L.H. NR 37 TC 37 Z9 41 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 8 PY 2009 VL 48 IS 35 BP 8458 EP 8465 DI 10.1021/bi900717p PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 492KV UT WOS:000269655600020 PM 19650649 ER PT J AU Klemm, L Duy, C Iacobucci, I Kuchen, S von Levetzow, G Feldhahn, N Henke, N Li, ZY Hoffmann, TK Kim, YM Hofmann, WK Jumaa, H Groffen, J Heisterkamp, N Martinelli, G Lieber, MR Casellas, R Muschen, M AF Klemm, Lars Duy, Cihangir Iacobucci, Ilaria Kuchen, Stefan von Levetzow, Gregor Feldhahn, Niklas Henke, Nadine Li, Zhiyu Hoffmann, Thomas K. Kim, Yong-mi Hofmann, Wolf-Karsten Jumaa, Hassan Groffen, John Heisterkamp, Nora Martinelli, Giovanni Lieber, Michael R. Casellas, Rafael Mueschen, Markus TI The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia SO CANCER CELL LA English DT Article ID INDUCED CYTIDINE DEAMINASE; ACUTE LYMPHOBLASTIC-LEUKEMIA; KINASE DOMAIN MUTATIONS; ACTIVATION-INDUCED DEAMINASE; CLASS SWITCH RECOMBINATION; TRANSCRIPTION FACTOR PAX5; NF-KAPPA-B; SOMATIC HYPERMUTATION; ANTIBODY DIVERSIFICATION; PHILADELPHIA-CHROMOSOME AB Chronic myeloid leukemia (CIVIL) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CIVIL cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CIVIL cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression. C1 [Klemm, Lars; Duy, Cihangir; von Levetzow, Gregor; Kim, Yong-mi; Groffen, John; Heisterkamp, Nora; Lieber, Michael R.; Mueschen, Markus] Univ So Calif, Leukemia & Lymphoma Program, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90027 USA. [Klemm, Lars; Duy, Cihangir; von Levetzow, Gregor; Kim, Yong-mi; Groffen, John; Heisterkamp, Nora; Mueschen, Markus] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Klemm, Lars; Duy, Cihangir; von Levetzow, Gregor; Feldhahn, Niklas; Henke, Nadine; Hoffmann, Thomas K.; Mueschen, Markus] Univ Dusseldorf, D-40225 Dusseldorf, Germany. [Iacobucci, Ilaria; Martinelli, Giovanni] Univ Bologna, Dept Hematol & Oncol L & A Seragnoli, I-40138 Bologna, Italy. [Kuchen, Stefan; Li, Zhiyu; Casellas, Rafael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Hofmann, Wolf-Karsten] Univ Heidelberg Hosp, Dept Hematol Oncol, D-68167 Mannheim, Germany. [Jumaa, Hassan] Max Planck Inst Immunobiol, Freiburg, Germany. [Hoffmann, Thomas K.] Univ Duisburg Essen, Dept Otorhinolaryngol, D-45147 Essen, Germany. RP Muschen, M (reprint author), Univ So Calif, Leukemia & Lymphoma Program, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90027 USA. EM mmuschen@chla.usc.edu OI Nickel, Nadine/0000-0002-0609-0735; Kuchen, Stefan/0000-0003-4899-8132 FU NIH/NCI [R01CA137060, R01CA139032]; Leukemia and Lymphoma Society; V Foundation for Cancer Research; Deutsche Forschungsgemeinschaft (German Science Foundation) [MU1616/5-1]; Kenneth T. and Eileen L. Norris Foundation FX We thank Michel C. Nussenzweig (New York) and Tasuku Honjo (Kyoto) for sharing AID-/- Balb/c mice with us. We are indebted to Tanja A. Gruber for help with CGH analysis, Bonaventure Ndikung Soh for KDE analysis, and Kirsten Schneider and Jessica Langer for help with sequencing. This work is supported by grants from the NIH/NCI through R01CA137060 (M.M.), R01CA139032 (M.M.), the Leukemia and Lymphoma Society (to M.M.), the V Foundation for Cancer Research (M.M.), the Deutsche Forschungsgemeinschaft (German Science Foundation) through MU1616/5-1, and the Kenneth T. and Eileen L. Norris Foundation (J.G., M.M.). NR 55 TC 86 Z9 89 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 8 PY 2009 VL 16 IS 3 BP 232 EP 245 DI 10.1016/j.ccr.2009.07.030 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 493CS UT WOS:000269711500010 PM 19732723 ER PT J AU Qian, XL Li, GR Vass, WC Papageorge, A Walker, RC Asnaghi, L Steinbach, PJ Tosato, G Hunter, K Lowy, DR AF Qian, Xiaolan Li, Guorong Vass, William C. Papageorge, Alex Walker, Renard C. Asnaghi, Laura Steinbach, Peter J. Tosato, Giovanna Hunter, Kent Lowy, Douglas R. TI The Tensin-3 Protein, Including its SH2 Domain, Is Phosphorylated by Src and Contributes to Tumorigenesis and Metastasis SO CANCER CELL LA English DT Article ID GTPASE-ACTIVATING PROTEIN; HUMAN BREAST-CANCER; CELL LUNG-CANCER; SIGNAL-TRANSDUCTION; NEGATIVE REGULATOR; TUMOR-SUPPRESSOR; FAMILY-MEMBER; GROWTH; DLC-1; MIGRATION AB In cell lines from advanced lung cancer, breast cancer, and melanoma, endogenous tensin-3 contributes to cell migration, anchorage-in dependent growth, and tumorigenesis. Although SH2 domains have not been reported previously to be phosphorylated, the tensin-3 SH2 domain is a physiologic substrate for Src. Tyrosines in the SH2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. In a mouse breast cancer model, tensin-3 tyrosines are phosphorylated in a Src-associated manner in primary tumors, and experimental metastases induced by tumor-derived cell lines depend on endogenous tensin-3. Thus, tensin-3 is implicated as an oncoprotein regulated by Src and possessing an SH2 domain with a previously undescribed mechanism for the regulation of ligand binding. C1 [Qian, Xiaolan; Li, Guorong; Vass, William C.; Papageorge, Alex; Asnaghi, Laura; Tosato, Giovanna; Lowy, Douglas R.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Walker, Renard C.; Hunter, Kent] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinbach, Peter J.] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lowyd@mail.nih.gov FU Intramural Research Program; National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank Jennifer Mulla and Anthony Viera for technical assistance; Ken Yamada, Glenn Merlino, and Larry Samelson for helpful discussions; and Robert Cardiff, Robert Dickson, John Minna, and Curt Harris for cell lines. NR 40 TC 39 Z9 40 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 8 PY 2009 VL 16 IS 3 BP 246 EP 258 DI 10.1016/j.ccr.2009.07.031 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 493CS UT WOS:000269711500011 PM 19732724 ER PT J AU Rosen, BD Fernandes, VRS Nasir, K Helle-Valle, T Jerosch-Herold, M Bluemke, DA Lima, JAC AF Rosen, Boaz D. Fernandes, Veronica R. S. Nasir, Khuram Helle-Valle, Thomas Jerosch-Herold, Michael Bluemke, David A. Lima, Joao A. C. TI Age, Increased Left Ventricular Mass, and Lower Regional Myocardial Perfusion Are Related to Greater Extent of Myocardial Dyssynchrony in Asymptomatic Individuals The Multi-Ethnic Study of Atherosclerosis SO CIRCULATION LA English DT Article DE aging; dyssynchrony; hypertrophy; magnetic resonance imaging; perfusion ID DIASTOLIC HEART-FAILURE; BUNDLE-BRANCH-BLOCK; EJECTION FRACTION; SYSTOLIC FUNCTION; CARDIOVASCULAR HEALTH; HARP MRI; HYPERTROPHY; ABNORMALITIES; RELAXATION; ASYNCHRONY AB Background-Age and left ventricular (LV) hypertrophy are risk factors for the development of LV dysfunction and congestive heart failure. Our goal was to study the relationships of LV mass and age with myocardial dyssynchrony among asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis. Methods and Results-A total of 1100 individuals underwent tagged magnetic resonance imaging. Regional LV function was analyzed with the use of harmonic phase imaging. Time to peak systolic circumferential strain and strain rate were measured in 12 segments, and myocardial dyssynchrony was expressed as the SD of time to peak strain and strain rate. Relationships of age, LV mass, and myocardial perfusion with timing of strain, strain rate, and dyssynchrony were studied. There was a positive relationship between age and time to peak strain before (regression coefficient=0.37 ms/year of age; 95% confidence interval, 0.05 to 0.70; P=0.025) and after adjustment for demographic characteristics and risk factors (P=0.007). Positive associations between age and SD of time to peak strain (regression coefficient=0.33 ms/year of age; P=0.002) and SD of time to peak systolic strain rate were documented (P=0.045). Importantly, we found that LV mass index is directly related to time to peak strain (P < 0.001), time to peak strain rate, and the SD of time to strain rate (P=0.001 for all). Finally, decreased myocardial perfusion at rest was associated with delayed contraction and increased extent of dyssynchrony. Conclusions-In asymptomatic individuals, age, increased LV mass, and decreased myocardial perfusion are related to delayed myocardial contraction and greater extent of dyssynchrony. Increased dyssynchrony may mediate the association of myocardial dysfunction with age and LV hypertrophy. (Circulation. 2009; 120:859-866.) C1 [Rosen, Boaz D.; Fernandes, Veronica R. S.; Nasir, Khuram; Helle-Valle, Thomas; Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Rosen, Boaz D.] Univ Utah, Salt Lake City, UT USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ Hosp, Div Cardiol, Blalock 524,600 N Wolfe St, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Jerosch-Herold, Michael/F-2496-2010; OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [RO1-HL66075-01]; MESA [NO1-HC-95162, NO1-HC-95168, NO1-HC-95169]; Johns Hopkins Reynolds Center FX This study was supported by a National Heart, Lung, and Blood Institute grant (RO1-HL66075-01) and MESA contracts (NO1-HC-95162, NO1-HC-95168, and NO1-HC-95169). Drs Lima and Bluemke were also supported by the Johns Hopkins Reynolds Center. NR 31 TC 30 Z9 30 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 8 PY 2009 VL 120 IS 10 BP 859 EP U80 DI 10.1161/CIRCULATIONAHA.108.787408 PG 24 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 492DC UT WOS:000269633700007 PM 19704101 ER PT J AU Dezfulian, C Shiva, S Alekseyenko, A Pendyal, A Beiser, DG Munasinghe, JP Anderson, SA Chesley, CF Hoek, TLV Gladwin, MT AF Dezfulian, Cameron Shiva, Sruti Alekseyenko, Aleksey Pendyal, Akshay Beiser, D. G. Munasinghe, Jeeva P. Anderson, Stasia A. Chesley, Christopher F. Hoek, T. L. Vanden Gladwin, Mark T. TI Nitrite Therapy After Cardiac Arrest Reduces Reactive Oxygen Species Generation, Improves Cardiac and Neurological Function, and Enhances Survival via Reversible Inhibition of Mitochondrial Complex I SO CIRCULATION LA English DT Article DE cardiopulmonary resuscitation; heart arrest; ischemia; nitric oxide; reperfusion ID ISCHEMIA-REPERFUSION INJURY; S-NITROSATION; CARDIOPULMONARY-RESUSCITATION; ISCHEMIA/REPERFUSION INJURY; MYOCARDIAL DYSFUNCTION; PLASMA NITRITE; OXIDE; PROTECTS; HEART; VIVO AB Background-Three-fourths of cardiac arrest survivors die before hospital discharge or suffer significant neurological injury. Except for therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO(2)(-)) increases cellular resilience to focal ischemia/reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia/reperfusion insult of cardiopulmonary arrest. Methods and Results-We developed a mouse model of cardiac arrest characterized by 12 minutes of normothermic asystole and a high cardiopulmonary resuscitation rate. In this model, global ischemia and cardiopulmonary resuscitation were associated with blood and organ nitrite depletion, reversible myocardial dysfunction, impaired alveolar gas exchange, neurological injury, and an approximate to 50% mortality. A single low dose of intravenous nitrite (50 nmol = 1.85 mu mol/kg = 0.13 mg/kg) compared with blinded saline placebo given at cardiopulmonary resuscitation initiation with epinephrine improved cardiac function, survival, and neurological outcomes. From a mechanistic standpoint, nitrite treatment restored intracardiac nitrite and increased S-nitrosothiol levels, decreased pathological cardiac mitochondrial oxygen consumption resulting from reactive oxygen species formation, and prevented oxidative enzymatic injury via reversible specific inhibition of respiratory chain complex I. Conclusion-Nitrite therapy after resuscitation from 12 minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction, death, and neurological impairment in survivors. (Circulation. 2009; 120:897-905.) C1 [Dezfulian, Cameron] Univ Miami, Miller Sch Med, Div Pulm Crit Care & Sleep Med, Dept Med, Miami, FL 33136 USA. [Dezfulian, Cameron] Univ Miami, Miller Sch Med, Cerebral Vasc Dis Res Ctr, Dept Neurol, Miami, FL 33136 USA. [Shiva, Sruti; Gladwin, Mark T.] Univ Pittsburgh, Hemostasis & Vasc Biol Res Inst, Pittsburgh, PA USA. [Shiva, Sruti] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Pendyal, Akshay] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Beiser, D. G.; Hoek, T. L. Vanden] Univ Chicago, Emergency Resuscitat Ctr, Chicago, IL 60637 USA. [Beiser, D. G.; Hoek, T. L. Vanden] Univ Chicago, Sect Emergency Med, Chicago, IL 60637 USA. [Munasinghe, Jeeva P.] NINDS, Bethesda, MD 20892 USA. [Anderson, Stasia A.] NHLBI, Anim Imaging Core, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA. RP Dezfulian, C (reprint author), Univ Miami, Miller Sch Med, Div Pulm Crit Care & Sleep Med, Dept Med, R-47 RMSB 7058,1600 NW 10th Ave, Miami, FL 33136 USA. EM cdezfulian@med.miami.edu OI Dezfulian, Cameron/0000-0002-4486-0446 FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania FX This work was funded by and performed in the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health. Dr Gladwin is supported by the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania. NR 44 TC 88 Z9 89 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 8 PY 2009 VL 120 IS 10 BP 897 EP 905 DI 10.1161/CIRCULATIONAHA.109.853267 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 492DC UT WOS:000269633700011 PM 19704094 ER PT J AU Wuchty, S AF Wuchty, Stefan TI What is a social tie? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID COMMUNICATION; NETWORK; SCIENCE C1 [Wuchty, Stefan] Northwestern Univ, NW Inst Complex, Evanston, IL 60201 USA. RP Wuchty, S (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM wuchtys@mail.nih.gov NR 15 TC 5 Z9 5 U1 1 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 SEP 8 PY 2009 VL 106 IS 36 BP 15099 EP 15100 DI 10.1073/pnas.0907905106 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492CR UT WOS:000269632400003 PM 19805245 ER PT J AU Andrew, AJ Miyagi, E Kao, S Strebel, K AF Andrew, Amy J. Miyagi, Eri Kao, Sandra Strebel, Klaus TI The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu SO RETROVIROLOGY LA English DT Article ID INTEGRAL MEMBRANE-PROTEIN; TYPE-1 VPU; CELL-SURFACE; TRANSMEMBRANE DOMAIN; PARTICLE RELEASE; ENVELOPE GLYCOPROTEIN; RESTRICTION FACTOR; MOLECULAR-CLONING; DOWN-MODULATION; IDENTIFICATION AB Background: The Human Immunodeficiency virus type 1 (HIV-1) Vpu protein enhances virus release from infected cells and induces proteasomal degradation of CD4. Recent work identified BST-2/CD317 as a host factor that inhibits HIV-1 virus release in a Vpu sensitive manner. A current working model proposes that BST-2 inhibits virus release by tethering viral particles to the cell surface thereby triggering their subsequent endocytosis. Results: Here we defined structural properties of BST-2 required for inhibition of virus release and for sensitivity to Vpu. We found that BST-2 is modified by N-linked glycosylation at two sites in the extracellular domain. However, N-linked glycosylation was not important for inhibition of HIV-1 virus release nor did it affect surface expression or sensitivity to Vpu. Rodent BST-2 was previously found to form cysteine-linked dimers. Analysis of single, double, or triple cysteine mutants revealed that any one of three cysteine residues present in the BST-2 extracellular domain was sufficient for BST-2 dimerization, for inhibition of virus release, and sensitivity to Vpu. In contrast, BST-2 lacking all three cysteines in its ectodomain was unable to inhibit release of wild type or Vpu-deficient HIV-1 virions. This defect was not caused by a gross defect in BST-2 trafficking as the mutant protein was expressed at the cell surface of transfected 293T cells and was down-modulated by Vpu similar to wild type BST-2. Conclusion: While BST-2 glycosylation was functionally irrelevant, formation of cysteine-linked dimers appeared to be important for inhibition of virus release. However lack of dimerization did not prevent surface expression or Vpu sensitivity of BST-2, suggesting Vpu sensitivity and inhibition of virus release are separable properties of BST-2. C1 [Andrew, Amy J.; Miyagi, Eri; Kao, Sandra; Strebel, Klaus] NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. EM andrewa@niaid.nih.gov; emiyagi@niaid.nih.gov; skao@niaid.nih.gov; kstrebel@niaid.nih.gov FU NIH Intramural AIDS Targeted Antiviral Program; NIAID FX We are grateful to Mohammad Khan, Ritu Goila-Gaur, Robert C. Walker Jr, and Ronald Willey for valuable suggestions and for critical comments on the manuscript. This work was supported in part by a Grant from the NIH Intramural AIDS Targeted Antiviral Program to K. S. and by the Intramural Research Program of the NIH, NIAID. NR 53 TC 93 Z9 100 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 8 PY 2009 VL 6 AR 80 DI 10.1186/1742-4690-6-80 PG 16 WC Virology SC Virology GA 509KM UT WOS:000271015400001 PM 19737401 ER PT J AU Gopich, IV Nettels, D Schuler, B Szabo, A AF Gopich, Irina V. Nettels, Daniel Schuler, Benjamin Szabo, Attila TI Protein dynamics from single-molecule fluorescence intensity correlation functions SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biodiffusion; fluorescence; molecular biophysics; proteins ID PEPTIDE DYNAMICS; ENERGY-TRANSFER; SPECTROSCOPY; STATISTICS; COLLAPSE AB Fluorescence intensity correlation functions contain information about photophysical and conformational dynamics. We propose and implement a simple procedure to analyze such functions measured in the presence of resonance energy transfer. When there is a separation of time scales and the conformational dynamics is modeled as diffusion in the potential of mean force along the interdye distance, we obtain an analytic expression for the conformational correlation time. This can be used to find the diffusion coefficient describing conformational fluctuations given the photon count rate and equilibrium distribution. C1 [Gopich, Irina V.; Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Nettels, Daniel; Schuler, Benjamin] Univ Zurich, Inst Biochem, CH-8057 Zurich, Switzerland. RP Gopich, IV (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM irinag@niddk.nih.gov RI Schuler, Benjamin/E-7342-2011; Szabo, Attila/H-3867-2012 OI Schuler, Benjamin/0000-0002-5970-4251; FU Swiss National Science Foundation; Human Frontier Science Program; National Institutes of Health, NIDDK FX This work was supported by the Swiss National Science Foundation, the Human Frontier Science Program, and the Intramural Research Program of the National Institutes of Health, NIDDK. NR 16 TC 33 Z9 33 U1 2 U2 18 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 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 7 PY 2009 VL 131 IS 9 AR 095102 DI 10.1063/1.3212597 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 492AH UT WOS:000269625400033 PM 19739874 ER PT J AU Shugart, YY Wang, Y Samuels, JF Grados, MA Greenberg, BD Knowles, JA McCracken, JT Rauch, SL Murphy, DL Rasmussen, SA Cullen, B Hoehn-Saric, R Pinto, A Fyer, AJ Piacentini, J Pauls, DL Bienvenu, OJ Riddle, MA Liang, KY Nestadt, G AF Shugart, Y. Y. Wang, Y. Samuels, J. F. Grados, M. A. Greenberg, B. D. Knowles, J. A. McCracken, J. T. Rauch, S. L. Murphy, D. L. Rasmussen, S. A. Cullen, B. Hoehn-Saric, R. Pinto, A. Fyer, A. J. Piacentini, J. Pauls, D. L. Bienvenu, O. J. Riddle, M. A. Liang, K. Y. Nestadt, G. TI A Family-Based Association Study of the Glutamate Transporter Gene SLC1A1 in Obsessive-Compulsive Disorder in 378 Families SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genetics; candidate genes; association; OCD; heterogeneity ID COMPLEX SEGREGATION ANALYSIS; LINKAGE ANALYSIS; HISTORY; TESTS; ADOLESCENTS; RATIONALE; CHILDREN; LOCUS AB SLC1A encodes the neuronal and epithelial glutamate transporter and was previously tested as a candidate for obsessive-compulsive disorder (OCD) by several research groups. Recently, three independent research groups reported significant association findings between OCD and several genetic variants in SLC1A1. This study reports the results from a family-based association study, which examined the association between 13 single nucleotide polymorphisms (SNPs) within or in proximity to the SLC1A1 gene. Although we did not replicate association findings for those significant SNPs reported by previous studies, our study indicated a strong association signal with the SNP RS301443 (P-value = 0.000067; Bonferroni corrected P-value = 0.0167) under a dominant model, with an estimated odds ratio of 3.5 (confidence interval: 2.66-4.50). Further, we conducted single SNP analysis after stratifying the full data set by the gender status of affecteds in each family. The P-value for RS301443 in families with the male affecteds was 0.00027, and the P-value in families with female affecteds was 0.076. The fact that we identified a signal which was not previously reported by the other research groups may be due to differences in study designs and sample ascertainment. However, it is also possible that this significant SNP may be part of a regulator for SLC1A1, given that it is roughly 7.5 kb away from the boundary of the SLC1A1 gene. However, this potential finding needs to be validated biologically. Further functional studies in this region are planned by this research group. (C) 2009 Wiley-Liss, Inc. C1 [Shugart, Y. Y.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wang, Y.; Samuels, J. F.; Grados, M. A.; Cullen, B.; Hoehn-Saric, R.; Bienvenu, O. J.; Riddle, M. A.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Greenberg, B. D.; Rasmussen, S. A.; Pinto, A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Knowles, J. A.; McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Rauch, S. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. [Fyer, A. J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Pauls, D. L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Liang, K. Y.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Shugart, YY (reprint author), Dept Epidemiol & Biostat, 1629 Thames St,Suite 401, Baltimore, MD 21044 USA. EM yyao@jhsph.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 NR 38 TC 46 Z9 48 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2009 VL 150B IS 6 BP 886 EP 892 DI 10.1002/ajmg.b.30914 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 491SO UT WOS:000269600000014 PM 19152386 ER PT J AU Wolitz, R Emanuel, E Shah, S AF Wolitz, Rebecca Emanuel, Ezekiel Shah, Seema TI Rethinking the responsiveness requirement for international research SO LANCET LA English DT Editorial Material ID DEVELOPING-COUNTRIES C1 [Shah, Seema] NIAID, HJF Liaison Off, Div Aids, Dept Bioeth,NIH,Clin Ctr, Bethesda, MD 20892 USA. RP Shah, S (reprint author), NIAID, HJF Liaison Off, Div Aids, Dept Bioeth,NIH,Clin Ctr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov NR 24 TC 18 Z9 18 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 5 PY 2009 VL 374 IS 9692 BP 847 EP 849 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 492QU UT WOS:000269675000032 PM 19733781 ER PT J AU Goode, EL Szabo, C Prokunina-Olsson, L Vierkant, RA Fredericksen, ZS Collins, FS White, KL Schmidt, M Fridley, BL Couch, FJ AF Goode, Ellen L. Szabo, Csilla Prokunina-Olsson, Ludmila Vierkant, Robert A. Fredericksen, Zachary S. Collins, Francis S. White, Kristin L. Schmidt, Michele Fridley, Brooke L. Couch, Fergus J. TI No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer SO BMC CANCER LA English DT Article ID GENETIC-VARIATION; COLON-CANCER; PATHWAY; TUMORIGENESIS; OBESITY; COMPLEX AB Background: TCF7L2 is a transcription factor involved in Wnt/beta-catenin signaling which has a variant known to be associated with risk of Type 2 diabetes and, in some studies, with risk of certain cancers, including familial breast cancer. No studies of ovarian cancer have been reported to date. Methods: Two clinic-based case-control studies at the Mayo Clinic were assessed including 798 breast cancer cases, 843 breast cancer controls, 391 ovarian cancer cases, and 458 ovarian cancer controls. Genotyping at TCF7L2 rs12255372 used a 5' endonuclease assay, and statistical analysis used logistic regression among participants as a whole and among a priori-defined subsets. Results: No associations with risk of breast or ovarian cancer were observed (ordinal model, p = 0.62 and p = 0.75, respectively). In addition, no associations were observed among sub-groups defined by age, BMI, family history, stage, grade, histology, or tumor behavior. Conclusion: Although the biology of the Wnt/beta-catenin signaling pathway and prior association between rs12255372 and numerous phenotypes warranted examination of this TCF7L2 SNP, no compelling evidence for association with breast or ovarian cancer was observed. C1 [Goode, Ellen L.; Szabo, Csilla; Couch, Fergus J.] Mayo Clin, Coll Med, Lab Med & Pathol, Rochester, MN 55905 USA. [Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Collins, Francis S.] NIH, Off Director, Bethesda, MD 20892 USA. RP Goode, EL (reprint author), Mayo Clin, Coll Med, Lab Med & Pathol, Rochester, MN 55905 USA. EM egoode@mayo.edu; szabo.csilla@mayo.edu; prokuninal@mail.nih.gov; vierkant.robert@mayo.edu; Fredericksen.zachary@mayo.edu; Francis.Collins@nih.gov; white.kristin@mayo.edu; schmidt.michele1@mayo.edu; fridley.brooke@mayo.edu; couch.fergus@mayo.edu RI Fridley, Brooke/D-8315-2015; OI Fridley, Brooke/0000-0001-7739-7956; Vierkant, Robert/0000-0001-6242-5221; Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU Mayo foundation; [R01 CA122443] FX This work was supported, in part, by funding from the Mayo foundation and R01 CA122443. NR 21 TC 13 Z9 13 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 4 PY 2009 VL 9 AR 312 DI 10.1186/1471-2407-9-312 PG 4 WC Oncology SC Oncology GA 500NL UT WOS:000270309400001 PM 19732438 ER PT J AU Zielinski, R Przytycki, PF Zheng, J Zhang, D Przytycka, TM Capala, J AF Zielinski, Rafal Przytycki, Pawel F. Zheng, Jie Zhang, David Przytycka, Teresa M. Capala, Jacek TI The crosstalk between EGF, IGF, and Insulin cell signaling pathways - computational and experimental analysis SO BMC SYSTEMS BIOLOGY LA English DT Article ID INDUCED APOPTOSIS; RECEPTOR; ACTIVATION; NETWORKS; CANCER; RESISTANCE; SYSTEMS; MODELS; TNF AB Background: Cellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways. Results: We study the combined signaling network of three major pro-survival signaling pathways: Epidermal Growth Factor Receptor (EGFR), Insulin-like Growth Factor-1 Receptor (IGF-1R), and Insulin Receptor (IR). Our study involves static analysis and dynamic modeling of this network, as well as an experimental verification of the model by measuring the response of selected signaling molecules to differential stimulation of EGF, IGF and insulin receptors. We introduced two novel measures of the importance of a node in the context of such crosstalk. Based on these measures several molecules, namely Erk1/2, Akt1, Jnk, p70S6K, were selected for monitoring in the network simulation and for experimental studies. Our simulation method relies on the Boolean network model combined with stochastic propagation of the signal. Most (although not all) trends suggested by the simulations have been confirmed by experiments. Conclusion: The simple model implemented in this paper provides a valuable first step in modeling signaling networks. However, to obtain a fully predictive model, a more detailed knowledge regarding parameters of individual interactions might be necessary. C1 [Zheng, Jie; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Zielinski, Rafal; Capala, Jacek] NCI, NIH, Bethesda, MD 20892 USA. [Przytycki, Pawel F.] Columbia Univ, Columbia Coll, New York, NY USA. [Zhang, David] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. RP Przytycka, TM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. EM zielinkir@mail.nih.gov; pfp2104@columbia.edu; zhengj@ncbi.nlm.nih.gov; dyzzy@umd.edu; przytyck@ncbi.nlm.nih.gov; capalaj@mail.nih.gov RI Zheng, Jie/C-1356-2011 OI Zheng, Jie/0000-0001-6774-9786 FU Intramural Research Program of the NIH; National Library of Medicine; National Cancer Institute; Center for Cancer Research; National Institutes of Health [N01-CO-12400, N01-CO-12401] FX This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine, National Cancer Institute, Center for Cancer Research and was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contracts N01-CO-12400 and N01-CO-12401. 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. NR 34 TC 25 Z9 25 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD SEP 4 PY 2009 VL 3 AR 88 DI 10.1186/1752-0509-3-88 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 506DX UT WOS:000270754900002 PM 19732446 ER PT J AU Wang, ZB Zang, CZ Cui, KR Schones, DE Barski, A Peng, WQ Zhao, KJ AF Wang, Zhibin Zang, Chongzhi Cui, Kairong Schones, Dustin E. Barski, Artem Peng, Weiqun Zhao, Keji TI Genome-wide Mapping of HATs and HDACs Reveals Distinct Functions in Active and Inactive Genes SO CELL LA English DT Article ID HISTONE DEACETYLASE; CHROMATIN SIGNATURES; CODING REGIONS; COMPLEX; YEAST; ACETYLATION; METHYLATION; ACETYLTRANSFERASE; TRANSCRIPTION; NUCLEOSOMES AB Histone acetyltransferases (HATs) and deacetylases (HDACs) function antagonistically to control histone acetylation. As acetylation is a histone mark for active transcription, HATs have been associated with active and HDACs with inactive genes. We describe here genome-wide mapping of HATs and HDACs binding on chromatin and find that both are found at active genes with acetylated histones. Our data provide evidence that HATs and HDACs are both targeted to transcribed regions of active genes by phosphorylated RNA Pol II. Furthermore, the majority of HDACs in the human genome function to reset chromatin by removing acetylation at active genes. Inactive genes that are primed by MLL-mediated histone H3K4 methylation are subject to a dynamic cycle of acetylation and deacetylation by transient HAT/HDAC binding, preventing Pol II from binding to these genes but poising them for future activation. Silent genes without any H3K4 methylation signal show no evidence of being bound by HDACs. C1 [Wang, Zhibin; Cui, Kairong; Schones, Dustin E.; Barski, Artem; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI Zang, Chongzhi/D-1445-2011; OI Barski, Artem/0000-0002-1861-5316 FU George Washington University; Division of Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX The mRNA profiles were analyzed on Affymetrix gene chips by the National Heart, Lung, and Blood Institute (NHLBI) Genomics Core Facility. D. E. S. was supported by the Lenfant Biomedical Fellowship of the NHLBI. C.Z. and W. P. were partially supported by the University Facilitating Fund of the George Washington University. The research was supported by the Division of Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 54 TC 577 Z9 591 U1 11 U2 63 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 4 PY 2009 VL 138 IS 5 BP 1019 EP 1031 DI 10.1016/j.cell.2009.06.049 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 491FW UT WOS:000269564600025 PM 19698979 ER PT J AU Castilho, RM Squarize, CH Chodosh, LA Williams, BO Gutkind, JS AF Castilho, Rogerio M. Squarize, Cristiane H. Chodosh, Lewis A. Williams, Bart O. Gutkind, J. Silvio TI mTOR Mediates Wnt-Induced Epidermal Stem Cell Exhaustion and Aging SO CELL STEM CELL LA English DT Article ID HAIR FOLLICLE MORPHOGENESIS; BETA-CATENIN; BREAST-CANCER; SIGNALING CONTROLS; ROOT SHEATH; LIFE-SPAN; SKIN; PATHWAY; GROWTH; ACTIVATION AB Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. Although Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. Although Wnt1 induced the activation of beta-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function. These findings suggest that whereas activation of beta-catenin contributes to tumor growth, epithelial stem cells may be endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation. C1 [Castilho, Rogerio M.; Squarize, Cristiane H.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Chodosh, Lewis A.] Univ Penn, Sch Med, Dept Canc Biol, Philadelphia, PA 19104 USA. [Chodosh, Lewis A.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Williams, Bart O.] Van Andel Res Inst, Lab Cell Signaling & Carcinogenesis, Grand Rapids, MI 49503 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Castilho, Rogerio/E-4987-2010; Gutkind, J. Silvio/A-1053-2009; Williams, Bart/A-3539-2013 OI Williams, Bart/0000-0002-5261-5301 FU Intramural Research Program; Craniofacial Tissue Remodeling Initiative of the NIH; NIDCR FX a We are grateful to Dr. R. M. Porter (Wales College of Medicine) for the polyclonal antibody against IRS and to Dr. T. Finkel (National Heart, Lung, and Blood Institute/ National Institutes of Health [NIH]) for critical reading of the manuscript. This research was supported by the Intramural Research Program and the Craniofacial Tissue Remodeling Initiative of the NIH, NIDCR. NR 55 TC 171 Z9 175 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD SEP 4 PY 2009 VL 5 IS 3 BP 279 EP 289 DI 10.1016/j.stem.2009.06.017 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 529VA UT WOS:000272545700014 PM 19733540 ER PT J AU Lee-Young, RS Griffee, SR Lynes, SE Bracy, DP Ayala, JE McGuinness, OP Wasserman, DH AF Lee-Young, Robert S. Griffee, Susan R. Lynes, Sara E. Bracy, Deanna P. Ayala, Julio E. McGuinness, Owen P. Wasserman, David H. TI Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FATTY-ACID OXIDATION; NITRIC-OXIDE RELEASE; GLUCOSE-TRANSPORT; DOSE-RESPONSE; MOUSE MODEL; BLOOD-FLOW; CONTRACTION; TISSUES; NNOS; MICE AB AMP-activated protein kinase (AMPK) has been postulated as a super-metabolic regulator, thought to exert numerous effects on skeletal muscle function, metabolism, and enzymatic signaling. Despite these assertions, little is known regarding the direct role(s) of AMPK in vivo, and results obtained in vitro or in situ are conflicting. Using a chronically catheterized mouse model (carotid artery and jugular vein), we show that AMPK regulates skeletal muscle metabolism in vivo at several levels, with the result that a deficit in AMPK activity markedly impairs exercise tolerance. Compared with wild-type littermates at the same relative exercise capacity, vascular glucose delivery and skeletal muscle glucose uptake were impaired; skeletal muscle ATP degradation was accelerated, and arterial lactate concentrations were increased in mice expressing a kinase-dead AMPK alpha 2 subunit (alpha 2-KD) in skeletal muscle. Nitric-oxide synthase (NOS) activity was significantly impaired at rest and in response to exercise in alpha 2-KD mice; expression of neuronal NOS (NOS mu) was also reduced. Moreover, complex I and IV activities of the electron transport chain were impaired 32 +/- 8 and 50 +/- 7%, respectively, in skeletal muscle of alpha 2-KD mice (p < 0.05 versus wild type), indicative of impaired mitochondrial function. Thus, AMPK regulates neuronal NOS mu expression, NOS activity, and mitochondrial function in skeletal muscle. In addition, these results clarify the role of AMPK in the control of muscle glucose uptake during exercise. Collectively, these findings demonstrate that AMPK is central to substrate metabolism in vivo, which has important implications for exercise tolerance in health and certain disease states characterized by impaired AMPK activation in skeletal muscle. C1 [Lee-Young, Robert S.; Griffee, Susan R.; Lynes, Sara E.; Bracy, Deanna P.; Ayala, Julio E.; McGuinness, Owen P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Ayala, Julio E.; McGuinness, Owen P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. RP Lee-Young, RS (reprint author), 823 Light Hall,2200 Pierce Ave, Nashville, TN 37232 USA. EM robert.s.lee-young@vanderbilt.edu FU National Institutes of Health Grants [U24 DK-59637, R01 DK-54902] FX This work was supported, in whole or in part, by National Institutes of Health Grants U24 DK-59637 and R01 DK-54902 (to D. H. W.). NR 57 TC 74 Z9 78 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 4 PY 2009 VL 284 IS 36 BP 23925 EP 23934 DI 10.1074/jbc.M109.021048 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 488WE UT WOS:000269380200006 PM 19525228 ER PT J AU Babelova, A Moreth, K Tsalastra-Greul, W Zeng-Brouwers, J Eickelberg, O Young, MF Bruckner, P Pfeilschifter, J Schaefer, RM Grone, HJ Schaefer, L AF Babelova, Andrea Moreth, Kristin Tsalastra-Greul, Wasiliki Zeng-Brouwers, Jinyang Eickelberg, Oliver Young, Marian F. Bruckner, Peter Pfeilschifter, Josef Schaefer, Roland M. Groene, Hermann-Josef Schaefer, Liliana TI Biglycan, a Danger Signal That Activates the NLRP3 Inflammasome via Toll-like and P2X Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEUCINE-RICH PROTEOGLYCANS; INNATE IMMUNE-RESPONSE; NALP3 INFLAMMASOME; CASPASE-1; IL-1-BETA; HYALURONAN; GENE; ATP; MACROPHAGES; SECRETION AB The role of endogenous inducers of inflammation is poorly understood. To produce the proinflammatory master cytokine interleukin (IL)-1 beta, macrophages need double stimulation with ligands to both Toll-like receptors (TLRs) for IL-1 beta gene transcription and nucleotide-binding oligomerization domain-like receptors for activation of the inflammasome. It is particularly intriguing to define how this complex regulation is mediated in the absence of an infectious trigger. Biglycan, a ubiquitous leucine-rich repeat proteoglycan of the extracellular matrix, interacts with TLR2/4 on macrophages. The objective of this study was to define the role of biglycan in the synthesis and activation of IL-1 beta. Here we show that in macrophages, soluble biglycan induces the NLRP3/ASC inflammasome, activating caspase-1 and releasing mature IL-1 beta without the need for additional costimulatory factors. This is brought about by the interaction of biglycan with TLR2/4 and purinergic P2X(4)/P2X7 receptors, which induces receptor cooperativity. Furthermore, reactive oxygen species formation is involved in biglycan-mediated activation of the inflammasome. By signaling through TLR2/4, biglycan stimulates the expression of NLRP3 and proIL-1 beta mRNA. Both in a model of non-infectious inflammatory renal injury (unilateral ureteral obstruction) and in lipopolysaccharide-induced sepsis, biglycan-deficient mice displayed lower levels of active caspase-1 and mature IL-1 beta in the kidney, lung, and circulation. Our results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and describe a fundamental paradigm of how tissue stress or injury is monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response. C1 [Babelova, Andrea; Moreth, Kristin; Tsalastra-Greul, Wasiliki; Zeng-Brouwers, Jinyang; Pfeilschifter, Josef; Schaefer, Liliana] Univ Frankfurt Klinikum, Inst Allgemeine Pharmakol & Toxikol, Pharmazentrum Frankfurt ZAFES, D-60590 Frankfurt, Germany. [Moreth, Kristin; Zeng-Brouwers, Jinyang; Schaefer, Roland M.] Univ Munster, Dept Med D, D-48149 Munster, Germany. [Bruckner, Peter] Univ Munster, Inst Physiol Chem & Pathobiochem, D-48149 Munster, Germany. [Moreth, Kristin; Zeng-Brouwers, Jinyang; Bruckner, Peter; Schaefer, Roland M.] Univ Munster, Interdisciplinary Ctr Clin Res, D-48149 Munster, Germany. [Eickelberg, Oliver] Univ Munich, Comprehens Pneumol Ctr, D-85764 Neuherberg, Germany. [Young, Marian F.] NIH, Craniofacial & Skeletal Dis Branch, NIDCR, Bethesda, MD 20892 USA. [Groene, Hermann-Josef] German Canc Res Ctr, Dept Cellular & Mol Pathol, D-69120 Heidelberg, Germany. RP Schaefer, L (reprint author), Univ Frankfurt Klinikum, Inst Allgemeine Pharmakol & Toxikol, Pharmazentrum Frankfurt ZAFES, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM Schaefer@med.uni-frankfurt.de RI Eickelberg, Oliver/A-5461-2013 OI Eickelberg, Oliver/0000-0001-7170-0360 FU Deutsche Forschungsgemeinschaft [SFB 815, SCHA 1082/2-1]; Excellence Cluster Cardiopulmonary System [SFB 405]; Interdisciplinary Center of Clinical Research, Muenster [Schae2/026/06, KliFo 118]; Else Kroner-Fresenius-Stiftung; National Institutes of Health; NIDCR; Intramural Research Program FX This work was supported by Deutsche Forschungsgemeinschaft SFB 815, Project A5 ( to L. S.) and SCHA 1082/2-1( to L. S. and H.-J.G.), the Excellence Cluster Cardiopulmonary System ( to L. S. and O.E.), SFB 405, Project B10 ( to H.-J.G.), Interdisciplinary Center of Clinical Research, Muenster, Grant Schae2/026/06 ( to L. S., R. M. S., and P. B.), KliFo 118 ( to O. E.), and Else Kroner-Fresenius-Stiftung( to L. S.). This work was also supported in part by the National Institutes of Health, NIDCR, Intramural Research Program ( to M. F. Y.). NR 63 TC 192 Z9 201 U1 3 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 4 PY 2009 VL 284 IS 36 BP 24035 EP 24048 DI 10.1074/jbc.M109.014266 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 488WE UT WOS:000269380200018 PM 19605353 ER PT J AU Smirnovas, V Kim, JI Lu, XJ Atarashi, R Caughey, B Surewicz, WK AF Smirnovas, Vytautas Kim, Jae-Il Lu, Xiaojun Atarashi, Ryuichiro Caughey, Byron Surewicz, Witold K. TI Distinct Structures of Scrapie Prion Protein (PrPSc)-seeded Versus Spontaneous Recombinant Prion Protein Fibrils Revealed by Hydrogen/Deuterium Exchange SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IN-VITRO; AMYLOID FIBRILS; EMERGING PRINCIPLES; CONVERSION; RESISTANT; CORE; FORM; INFECTIVITY; DOMAIN; INHERITANCE AB The detailed structures of prion disease-associated, partially protease-resistant forms of prion protein (e. g. PrPSc) are largely unknown. PrPSc appears to propagate itself by autocatalyzing the conformational conversion and oligomerization of normal prion protein (PrPC). One manifestation of PrPSc templating activity is its ability, in protein misfolding cyclic amplification reactions, to seed the conversion of recombinant prion protein (rPrP) into aggregates that more closely resemble PrPSc than spontaneously nucleated rPrP amyloids in terms of proteolytic fragmentation and infrared spectra. The absence of posttranslational modifications makes these rPrP aggregates more amenable to detailed structural analyses than bona fide PrPSc. Here, we compare the structures of PrPSc-seeded and spontaneously nucleated aggregates of hamster rPrP by using H/D exchange coupled with mass spectrometry. In spontaneously formed fibrils, very slow H/D exchange in region similar to 163-223 represents a systematically H-bonded cross-beta amyloid core structure. PrPSc-seeded aggregates have a subpopulation of molecules in which this core region extends N-terminally as far as to residue similar to 145, and there is a significant degree of order within residues similar to 117-133. The formation of tightly H-bonded structures by these more N-terminal residues may account partially for the generation of longer protease-resistant regions in the PrPSc-seeded rPrP aggregates; however, part of the added protease resistance is dependent on the presence of SDS during proteolysis, emphasizing the multifactorial influences on proteolytic fragmentation patterns. These results demonstrate that PrPSc has a distinct templating activity that induces ordered, systematically H-bonded structure in regions that are dynamic and poorly defined in spontaneously formed aggregates of rPrP. C1 [Smirnovas, Vytautas; Kim, Jae-Il; Lu, Xiaojun; Surewicz, Witold K.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Atarashi, Ryuichiro; Caughey, Byron] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Surewicz, WK (reprint author), Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. EM witold.surewicz@case.edu RI Smirnovas, Vytautas/C-5583-2009; OI Smirnovas, Vytautas/0000-0002-1829-5455 FU National Institutes of Health [NS44158, AG14359] FX This work was supported, in whole or part, by National Institutes of Health Grants NS44158 and AG14359. NR 48 TC 43 Z9 44 U1 1 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 4 PY 2009 VL 284 IS 36 BP 24233 EP 24241 DI 10.1074/jbc.M109.036558 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 488WE UT WOS:000269380200037 PM 19596861 ER PT J AU Berquist, BR Wilson, DM AF Berquist, Brian R. Wilson, David M., III TI Nucleic Acid Binding Activity of Human Cockayne Syndrome B Protein and Identification of Ca2+ as a Novel Metal Cofactor SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE CSB/ERCC6; SWI/SNF2; calcium; DNA-dependent ATPase; nucleic acid binding ID NUCLEOTIDE EXCISION-REPAIR; RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; ABASIC ENDONUCLEASE ACTIVITY; STRAND-ANNEALING ACTIVITIES; CSB ERCC6 GENE; DNA-REPAIR; XERODERMA-PIGMENTOSUM; HELICASE DOMAIN; SINGLE-MOLECULE AB The Cockayne syndrome group B protein (CSB) is a member of the SWI/SNF2 subgroup of Superfamily 2 ATPases/nucleic acid translocases/helicases, and is defective in the autosomal recessive segmental progeroid disorder Cockayne syndrome. This study examines the ATP-dependent and the ATP-independent biochemical functions of human CSB. We show that Ca2+ is a novel metal cofactor of CSB for ATP hydrolysis, mainly through the enhancement of k(cat), and that a variety of biologically relevant model nucleic acid substrates can function to activate CSB ATPase activity with either Mg2+ or Ca2+, present. However, CSB lacked detectable ATP- or dependent helicase and single- or double-stranded nucleic acid translocase activities in the presence of either divalent metal. CSB was found to support ATP-independent complementary strand annealing of DNA/DNA, DNA/RNA, and RNA/RNA duplexes, with Ca2+ again promoting optimal activity. CSB formed a stable protein:DNA complex with a 34mer double-stranded DNA in electrophoretic mobility-shift assays, independent of divalent metal or nucleotide (e.g. ATP). Moreover, CSB was able to form a stable complex with a range of nucleic acid substrates, including bubble and "pseudo-triplex" double-stranded DNAs that resemble replication and transcription intermediates, as well as forked duplexes of DNA/DNA, DNA/RNA, and RNA/RNA composition, the latter two of which do not promote CSB ATPase activity. Association of CSB with DNA, independent of ATP binding or hydrolysis, was seemingly sufficient to displace or rearrange a stable pre-bound protein:DNA complex, a property potentially important for its roles in transcription and DNA repair. Published by Elsevier Ltd. C1 [Berquist, Brian R.; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU National Institutes of Health, National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 63 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 4 PY 2009 VL 391 IS 5 BP 820 EP 832 DI 10.1016/j.jmb.2009.06.078 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 495OC UT WOS:000269901900004 PM 19580815 ER PT J AU Toyooka, N Zhou, DJ Nemoto, H Tezuka, Y Kadota, S Andriamaharavo, NR Garraffo, HM Spande, TF Daly, JW AF Toyooka, Naoki Zhou, Dejun Nemoto, Hideo Tezuka, Yasuhiro Kadota, Shigetoshi Andriamaharavo, Nirina R. Garraffo, H. Martin Spande, Thomas F. Daly, John W. TI Efficient Enantio- and Diastereodivergent Synthesis of Poison-Frog Alkaloids 251O and trans-223B SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; ENANTIOSELECTIVE SYNTHESIS; PYRROLIZIDINE ALKALOIDS; BATRACHOTOXIN ALKALOIDS; CHIROSPECIFIC SYNTHESIS; CHEMICAL DEFENSE; PASSERINE BIRDS; AMPHIBIAN SKIN; INDOLIZIDINE; VENOM AB An efficient and flexible synthesis of poison-frog alkaloids 251O and trans-223B has been achieved by using for both alkaloids an enantiodivergent process starting from the common lactam 1. The relative stereochemistry of 251O and trans-223B was determined to be 7 (R = n-C7H15, R' = n-Pr) and 14 by the present enantioselective synthesis. C1 [Toyooka, Naoki; Zhou, Dejun; Nemoto, Hideo] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Toyama 9300194, Japan. [Tezuka, Yasuhiro; Kadota, Shigetoshi] Toyama Univ, Inst Nat Med, Toyama 9300194, Japan. [Andriamaharavo, Nirina R.; Garraffo, H. Martin; Spande, Thomas F.; Daly, John W.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Toyooka, N (reprint author), Toyama Univ, Grad Sch Med & Pharmaceut Sci, Sugitani 2630, Toyama 9300194, Japan. EM toyooka@pha.u-toyama.ac.jp FU Japan Society for the Promotion of Science; NIDDK FX This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. Work at NIH was supported by intramural funds of NIDDK. NR 31 TC 10 Z9 10 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 EI 1520-6904 J9 J ORG CHEM JI J. Org. Chem. PD SEP 4 PY 2009 VL 74 IS 17 BP 6784 EP 6791 DI 10.1021/jo901100m PG 8 WC Chemistry, Organic SC Chemistry GA 487GA UT WOS:000269257800040 PM 19637860 ER PT J AU Vanacore, R Ham, AJL Voehler, M Sanders, CR Conrads, TP Veenstra, TD Sharpless, KB Dawson, PE Hudson, BG AF Vanacore, Roberto Ham, Amy-Joan L. Voehler, Markus Sanders, Charles R. Conrads, Thomas P. Veenstra, Timothy D. Sharpless, K. Barry Dawson, Philip E. Hudson, Billy G. TI A Sulfilimine Bond Identified in Collagen IV SO SCIENCE LA English DT Article ID BASEMENT-MEMBRANE COLLAGEN; COVALENT CROSS-LINK; CRYSTAL-STRUCTURE; IMMUNE PRIVILEGE; STRUCTURAL BASIS; METHIONINE; DOMAIN; STABILIZATION; AUTOANTIGEN; INTEGRINS AB Collagen IV networks are ancient proteins of basement membranes that underlie epithelia in metazoa from sponge to human. The networks provide structural integrity to tissues and serve as ligands for integrin cell-surface receptors. They are assembled by oligomerization of triple-helical protomers and are covalently crosslinked, a key reinforcement that stabilizes networks. We used Fourier-transform ion cyclotron resonance mass spectrometry and nuclear magnetic resonance spectroscopy to show that a sulfilimine bond (-S=N-) crosslinks hydroxylysine-211 and methionine-93 of adjoining protomers, a bond not previously found in biomolecules. This bond, the nitrogen analog of a sulfoxide, appears to have arisen at the divergence of sponge and cnidaria, an adaptation of the extracellular matrix in response to mechanical stress in metazoan evolution. C1 [Vanacore, Roberto; Hudson, Billy G.] Vanderbilt Univ, Dept Med, Div Nephrol, Nashville, TN 37232 USA. [Vanacore, Roberto; Hudson, Billy G.] Vanderbilt Univ, Ctr Matrix Biol, Nashville, TN 37232 USA. [Ham, Amy-Joan L.; Sanders, Charles R.; Hudson, Billy G.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Voehler, Markus] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA. [Hudson, Billy G.] Vanderbilt Univ, Dept Pathol, Nashville, TN 37232 USA. [Conrads, Thomas P.; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Sharpless, K. Barry; Dawson, Philip E.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Sharpless, K. Barry; Dawson, Philip E.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Dawson, Philip E.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. RP Vanacore, R (reprint author), Vanderbilt Univ, Dept Med, Div Nephrol, Nashville, TN 37232 USA. EM roberto.vanacore@vanderbilt.edu; billy.hudson@vanderbilt.edu RI Vanacore, Roberto/C-9763-2012 FU NIH [DK065123, DK18381, DC007416, GM059380]; W. M. Keck Foundation; Skaggs Institute for Chemical Biology FX We thank D. Liebler for facilitating the initial contact with T. D. Veenstra from SAIC-Frederick, Incorporated, and C. Bolm (Aachen University, Germany) for helpful discussions. The technical assistance of P. Todd and M. Rafi is greatly appreciated. We would also like to thank S. Hill and H. McDonald, from the Proteomics Laboratory at the Mass Spectrometry Research Center of Vanderbilt University, for their assistance with the Orbitrap-LTQ (Therme Electron, San Jose, CA) instrument. This work was supported in part by NIH grants DK065123 and DK18381 (to B. G. H.), DC007416 (C. R. S.), and GM059380 (P. E. D.); the W. M. Keck Foundation (K. B. S.); and the Skaggs Institute for Chemical Biology (K. B. S.). R. V. and B. G. H. have filed a provisional patent (1 June 2009) on the potential enzyme system that catalyses the sulfilimine bond formation and that may be involved in pathophysiological processes. NR 30 TC 75 Z9 77 U1 4 U2 37 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 4 PY 2009 VL 325 IS 5945 BP 1230 EP 1234 DI 10.1126/science.1176811 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 490RY UT WOS:000269523200033 PM 19729652 ER PT J AU Hait, NC Allegood, J Maceyka, M Strub, GM Harikumar, KB Singh, SK Luo, C Marmorstein, R Kordula, T Milstien, S Spiegel, S AF Hait, Nitai C. Allegood, Jeremy Maceyka, Michael Strub, Graham M. Harikumar, Kuzhuvelil B. Singh, Sandeep K. Luo, Cheng Marmorstein, Ronen Kordula, Tomasz Milstien, Sheldon Spiegel, Sarah TI Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate SO SCIENCE LA English DT Article ID MEDIATED PHOSPHORYLATION; DEACETYLASE INHIBITORS; SPHINGOSINE-KINASE-2; ACTIVATION; FAMILY AB The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) can act intracellularly independently of its cell surface receptors through unknown mechanisms. Sphingosine kinase 2 (SphK2), one of the isoenzymes that generates S1P, was associated with histone H3 and produced S1P that regulated histone acetylation. S1P specifically bound to the histone deacetylases HDAC1 and HDAC2 and inhibited their enzymatic activity, preventing the removal of acetyl groups from lysine residues within histone tails. SphK2 associated with HDAC1 and HDAC2 in repressor complexes and was selectively enriched at the promoters of the genes encoding the cyclin-dependent kinase inhibitor p21 or the transcriptional regulator c-fos, where it enhanced local histone H3 acetylation and transcription. Thus, HDACs are direct intracellular targets of S1P and link nuclear S1P to epigenetic regulation of gene expression. C1 [Hait, Nitai C.; Allegood, Jeremy; Maceyka, Michael; Strub, Graham M.; Harikumar, Kuzhuvelil B.; Singh, Sandeep K.; Kordula, Tomasz; Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Hait, Nitai C.; Allegood, Jeremy; Maceyka, Michael; Strub, Graham M.; Harikumar, Kuzhuvelil B.; Singh, Sandeep K.; Kordula, Tomasz; Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23298 USA. [Luo, Cheng; Marmorstein, Ronen] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Luo, Cheng; Marmorstein, Ronen] Univ Penn, Wistar Inst, Philadelphia, PA 19104 USA. [Luo, Cheng] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China. [Milstien, Sheldon] NIMH, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu OI Harikumar, KB/0000-0002-1763-4179 FU NIH [R37GM043880, R01CA61774]; National Research Service Award [F30NSO58008]; NIMH Intramural Research Program FX This work was supported by grants from the NIH R37GM043880 and R01CA61774 (S. S.). G. S. was supported by National Research Service Award F30NSO58008. S. M. was supported by the NIMH Intramural Research Program. NR 21 TC 354 Z9 370 U1 1 U2 31 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 4 PY 2009 VL 325 IS 5945 BP 1254 EP 1257 DI 10.1126/science.1176709 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 490RY UT WOS:000269523200040 PM 19729656 ER PT J AU Allam, A Conze, DB Torchia, MLG Munitic, I Yagita, H Sowell, RT Marzo, AL Ashwell, JD AF Allam, Atef Conze, Dietrich B. Torchia, Maria Letizia Giardino Munitic, Ivana Yagita, Hideo Sowell, Ryan T. Marzo, Amanda L. Ashwell, Jonathan D. TI The CD8(+) memory T-cell state of readiness is actively maintained and reversible SO BLOOD LA English DT Article ID B-CELLS; CD28-MEDIATED COSTIMULATION; BONE-MARROW; PROLIFERATION; EXPRESSION; INFECTION; EFFECTOR; ANTIGEN; NAIVE; LYMPHOCYTE AB The ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G(1) to the G(0) cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-gamma production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase-dependent manner. Consistent with these results, maintenance of G1 in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance. (Blood. 2009; 114: 2121-2130) C1 [Allam, Atef; Conze, Dietrich B.; Torchia, Maria Letizia Giardino; Munitic, Ivana; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Yagita, Hideo] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. [Sowell, Ryan T.; Marzo, Amanda L.] Rush Univ, Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 37,Rm 3002, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU National Institutes of Health; Center for Cancer Research; National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. NR 44 TC 25 Z9 26 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 3 PY 2009 VL 114 IS 10 BP 2121 EP 2130 DI 10.1182/blood-2009-05-220087 PG 10 WC Hematology SC Hematology GA 490RZ UT WOS:000269523300018 PM 19617575 ER PT J AU Takikita, M Hu, N Shou, JZ Wang, QH Giffen, C Taylor, PR Hewitt, SM AF Takikita, Mikiko Hu, Nan Shou, Jian-zhong Wang, Quan-Hong Giffen, Carol Taylor, Philip R. Hewitt, Stephen M. TI Biomarkers of apoptosis and survival in esophageal squamous cell carcinoma SO BMC CANCER LA English DT Article ID PROGNOSTIC-SIGNIFICANCE; PROSTATE-CANCER; BCL-2 PROTEIN; FAS LIGAND; EXPRESSION; DEATH; FADD; PHOSPHORYLATION; ASSOCIATION; PROGRESSION AB Background: Cancer of the esophagus is a deadly malignancy, and development of biomarkers that predict survival is an urgent need. The apoptotic pathways have been hypothesized as important in progression of esophageal squamous cell carcinoma (ESCC). We investigated a panel of proteins that regulate apoptosis as candidate of biomarkers of prognosis in ESCC. Methods: Tissue microarray (TMA) including 313 surgically-resected cases of ESCC specimens was built for immunohistochemical interrogation. We evaluated seven genes in the FasL-Fas apoptotic pathway-FasL, Fas, FAS-associated death domain protein (FADD), phosphorylated-FADD, and caspase 8 and 10, and the antiapoptotic protein bcl-2. We studied pathway integrity and relations to risk and clinical factors, and determined the prognostic significance of each marker. Results: Five markers showed strong inter-marker correlations (r >= 0.28, p < 0.001), including FasL, Fas, FADD, and caspases 8 and 10. FasL and FADD also showed modest correlations with one or more cancer risk factors, but none of the markers was significantly associated with either tumor stage or lymph node metastasis, the only two clinical factors that predicted survival in these ESCC cases. Multivariate-adjusted proportional hazard regression models showed no association between protein expression and risk of death for any of the seven markers examined. Conclusion: Individual biomarkers in the apoptosis pathway do not appear to predict survival of patients with ESCC. C1 [Hu, Nan; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Takikita, Mikiko; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Shou, Jian-zhong] Chinese Acad Med Sci, Canc Inst & Hosp, Beijing 100037, Peoples R China. [Wang, Quan-Hong] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. RP Taylor, PR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM takikitm@mail.nih.gov; nhu@mail.nih.gov; shoujianzhong@hotmail.com; zhongmeiketi@yahoo.com.cn; GiffenC@imsweb.com; ptaylor@mail.nih.gov; genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research and Division of Cancer Epidemiology and Genetics FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Division of Cancer Epidemiology and Genetics. NR 16 TC 5 Z9 5 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 3 PY 2009 VL 9 AR 310 DI 10.1186/1471-2407-9-310 PG 6 WC Oncology SC Oncology GA 500NK UT WOS:000270309300001 PM 19728877 ER PT J AU Baek, JH Han, MJ Lee, SY Yoo, JS AF Baek, Jong Hwan Han, Mee-Jung Lee, Sang Yup Yoo, Jong-Shin TI Transcriptome and proteome analyses of adaptive responses to methyl methanesulfonate in Escherichia coli K-12 and ada mutant strains SO BMC MICROBIOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION SYSTEM; SIMPLE ALKYLATING-AGENTS; DNA-REPAIR; GENE-EXPRESSION; REGULATORY MECHANISMS; DAMAGE; RESISTANCE; INDUCTION; REGULON; OVEREXPRESSION AB Background: The Ada-dependent adaptive response system in Escherichia coli is important for increasing resistance to alkylation damage. However, the global transcriptional and translational changes during this response have not been reported. Here we present time-dependent global gene and protein expression profiles following treatment with methyl methanesulfonate (MMS) in E. coli W3110 and its ada mutant strains. Results: Transcriptome profiling showed that 1138 and 2177 genes were differentially expressed in response to MMS treatment in the wild-type and mutant strains, respectively. A total of 81 protein spots representing 76 nonredundant proteins differentially expressed were identified using 2-DE and LC-MS/MS. In the wild-type strain, many genes were differentially expressed upon long-exposure to MMS, due to both adaptive responses and stationary phase responses. In the ada mutant strain, the genes involved in DNA replication, recombination, modification and repair were up-regulated 0.5 h after MMS treatment, indicating its connection to the SOS and other DNA repair systems. Interestingly, expression of the genes involved in flagellar biosynthesis, chemotaxis, and two-component regulatory systems related to drug or antibiotic resistance, was found to be controlled by Ada. Conclusion: These results show in detail the regulatory components and pathways controlling adaptive response and how the related genes including the Ada regulon are expressed with this response. C1 [Baek, Jong Hwan; Han, Mee-Jung; Lee, Sang Yup] Korea Adv Inst Sci & Technol, Ctr Syst & Synthet Biotechnol, Metab & Biomol Engn Natl Res Lab,Program BK21, Dept Chem & Biomol Engn,Bioproc Engn Res Ctr, Taejon 305701, South Korea. [Baek, Jong Hwan; Han, Mee-Jung; Lee, Sang Yup] Korea Adv Inst Sci & Technol, Inst Biocentury, Taejon 305701, South Korea. [Baek, Jong Hwan] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Han, Mee-Jung] Dongyang Univ, Dept Chem & Biomol Engn, Yeongju 750711, Gyeongbuk, South Korea. [Lee, Sang Yup] Korea Adv Inst Sci & Technol, Dept Biol Sci, Dept Bio & Brain Engn, Taejon 305701, South Korea. [Lee, Sang Yup] Korea Adv Inst Sci & Technol, Bioinformat Res Ctr, Taejon 305701, South Korea. [Yoo, Jong-Shin] Korea Basic Sci Inst, Mass Spectrometry Res Ctr, Cheongwon Gun 863883, Chungbuk, South Korea. RP Lee, SY (reprint author), Korea Adv Inst Sci & Technol, Ctr Syst & Synthet Biotechnol, Metab & Biomol Engn Natl Res Lab,Program BK21, Dept Chem & Biomol Engn,Bioproc Engn Res Ctr, 335 Gwahangno, Taejon 305701, South Korea. EM swcry@kaist.ac.kr; mjhan@kaist.ac.kr; leesy@kaist.ac.kr; jongshin@kbsi.re.kr RI Lee, Sang Yup/C-1526-2011 OI Lee, Sang Yup/0000-0003-0599-3091 FU Ministry of Education, Science and Technology through the Korean Science and Engineering Foundation [M10309020000-03B5002-00000]; LG Chem Chair Professorship; IBM SUR program; Microsoft FX This work was supported by the Korean Systems Biology Research Grant from the Ministry of Education, Science and Technology through the Korean Science and Engineering Foundation (M10309020000-03B5002-00000). Further supports by LG Chem Chair Professorship, IBM SUR program and Microsoft are appreciated. NR 41 TC 6 Z9 6 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD SEP 3 PY 2009 VL 9 AR 186 DI 10.1186/1471-2180-9-186 PG 13 WC Microbiology SC Microbiology GA 503DB UT WOS:000270511500001 PM 19728878 ER PT J AU Xu, JH Knutson, JR AF Xu, Jianhua Knutson, Jay R. TI Quasi-Static Self-Quenching of Trp-X and X-Trp Dipeptides in Water: Ultrafast Fluorescence Decay SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TIME-RESOLVED FLUORESCENCE; TRYPTOPHAN FLUORESCENCE; CYCLIC HEXAPEPTIDES; SOLVENT RELAXATION; PHOSPHOLIPASE A(2); AQUEOUS-SOLUTION; EXCITED-STATE; DYNAMICS; PROTEINS; PEPTIDE AB Time-resolved fluorescence decay profiles of N-acetyl-L-tryptophanamide (NATA) and tryptophan (Trp) dipeptides of the form Trp-X and X-Trp, where X is another aminoacyl residue, have been investigated using an ultraviolet upconversion spectrophoto fluorometer with time resolution better than 350 fs, together with a time-correlated single photon counting apparatus on the 100 ps to 20 ns time scale, We analyzed the set of fluorescence decay profiles at multiple wavelengths using the global analysis technique. Nanosecond fluorescence transients for Trp dipeptides all show multiexponential decay, while NATA exhibits a monoexponential decay near 3 ns independent of pH. In the first 100 ps, a time constant for the water "bulk relaxation" around Trp, NATA and Trp dipeptides are seen near 1-2 ps, with an associated preexponential amplitude that is positive or negative, depending on emission wavelength, as expected for a population conserving spectral shift. The initial brightness (sub-picosecond) we measure for all these dipeptides is less than that of NATA, implying even faster (<200 fs) intramolecular (quasi-) static quenching occurs within them, A new, third, ultrafast decay, hearing an exponential time constant of 20-30 ps with positive amplitude, has been found in many of these dipeptides. We believe it verifies our previous predictions of dipeptide QSSQ ("quasi-static self-quenching")-the loss of quantum yield to sub-100-ps decay process (Chen, R. F.; et al. Biochemistry 1991, 30, 5184). Most important, this term is found in proteins as well (Xu, J.; et al. J. Am. Chem. Soc. 2006, 128, 1214; Biophys. J. 2008, 94, 546; 2009, 96, 46a), suggesting an ultrafast quenching mechanism must be common to both. C1 [Xu, Jianhua; Knutson, Jay R.] NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Knutson, JR (reprint author), NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NIH, NHLBI FX This research was supported by the Intramural Research Program of the NIH, NHLBI. We,also thank Profs. Patrik Callis, Dmitri Toptygin, and Ludwig Brand for helpful discussions about Trp photophysics. J.R.K. wished to thank Dr. R. F. Chen for guidance in this interesting topic. NR 45 TC 16 Z9 16 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 EI 1520-5207 J9 J PHYS CHEM B JI J. Phys. Chem. B PD SEP 3 PY 2009 VL 113 IS 35 BP 12084 EP 12089 DI 10.1021/jp903078x PG 6 WC Chemistry, Physical SC Chemistry GA 487EE UT WOS:000269252700034 PM 19708715 ER PT J AU Voortman, J Pham, TV Knol, JC Giaccone, G Jimenez, CR AF Voortman, Johannes Pham, Thang V. Knol, Jaco C. Giaccone, Giuseppe Jimenez, Connie R. TI Prediction of outcome of non-small cell lung cancer patients treated with chemotherapy and bortezomib by time-course MALDI-TOF-MS serum peptide profiling SO PROTEOME SCIENCE LA English DT Article ID MASS-SPECTROMETRY; SOLID TUMORS; COMBINATION; THERAPY; GEMCITABINE; CISPLATIN; PATTERNS; REGIMENS; LINE AB Background: Only a minority of patients with advanced non-small cell lung cancer (NSCLC) benefit from chemotherapy. Serum peptide profiling of NSCLC patients was performed to investigate patterns associated with treatment outcome. Using magnetic bead-assisted serum peptide capture coupled to matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF-MS), serum peptide mass profiles of 27 NSCLC patients treated with cisplatin-gemcitabine chemotherapy and bortezomib were obtained. Support vector machine-based algorithms to predict clinical outcome were established based on differential pre-treatment peptide profiles and dynamic changes in peptide abundance during treatment. Results: A 6-peptide ion signature distinguished with 82% accuracy, sensitivity and specificity patients with a relatively short vs. long progression-free survival (PFS) upon treatment. Prediction of long PFS was associated with longer overall survival. Inclusion of 7 peptide ions showing differential changes in abundance during treatment led to a 13-peptide ion signature with 86% accuracy at 100% sensitivity and 73% specificity. A 5-peptide ion signature could separate patients with a partial response vs. non-responders with 89% accuracy at 100% sensitivity and 83% specificity. Differential peptide profiles were also found when comparing the NSCLC serum profiles to those from cancer-free control subjects. Conclusion: This study shows that serum peptidome profiling using MALDI-TOF-MS coupled to pattern diagnostics may aid in prediction of treatment outcome of advanced NSCLC patients treated with chemotherapy. C1 [Voortman, Johannes; Pham, Thang V.; Knol, Jaco C.; Giaccone, Giuseppe; Jimenez, Connie R.] Vrije Univ Amsterdam, Med Ctr, VUmc Canc Ctr Amsterdam, Dept Med Oncol,OncoProte Lab, Amsterdam, Netherlands. [Voortman, Johannes; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jimenez, CR (reprint author), Vrije Univ Amsterdam, Med Ctr, VUmc Canc Ctr Amsterdam, Dept Med Oncol,OncoProte Lab, Amsterdam, Netherlands. EM j.voortman@gmail.com; t.pham@vumc.nl; j.knol@vumc.nl; giacconeg@mail.nih.gov; c.jimenez@vumc.nl RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU Netherlands Organization of Scientific Research ZonMW-AGIKO stipend [920-03-290] FX Drs Lyle Burton and Ron Bonner (Applied Biosystems/Sciex) are acknowledged for early access to new versions of MarkerView software. The VUmc-Cancer Center Amsterdam is acknowledged for support of CRJ, TVP and JCK and proteomics infrastructure. JV was supported by a Netherlands Organization of Scientific Research ZonMW-AGIKO stipend, grant 920-03-290. NR 23 TC 24 Z9 25 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-5956 J9 PROTEOME SCI JI Proteome Sci. PD SEP 3 PY 2009 VL 7 AR 34 DI 10.1186/1477-5956-7-34 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 497OS UT WOS:000270070000001 PM 19728888 ER PT J AU Cash, JN Rejon, CA McPherron, AC Bernard, DJ Thompson, TB AF Cash, Jennifer N. Rejon, Carlis A. McPherron, Alexandra C. Bernard, Daniel J. Thompson, Thomas B. TI The structure of myostatin: follistatin 288: insights into receptor utilization and heparin binding SO EMBO JOURNAL LA English DT Article DE Alk5; follistatin; heparin; myostatin; TGF-beta ID GROWTH-FACTOR-BETA; BONE-MORPHOGENETIC PROTEIN; SKELETAL-MUSCLE MASS; TGF-BETA; II RECEPTORS; CRYSTAL-STRUCTURE; ACTIVIN-BINDING; DIFFERENTIATION FACTOR-11; MOLECULAR RECOGNITION; HETEROMERIC COMPLEX AB Myostatin is a member of the transforming growth factor-beta (TGF-beta) family and a strong negative regulator of muscle growth. Here, we present the crystal structure of myostatin in complex with the antagonist follistatin 288 (Fst288). We find that the prehelix region of myostatin very closely resembles that of TGF-beta class members and that this region alone can be swapped into activin A to confer signalling through the non-canonical type I receptor Alk5. Furthermore, the N-terminal domain of Fst288 undergoes conformational rearrangements to bind myostatin and likely acts as a site of specificity for the antagonist. In addition, a unique continuous electropositive surface is created when myostatin binds Fst288, which significantly increases the affinity for heparin. This translates into stronger interactions with the cell surface and enhanced myostatin degradation in the presence of either Fst288 or Fst315. Overall, we have identified several characteristics unique to myostatin that will be paramount to the rational design of myostatin inhibitors that could be used in the treatment of muscle-wasting disorders. The EMBO Journal (2009) 28, 2662-2676. doi: 10.1038/emboj.2009.205; Published online 30 July 2009 Subject Categories: signal transduction; structural biology C1 [Cash, Jennifer N.; Thompson, Thomas B.] Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. [Rejon, Carlis A.; Bernard, Daniel J.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada. [McPherron, Alexandra C.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Thompson, TB (reprint author), Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, 231 Albert Sabin Way,MSB 3109, Cincinnati, OH 45267 USA. EM thompstb@ucmail.uc.edu FU NIHGM [R01 GM084186]; AHA [0635097N]; MDA [93887]; Canadian Institutes of Health Research [MOP-89991]; NIDDK, NIH, USA; CIHR FX We thank C Kattamuri and E Angerman for activin A purification, and R Kovall and A Herr for comments on the paper. This work was supported by research grants from the NIHGM R01 (GM084186), AHA (0635097N), and MDA (93887) to TBT. JNC was supported by an AHA predoctoral fellowship. Support was provided by Canadian Institutes of Health Research grant MOP-89991 to DJB who is a Chercheur-boursier of the Fonds de la recherche en sante du Quebec. Support was contributed by the Intramural Research Program of the NIDDK, NIH, USA (ACM). CAR was partly supported by a CIHR award to Terry Hebert. NR 94 TC 58 Z9 63 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 2 PY 2009 VL 28 IS 17 BP 2662 EP 2676 DI 10.1038/emboj.2009.205 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 490IM UT WOS:000269494200015 PM 19644449 ER PT J AU Mitchell, DGV Luo, Q Avny, SB Kasprzycki, T Gupta, K Chen, G Finger, EC Blair, RJR AF Mitchell, Derek G. V. Luo, Qian Avny, Shelley B. Kasprzycki, Tomasz Gupta, Karanvir Chen, Gang Finger, Elizabeth C. Blair, R. James R. TI Adapting to Dynamic Stimulus-Response Values: Differential Contributions of Inferior Frontal, Dorsomedial, and Dorsolateral Regions of Prefrontal Cortex to Decision Making SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ANTERIOR CINGULATE CORTEX; COGNITIVE CONTROL MECHANISMS; ATTENTIONAL SELECTION; ORBITOFRONTAL CORTEX; NEURAL MECHANISMS; REVERSAL; REWARD; FMRI; CONFLICT; DORSAL AB Dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), and inferior frontal gyrus (IFG) have all been implicated in resolving decision conflict whether this conflict is generated by having to select between responses of similar value or by making selections following a reversal in reinforcement contingencies. However, work distinguishing their individual functional contributions remains preliminary. We used functional magnetic resonance imaging to delineate the functional role of these systems with regard to both forms of decision conflict. Within dmPFC and dlPFC, blood oxygen level-dependent responses increased in response to decision conflict regardless of whether the conflict occurred in the context of a reduction in the difference in relative value between objects, or an error following a reversal of reinforcement contingencies. Conjunction analysis confirmed that overlapping regions of dmPFC and dlPFC were activated by both forms of decision conflict. Unlike these regions, however, activity in IFG was not modulated by reductions in the relative value of available options. Moreover, although all three regions of prefrontal cortex showed enhanced activity to reversal errors, only dmPFC and dlPFC were also modulated by the magnitude of value change during the reversal. These data are interpreted with reference to models of dmPFC, dlPFC, and IFG functioning. C1 [Mitchell, Derek G. V.; Kasprzycki, Tomasz; Gupta, Karanvir] Univ Western Ontario, Schulich Sch Med & Dent, Dept Psychiat, London, ON N6A 5A5, Canada. [Mitchell, Derek G. V.; Kasprzycki, Tomasz; Gupta, Karanvir] Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, London, ON N6A 5A5, Canada. [Finger, Elizabeth C.] Univ Western Ontario, Schulich Sch Med & Dent, Dept Clin Neurol Sci, London, ON N6A 5A5, Canada. [Luo, Qian; Chen, Gang; Blair, R. James R.] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Avny, Shelley B.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. RP Mitchell, DGV (reprint author), Univ Western Ontario, Schulich Sch Med & Dent, Dept Psychiat, 339 Windermere Rd, London, ON N6A 5A5, Canada. EM dmitch8@uwo.ca RI Finger, Elizabeth/B-6453-2015 FU National Institutes of Health in Bethesda, Maryland; Intramural Research Program of the National Institutes of Health-National Institute of Mental Health; Natural Sciences and Engineering Research Council of Canada FX This research was conducted at the National Institutes of Health in Bethesda, Maryland, and was supported by the Intramural Research Program of the National Institutes of Health-National Institute of Mental Health and by a grant to D. G. V. M. from the Natural Sciences and Engineering Research Council of Canada. NR 33 TC 24 Z9 24 U1 3 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 2 PY 2009 VL 29 IS 35 BP 10827 EP 10834 DI 10.1523/JNEUROSCI.0963-09.2009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 490RB UT WOS:000269518500006 PM 19726640 ER PT J AU Wu, XS Wu, LG AF Wu, Xin-Sheng Wu, Ling-Gang TI Rapid Endocytosis Does Not Recycle Vesicles within the Readily Releasable Pool SO JOURNAL OF NEUROSCIENCE LA English DT Article ID KISS-AND-RUN; TERM SYNAPTIC DEPRESSION; CALCIUM-CHANNEL TYPES; CALYX-TYPE SYNAPSE; HIPPOCAMPAL SYNAPSES; NERVE-TERMINALS; MEDIAL NUCLEUS; TRAPEZOID BODY; CAPACITANCE MEASUREMENTS; TRANSMITTER RELEASE AB Endocytosis is essential in maintaining exocytosis at secretory cells. Rapid endocytosis with a time course less than a few seconds is widely observed at nerve terminals and non-neuronal secretory cells. It is generally assumed that rapid endocytosis recycles vesicles within the readily releasable pool (RRP) via a kiss-and-run mechanism that involves rapid opening and closure of a fusion pore at the release site. The present work suggests that both rapid (tau less than similar to 2 s) and slow (tau = similar to 10-20 s) endocytosis do not recycle vesicles to the RRP but to a recycling pool at least a few times larger than the RRP at a nerve terminal, the calyx of Held in rat brainstem. Challenging the long-held view that rapid endocytosis offers a rapid, local vesicle recycling within the RRP, our finding calls for reconsideration of the function and the underlying mechanism of rapid endocytosis. We suggest that rapid endocytosis provides the nerve terminal the ability to recycle vesicles rapidly via the recycling pool and to maintain the normal morphology of the nerve terminal, including the release site, by rapidly clearing the fused vesicle membrane from the release site during intense firing. C1 [Wu, Xin-Sheng; Wu, Ling-Gang] Natl Inst Neurol Disorders & Stroke, Synapt Transmiss Sect, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Transmiss Sect, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov FU National Institute of Neurological Disorders; Stroke Intramural Research Program FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. We thank Drs. Benjamin Mcneil and Jianhua Xu for comments on this manuscript. NR 40 TC 31 Z9 32 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 2 PY 2009 VL 29 IS 35 BP 11038 EP 11042 DI 10.1523/JNEUROSCI.2367-09.2009 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 490RB UT WOS:000269518500028 PM 19726662 ER PT J AU Yabroff, KR Schrag, D AF Yabroff, K. Robin Schrag, Deborah TI Challenges and Opportunities for Use of Cost-Effectiveness Analysis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID COLORECTAL-CANCER; DRUGS; CHEMOTHERAPY; MUTATIONS; CETUXIMAB C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schrag, Deborah] Harvard Univ, Sch Med, Boston, MA USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 21 TC 7 Z9 8 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 2 PY 2009 VL 101 IS 17 BP 1161 EP U11 DI 10.1093/jnci/djp258 PG 3 WC Oncology SC Oncology GA 491WS UT WOS:000269613500001 PM 19666852 ER PT J AU Lee, JH Smith, MA Liu, W Gold, EM Lewis, B Song, HT Frank, JA AF Lee, Jae-Ho Smith, Melissa A. Liu, Wei Gold, Eric M. Lewis, Bobbi Song, Ho-Taek Frank, Joseph A. TI Enhanced stem cell tracking via electrostatically assembled fluorescent SPION-peptide complexes SO NANOTECHNOLOGY LA English DT Article ID CONTRAST AGENTS; TRANSFECTION AGENTS; IRON-OXIDES; NANOPARTICLES; MRI; FERUMOXIDES; THERAPY; GENE AB For cellular MRI there is a need to label cells with superparamagnetic iron oxide nanoparticles (SPION) that have multiple imaging moieties that are nontoxic and have increased NMR relaxation properties to improve the detection and tracking of therapeutic cells. Although increases in the relaxation properties of SPION have been accomplished, detection of tagged cells is limited by either poor cell labeling efficiency or low intracellular iron content. A strategy via a complex formation with transfection agents to overcome these obstacles has been reported. In this paper, we report a complex formation between negatively charged fluorescent monodisperse SPION and positively charged peptides and use the complex formation to improve the MR properties of labeled stem cells. As a result, labeled stem cells exhibited a strong fluorescent signal and enhanced T2*-weighted MR imaging in vitro and in vivo in a flank tumor model. C1 [Lee, Jae-Ho; Smith, Melissa A.; Liu, Wei; Gold, Eric M.; Lewis, Bobbi; Song, Ho-Taek; Frank, Joseph A.] NIH, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. [Lee, Jae-Ho] Natl Canc Inst Hlth Frederick, CCR Nanobiol Program, Membrane Struct & Funct Sect, Frederick, MD 21702 USA. [Liu, Wei] Philips Res N Amer, Briarcliff Manor, NY 10510 USA. [Song, Ho-Taek] Yonsei Univ, Coll Med, Dept Radiol, Seoul 120752, South Korea. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Lee, JH (reprint author), NIH, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. EM leejaeho@mail.nih.gov; wei.liu1@philips.com; hotsong@yuhs.ac; jafrank@helix.nih.gov FU Clinical Center at the National Institutes of Health FX This research was supported by the Intramural Research Program of the Clinical Center at the National Institutes of Health. The authors would like to acknowledge the help of Dr Leapman for TEM analysis and Dr E Kay Jordan for her assistance in taking care of in vivo experimental studies. NR 23 TC 8 Z9 8 U1 0 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 J9 NANOTECHNOLOGY JI Nanotechnology PD SEP 2 PY 2009 VL 20 IS 35 AR 355102 DI 10.1088/0957-4484/20/35/355102 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 482TL UT WOS:000268911500002 PM 19671960 ER PT J AU Hofmann, JN Crowe, J Postma, J Ybarra, V Keifer, MC AF Hofmann, Jonathan N. Crowe, Jennifer Postma, Julie Ybarra, Vickie Keifer, Matthew C. TI Perceptions of Environmental and Occupational Health Hazards Among Agricultural Workers in Washington State SO AAOHN JOURNAL LA English DT Article ID PARTICIPATORY RESEARCH; PESTICIDE EXPOSURE; NORTH-CAROLINA; COMMUNITY; FARMWORKERS; EMPOWERMENT; PROMOTION AB This study describes agricultural workers' perceptions of environmental and occupational health issues. Interviews were conducted with 389 agricultural workers in the Yakima Valley of central Washington State in the summers of 2004 and 2005. Undergraduate students from the community conducted interviews in Spanish or English. Environmental and occupational health issues were ranked by frequency of concern, and differences by demographics were evaluated using multivariate analyses. In both 2004 and 2005, agricultural workers expressed high levels of concern about working in hot weather, agricultural injuries, pesticides, and pediatric asthma. Agricultural workers' perceptions of environmental and occupational health issues differed by specific demographics, particularly age and ethnicity. Consideration should be given to these issues when designing research studies, creating educational materials, and developing interventions related to environmental and occupational hazards among agricultural workers. C1 [Hofmann, Jonathan N.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Crowe, Jennifer] Univ Nacl, Cent Amer Inst Studies Tox Subst IRET, Heredia, Costa Rica. [Postma, Julie] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Keifer, Matthew C.] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Ybarra, Vickie] Yakima Valley Farm Workers Clin, Yakima, WA USA. [Crowe, Jennifer] Univ Washington, Pacific NW Agr Safety & Hlth Ctr PNASH, Seattle, WA 98195 USA. RP Hofmann, JN (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. FU NIEHS NIH HHS [R03 ES017359, R03 ES017359-01, R21 ES017906, R21 ES017906-01] NR 40 TC 4 Z9 5 U1 0 U2 5 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0891-0162 J9 AAOHN J JI AAOHN J. PD SEP PY 2009 VL 57 IS 9 BP 359 EP 371 DI 10.3928/08910162-20090817-01 PG 13 WC Public, Environmental & Occupational Health; Nursing SC Public, Environmental & Occupational Health; Nursing GA 700ID UT WOS:000285730500003 PM 19715263 ER PT J AU Resnik, DB AF Resnik, David B. TI Perspective: Disclosing Hidden Sources of Funding SO ACADEMIC MEDICINE LA English DT Article ID LUNG-CANCER AB In this article, the author discusses ethical and policy issues related to the disclosure of hidden sources of funding in research. The author argues that authors have an ethical obligation to disclose hidden sources of funding and that journals should adopt policies to enforce this obligation. Journal policies should require disclosure of hidden sources of funding that authors know about and that have a direct relation to their research. To stimulate this discussion, the author describes a recent case: investigators who conducted a lung cancer screening study had received funding from a private foundation that was supported by a tobacco company, but they did not disclose this relationship to the journal. Investigators and journal editors must be prepared to deal with these issues in a manner that promotes honesty, transparency, fairness, and accountability in research. The development of well-defined, reasonable policies pertaining to hidden sources of funding can be a step in this direction. C1 [Resnik, David B.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), 111 Alexander Dr,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences; National Institutes of Health FX This research was supported by the intramural program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 13 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD SEP PY 2009 VL 84 IS 9 BP 1226 EP 1228 DI 10.1097/ACM.0b013e3181b18835 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 505RJ UT WOS:000270712100017 PM 19707061 ER PT J AU Paquerault, S Samuelson, FW Petrick, N Myers, KJ Smith, RC AF Paquerault, Sophie Samuelson, Frank W. Petrick, Nicholas Myers, Kyle J. Smith, Robert C. TI Investigation of Reading Mode and Relative Sensitivity as Factors That Influence Reader Performance When Using Computer-Aided Detection Software SO ACADEMIC RADIOLOGY LA English DT Article DE Observer study evaluation; computer-aided detection; reading mode; relative sensitivity; free-response receiver operating characteristic ID BREAST-CANCER DETECTION; SCREENING MAMMOGRAPHY; DETECTION SYSTEM; CAD; RADIOLOGISTS; IMPROVEMENT; DIAGNOSIS; TRIAL AB Rationale and Objectives. The aim of this study was to investigate the effects of relative sensitivity (reader without computer-aided detection [CAD] vs stand-alone CAD) and reading mode on reader performance when using CAD software. Materials and Methods. Two sets of 100 images (low-contrast and high-contrast sets) were created by adding low-contrast or high-contrast simulated masses to random locations in 100 normal mammograms. This produced a relative sensitivity, substantially less for the low-contrast set and similar for the high-contrast set. Seven readers reviewed every image in each set and specified location and probability scores using three reading modes (without CAD, second read with CAD, and concurrent read with CAD). Reader detection accuracy was analyzed using areas under free-response receiver operating characteristic curves, sensitivity, and the number of false-positive findings per image. Results. For the low-contrast set, average differences in areas under free-response receiver operating characteristic curves, sensitivity, and false-positive findings per image without CAD were 0.02, 0.12, and 0.11, respectively, compared to second read and 0.05, 0.17, and 0.09 (not statistically significant), respectively, compared to concurrent read. For the high-contrast set, average differences were 0.002 (not statistically significant), 0.04, and 0.05, respectively, compared to second read and -0.004 (not statistically significant), 0.04, and 0.08 (not statistically significant), respectively, compared to concurrent read (all differences were statistically significant except as noted). Differences were greater in the low-contrast set than the high-contrast set. Differences between second read and concurrent read were not significant. Conclusions. Relative sensitivity is a critical factor that determines incremental improvement in reader performance when using CAD and appears to be more important than reading mode. Relative sensitivity may determine the clinical usefulness of CAD in different clinical applications and for different types of users. C1 [Paquerault, Sophie; Samuelson, Frank W.; Petrick, Nicholas; Myers, Kyle J.; Smith, Robert C.] US FDA, Ctr Devices & Radiol Hlth, Natl Inst Biomed Imaging & Bioengn, Joint Lab Assessment Med Imaging Syst, Silver Spring, MD 20993 USA. RP Paquerault, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, Natl Inst Biomed Imaging & Bioengn, Joint Lab Assessment Med Imaging Syst, 10903 New Hampshire Ave,Bldg 62,Room 3110, Silver Spring, MD 20993 USA. EM sophie.paquerault@fda.hhs.gov FU National Institute of Biomedical Imaging and Bioengineering (Bethesda, MD) FX The Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (Bethesda, MD) provided Partial support for this work. NR 28 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD SEP PY 2009 VL 16 IS 9 BP 1095 EP 1107 DI 10.1016/j.acra.2009.03.024 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 484SF UT WOS:000269067000009 PM 19523855 ER PT J AU Pletnev, S Morozova, KS Verkhusha, VV Dauter, Z AF Pletnev, Sergei Morozova, Kateryna S. Verkhusha, Vladislav V. Dauter, Zbigniew TI Rotational order-disorder structure of fluorescent protein FP480 SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article DE order-disorder structures; rotational order-disorder; fluorescent proteins ID LATTICE-TRANSLOCATION DEFECTS; ONE-DIMENSIONAL DISORDER; X-RAY-INTENSITIES; DIFFRACTION DATA; OD-STRUCTURES; CRYSTALS; CRYSTALLOGRAPHY; SOFTWARE; ANTIBODY AB In the last decade, advances in instrumentation and software development have made crystallography a powerful tool in structural biology. Using this method, structural information can now be acquired from pathological crystals that would have been abandoned in earlier times. In this paper, the order-disorder (OD) structure of fluorescent protein FP480 is discussed. The structure is composed of tetramers with 222 symmetry incorporated into the lattice in two different ways, namely rotated 90 degrees with respect to each other around the crystal c axis, with tetramer axes coincident with crystallographic twofold axes. The random distribution of alternatively oriented tetramers in the crystal creates a rotational OD structure with statistically averaged I422 symmetry, although the presence of very weak and diffuse additional reflections suggests that the randomness is only approximate. C1 [Pletnev, Sergei] Argonne Natl Lab, SAIC Frederick Inc, Basic Res Program, Argonne, IL 60439 USA. [Morozova, Kateryna S.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10467 USA. [Dauter, Zbigniew] Natl Canc Inst, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Bronx, NY 10461 USA. RP Pletnev, S (reprint author), Argonne Natl Lab, SAIC Frederick Inc, Basic Res Program, 9700 S Cass Ave, Argonne, IL 60439 USA. EM svp@ncifcrf.gov; dauter@anl.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E, GM073913]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported in part by Federal funds from the National Cancer Institute, National Institutes of Health (NIH; contract No. HHSN261200800001E), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by a grant from the NIH (GM073913) to VVV. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. Diffraction data were collected on the SER-CAT ID22 and GM-CA/CAT 23ID beamlines at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 32 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD SEP PY 2009 VL 65 BP 906 EP 912 DI 10.1107/S0907444909020927 PN 9 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 488LA UT WOS:000269350000004 PM 19690368 ER PT J AU Nowak, E Brzuszkiewicz, A Dauter, M Dauter, Z Rosenbaum, G AF Nowak, Elzbieta Brzuszkiewicz, Anna Dauter, Miroslawa Dauter, Zbigniew Rosenbaum, Gerd TI To scavenge or not to scavenge: that is the question SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article DE protein crystallography; radiation damage; scavengers; nicotinic acid ID RADIATION-DAMAGE; PROTEIN CRYSTALS; CRYOCRYSTALLOGRAPHY; CRYSTALLOGRAPHY; REDUCTION; DECAY AB Analysis of a series of diffraction data sets measured from four native as well as four nicotinic acid-soaked crystals of trypsin at 100 K shows a high variability in radiation-sensitivity among individual crystals for both nicotinic acid-soaked and native crystals. The level of radiation-sensitivity and the extent of its variability is statistically indistinguishable between the two conditions. This suggests that this potential scavenger does not have any statistically significant effect on the amount of radiation damage incurred in the crystals on X-ray irradiation. This is in contrast to previous results [Kauffmann et al. (2006), Structure, 14, 1099-1105] where only one crystal specimen was used for each condition (native and nicotinic acid-soaked). C1 [Nowak, Elzbieta; Brzuszkiewicz, Anna; Dauter, Zbigniew] Natl Canc Inst, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. [Dauter, Miroslawa] Argonne Natl Lab, SAIC Frederick Inc, Basic Res Program, Argonne, IL 60439 USA. [Rosenbaum, Gerd] Univ Georgia, Dept Biochem, SER CAT APS, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), Natl Canc Inst, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov; rosenbaum@anl.gov FU National Cancer Institute; National Institutes of Health [NO1-CO-12400]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported in part with Federal funds from the National Cancer Institute, National Institutes of Health contract No. NO1-CO-12400 and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. Diffraction data were collected on the SER-CAT beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 14 TC 14 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD SEP PY 2009 VL 65 BP 1004 EP 1006 DI 10.1107/S0907444909026821 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 488LA UT WOS:000269350000015 PM 19690379 ER PT J AU Brzuszkiewicz, A Nowak, E Dauter, Z Dauter, M Cieslinski, H Dlugolecka, A Kur, J AF Brzuszkiewicz, Anna Nowak, Elzbieta Dauter, Zbigniew Dauter, Miroslawa Cieslinski, Hubert Dlugolecka, Anna Kur, Jozef TI Structure of EstA esterase from psychrotrophic Pseudoalteromonas sp 643A covalently inhibited by monoethylphosphonate SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article ID COLD-ADAPTED ESTERASE; ESCHERICHIA-COLI; ACTIVE ESTERASE; GENE CLONING; CLASSIFICATION; REFINEMENT; SEQUENCE AB The crystal structure of the esterase EstA from the cold-adapted bacterium Pseudoalteromonas sp. 643A was determined in a covalently inhibited form at a resolution of 1.35 angstrom S. The enzyme has a typical SGNH hydrolase structure consisting of a single domain containing a five-stranded beta-sheet, with three helices at the convex side and two helices at the concave side of the sheet, and is ornamented with a couple of very short helices at the domain edges. The active site is located in a groove and contains the classic catalytic triad of Ser, His and Asp. In the structure of the crystal soaked in diethyl p-nitrophenyl phosphate (DNP), the catalytic serine is covalently connected to a phosphonate moiety that clearly has only one ethyl group. This is the only example in the Protein Data Bank of a DNP-inhibited enzyme with covalently bound monoethylphosphate. C1 [Brzuszkiewicz, Anna; Nowak, Elzbieta; Dauter, Zbigniew] Argonne Natl Lab, NCI, MCL, Synchrotron Radiat Res Sect, Argonne, IL 60439 USA. [Dauter, Miroslawa] Argonne Natl Lab, Basic Res Program, SAIC Frederick Inc, Argonne, IL 60439 USA. [Cieslinski, Hubert; Dlugolecka, Anna; Kur, Jozef] Gdansk Univ Technol, Dept Microbiol, PL-80952 Gdansk, Poland. RP Dauter, Z (reprint author), Argonne Natl Lab, NCI, MCL, Synchrotron Radiat Res Sect, 9700 S Cass Ave, Argonne, IL 60439 USA. EM dauter@anl.gov; kur@chem.pg.gda.pl FU National Cancer Institute, National Institutes of Health [NO1-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported in part by Federal funds from the National Cancer Institute, National Institutes of Health contract No. NO1-CO-12400 and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. Diffraction data were collected on the SBC 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 23 TC 7 Z9 7 U1 0 U2 4 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2053-230X J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD SEP PY 2009 VL 65 BP 862 EP 865 DI 10.1107/S1744309109030826 PN 9 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 489CX UT WOS:000269398400002 PM 19724118 ER PT J AU Cross, HR Li, M Petrich, BG Murphy, E Wang, Y Steenbergen, C AF Cross, H. R. Li, M. Petrich, B. G. Murphy, E. Wang, Y. Steenbergen, Ch TI Effect of p38 MAP kinases on contractility and ischemic injury in intact heart SO ACTA PHYSIOLOGICA HUNGARICA LA English DT Article DE p38 MAP kinase; contractile function; ischemia; NMR spectroscopy; energetics ID ACTIVATED PROTEIN-KINASE; N-TERMINAL KINASES; IN-VIVO; MYOCARDIAL-ISCHEMIA; CARDIAC MYOCYTES; STRESS-RESPONSE; RABBIT HEART; CELL-DEATH; INHIBITION; PHOSPHORYLATION AB The p38 MAP kinases are stress-activated MAP kinases whose induction is often associated with the onset of heart failure. This study investigated the role of p38 MAP kinase isoforms in the regulation of myocardial contractility and ischemia/reperfusion injury using mice with cardiac-specific expression of kinase dead (dominant negative) mutants of p38 alpha (p38 alpha dn) or p38 beta (p38 beta dn). Hearts were subjected to 20 min ischemia and 40 min reperfusion. Immunofluorescence staining for p38 alpha dn and p38 beta dn protein was performed on neonatal cardiomyocytes infected with adenovirus expressing flag-tagged p38 alpha dn and p38 beta dn protein. Basal contractile function was increased in both p38 alpha dn and p38 beta dn hearts compared to WT. Ischemic injury was increased in p38 beta dn vs. WT hearts, as indicated by lower post-ischemic recoveries of contractile function and ATP. However, despite a similar increase in contractility, ischemic injury was not increased in p38 alpha dn vs. WT hearts. Immunohistological analysis of cardiomyocytes with comparable levels of protein overexpression show that p38 alpha dn and p38 beta dn proteins were co-localized with sarcomeric alpha-actinin, however, p38 alpha dn was detected in the nucleus while p38 beta dn was exclusively detected in the cytosol. In summary, attenuated p38 activity led to increased myocardial contractility; specific isoforms of p38 and their sub-cellular localization may have different roles in modulating ischemic injury. C1 [Steenbergen, Ch] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. [Cross, H. R.] Duke Univ, Dept Pathol, Med Ctr, Durham, NC 27710 USA. [Murphy, E.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Li, M.; Petrich, B. G.; Wang, Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. [Li, M.; Petrich, B. G.; Wang, Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Steenbergen, C (reprint author), Johns Hopkins Univ, Dept Pathol, 720 Rutland Ave,Ross 632N, Baltimore, MD 21205 USA. EM csteenb1@jhmi.edu OI Wang, Yibin/0000-0003-0852-0767 FU National Institutes of Health; American Heart Association FX The authors thank the National Institutes of Health and American Heart Association for grant support ( to CS and YW). The authors also thank Dr. Robert E. London for use of the NMR facilities, and Ms. Haiying Pu for technical assistance. NR 31 TC 3 Z9 3 U1 0 U2 2 PU AKADEMIAI KIADO RT PI BUDAPEST PA PRIELLE K U 19, PO BOX 245,, H-1117 BUDAPEST, HUNGARY SN 0231-424X J9 ACTA PHYSIOL HUNG JI Acta Physiol. Hung. PD SEP PY 2009 VL 96 IS 3 BP 307 EP 323 DI 10.1556/APhysiol.96.2009.3.5 PG 17 WC Physiology SC Physiology GA 487ML UT WOS:000269278600005 PM 19706373 ER PT J AU Asthana, S Brinton, RD Henderson, VW McEwen, BS Morrison, JH Schmidt, PJ AF Asthana, Sanjay Brinton, Roberta Diaz Henderson, Victor W. McEwen, Bruce S. Morrison, John H. Schmidt, Peter J. CA Frontiers Proposal Estrogen Grp Cognitive Aging Work Grp TI Frontiers proposal. National Institute on Aging "bench to bedside: estrogen as a case study" SO AGE LA English DT Article DE Aging; Alzheimer's disease; Cognition; Dementia; Estrogen; Menopause; Progestogen ID POSTMENOPAUSAL HORMONE-THERAPY; HEALTH INITIATIVE MEMORY; RANDOMIZED CONTROLLED-TRIAL; CONJUGATED EQUINE ESTROGENS; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE RISK; WOMENS HEALTH; PLUS PROGESTIN; REPLACEMENT THERAPY; MENOPAUSAL TRANSITION AB On 28-29 September 2004, the National Institute on Aging (NIA) convened scientists for a workshop on the aging female brain focused on translating into clinical practice discoveries concerning estrogens and progestogens. Workshop objectives were to examine effects of estrogen and progestogen on brain and cognitive function in relation to aging, to examine consistencies and apparent discrepancies between Women's Health Initiative Memory Study findings and other research on cognitive function, to determine whether additional hormone interventions could be developed in this area, and to offer advice on design of clinical trials for other interventions that might ameliorate cognitive aging. Following the workshop, participants joined by other interested scientists organized into regional work groups to continue the dialogue begun in Bethesda and to propose recommendations for NIA. The resulting recommendations, referred to as the "Frontiers Proposal for Estrogen and Cognitive Aging", acknowledge the persistence of critical gaps in our understanding of how decline in ovarian steroid secretion during reproductive aging and use of ovarian steroid hormone therapy affect normal brain function and risk for late-life neurodegenerative disorders such as Alzheimer's disease. There is a pressing need for preclinical, human, and integrated studies on the relationship between the menopausal transition and midlife exposures to estrogens, progestogens and related compounds, and risks for age-associated cognitive disorders. Research is also needed on better predictors of adverse cognitive outcomes, valid biomarkers for risks associated with hormone therapy use, enhanced tools for monitoring brain function and disease progression, and novel forms of therapy for improving long-term cognitive outcomes. C1 [Asthana, Sanjay] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. [Asthana, Sanjay] Univ Wisconsin, Sch Med & Publ Hlth, GRECC, Madison, WI 53705 USA. [Brinton, Roberta Diaz] Univ So Calif, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90033 USA. [Henderson, Victor W.] Stanford Univ, Dept Hlth Res, Stanford, CA 94305 USA. [Henderson, Victor W.] Stanford Univ, Dept Policy Epidemiol, Stanford, CA 94305 USA. [Henderson, Victor W.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [McEwen, Bruce S.] Rockefeller Univ, Harold & Margaret Milliken Hatch Lab Neuroendocri, New York, NY 10021 USA. [Morrison, John H.] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. [Schmidt, Peter J.] NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Asthana, S (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. EM sa@medicine.wisc.edu; rbrinton@usc.edu; vhenderson@stanford.edu; mcewen@mail.rockefeller.edu; john.morrison@mssm.edu; peter.schmidt@nih.gov RI Morrison, John/F-9229-2012 FU NIA NIH HHS [R01 AG032236] NR 55 TC 18 Z9 18 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD SEP PY 2009 VL 31 IS 3 BP 199 EP 210 DI 10.1007/s11357-009-9087-2 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 489JY UT WOS:000269417600005 PM 19277902 ER PT J AU Deshpande, N Metter, EJ Bandinelli, S Guralnik, J Ferrucci, L AF Deshpande, Nandini Metter, E. Jeffrey Bandinelli, Stefania Guralnik, Jack Ferrucci, Luigi TI Gait speed under varied challenges and cognitive decline in older persons: a prospective study SO AGE AND AGEING LA English DT Article DE Elderly; cognition; gait speed; ageing; significant cognitive decline ID EXECUTIVE FUNCTION; ELDERLY PERSONS; INCHIANTI; PERFORMANCE; WALKING; ADULTS; TESTS; VARIABILITY; POPULATION; IMPAIRMENT AB Design: prospective study. Setting: population-based sample of community-dwelling older persons. Participants: 660 older participants (age >= 65 years). Measurements: usual gait speed, fastest gait speed, gait speed during 'walking-while-talking', depression, comorbidities, education, smoking and demographics were assessed at baseline. Cognition was evaluated at baseline and follow-up. A decline in MMSE score by >= 3 points was considered as significant cognitive decline (SCD). Results: adjusting for confounders, only fast speed was associated with cognitive performance at 3-year follow-up. One hundred thirty-five participants had SCD over 3 years. Participants in the lowest quartile of usual speed or walking-while-talking speed were more likely to develop SCD. Conversely, participants in the third and fourth quartiles of fast speed were more likely to develop SCD. J-test showed that the model including fast speed quartiles as a regressor was significantly more predictive of SCD than the models with usual speed or walking-while-talking speed quartiles. Conclusion: measuring fast gait speed in older persons may assist in identifying those at high risk of cognitive decline. C1 [Deshpande, Nandini] Univ Kansas, Med Ctr, Dept Phys Therapy & Rehabil Sci, Kansas City, KS 66160 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] Harbor Hosp, Longitudinal Study Sect, Clin Res Branch, NIA,NIH, Baltimore, MD 21225 USA. [Bandinelli, Stefania] Azienda Sani Firenze, Tuscany Reg Hlth Agcy, Geriatr Rehabil Unit, Florence, Italy. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Deshpande, N (reprint author), Univ Kansas, Med Ctr, Dept Phys Therapy & Rehabil Sci, MS 2002,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM nandinijd@yahoo.com FU Italian Ministry of Health [ICS 110.1\RS97.71]; National Institute on Aging [N01AG-916413, N01-AG-821336, N01-AG-5-0002]; NIA [R01 AG027012]; Intramural Research Program; National Institute on Aging; NIH FX The InCHIANTI study was supported as a 'targeted project' (ICS 110.1\RS97.71) by the Italian Ministry of Health and in part, by National Institute on Aging Contracts N01AG-916413, N01-AG-821336, N01-AG-5-0002 and NIA Grant R01 AG027012 and the Intramural Research Program, National Institute on Aging, NIH. There was no role of the financial sponsors in the design, execution, analysis and interpretation of data, or writing of the study. NR 25 TC 39 Z9 41 U1 4 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD SEP PY 2009 VL 38 IS 5 BP 509 EP 514 DI 10.1093/ageing/afp093 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 486KB UT WOS:000269193800005 PM 19549981 ER PT J AU Enoch, MA Johnson, K George, DT Schumann, G Moss, HB Kranzler, HR Goldman, D AF Enoch, Mary-Anne Johnson, Kenneth George, David T. Schumann, Gunter Moss, Howard B. Kranzler, Henry R. Goldman, David TI Ethical Considerations for Administering Alcohol or Alcohol Cues to Treatment-Seeking Alcoholics in a Research Setting: Can the Benefits to Society Outweigh the Risks to the Individual? SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review ID OPIOID RECEPTOR GENE; DEPENDENT PATIENTS; NALTREXONE RESPONSE; ETHANOL; OPRM1; POLYMORPHISM; DRINKING; EFFICACY; HUMANS C1 [Enoch, Mary-Anne] NIAAA, NIH, DICBR, LNG, Bethesda, MD 20892 USA. [Johnson, Kenneth] NIH, Combined Neurosci IRB, Bethesda, MD 20892 USA. [George, David T.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Schumann, Gunter] Kings Coll London, Inst Psychiat, Addict & MRC SGDP Ctr, London WC2R 2LS, England. [Moss, Howard B.] NIAAA, Off Director, NIH, Bethesda, MD 20892 USA. [Kranzler, Henry R.] Univ Connecticut, Dept Psychiat, Alcohol Res Ctr, Sch Med, Farmington, CT 06107 USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Room 3S32,MSC 9412s3n, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH; Bristol-Myers Squibb Co; Merck and Co., Inc; Forest Pharmaceuticals; European Commission FP-6 Integrated Project IMAGEN [PL037286]; U. K. Department of Health NIHR-Biomedical Research Centre "Mental Health'' FX This work was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH; Bristol-Myers Squibb Co. and Alkermes: Consulting and research funding; Merck and Co., Inc.: Research funding; Forest Pharmaceuticals: Consulting and honoraria; Sanofi-Aventis, Solvay Pharmaceuticals, elbion GmbH, H. Lundbeck A/S: Consulting (HRK); and in part by the European Commission FP-6 Integrated Project IMAGEN (PL037286) and by the U. K. Department of Health NIHR-Biomedical Research Centre "Mental Health'' (GS). NR 22 TC 6 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2009 VL 33 IS 9 BP 1508 EP 1512 DI 10.1111/j.1530-0277.2009.00988.x PG 5 WC Substance Abuse SC Substance Abuse GA 486EW UT WOS:000269179700002 PM 19519721 ER PT J AU Traverse, JH Henry, TD Vaughn, DE Ellis, SG Pepine, CJ Willerson, JT Zhao, DXM Piller, LB Penn, MS Byrne, BJ Perin, EC Gee, AP Hatzopoulos, AK McKenna, DH Forder, JR Taylor, DA Cogle, CR Olson, RE Jorgenson, BC Sayre, SL Vojvodic, RW Gordon, DJ Skarlatos, SI Moye, LA Simari, RD AF Traverse, Jay H. Henry, Timothy D. Vaughn, Douglas E. Ellis, Stephen G. Pepine, Carl J. Willerson, James T. Zhao, David X. M. Piller, Linda B. Penn, Marc S. Byrne, Barry J. Perin, Emerson C. Gee, Adrian P. Hatzopoulos, Antonis K. McKenna, David H. Forder, John R. Taylor, Doris A. Cogle, Christopher R. Olson, Rachel E. Jorgenson, Beth C. Sayre, Shelly L. Vojvodic, Rachel W. Gordon, David J. Skarlatos, Sonia I. Moye, Lemuel A. Simari, Robert D. CA CCTRN TI Rationale and design for TIME: A phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ISCHEMIC-MYOCARDIUM; PROGENITOR CELLS; NEOVASCULARIZATION; REGENERATION; CYTOKINES; THERAPY AB Several previous studies have demonstrated that administration of autologous bone marrow-derived mononuclear cells (BMMNCs) improves cardiac function in patients after acute myocardial infarction (AMI). However, optimum timing of administration has not been investigated in a clinical trial. The Cardiovascular Cell Therapy Research Network was developed and funded by the National Heart, Lung, and Blood Institute to address important questions such as timing of cell delivery and to accelerate research in the use of cell-based therapies. The TIME trial is a randomized, phase II, double-blind, placebo-controlled clinical trial. The 5 member clinical sites of the Cardiovascular Cell Therapy Research Network will enroll 120 eligible patients with moderate-to-large anterior AMIs who have undergone successful percutaneous coronary intervention of the left anterior descending coronary artery and have a left ventricular (LV) ejection fraction <= 45% by echocardiography. Participants will have bone marrow aspirations and intracoronary infusions of 150 x 10(6) BMMNCs or placebo on day 3 or day 7 post-AMI. Objectives of this study are (1) to evaluate effects of BMMNCs on regional and global LV function compared to placebo therapy in patients with acute AMI as assessed by cardiac magnetic resonance imaging at 6 months and (2) to assess whether effects of BMMNC infusion on global and regional LV function and safety are influenced by the time of administration. This study will provide further insight into the clinical feasibility and appropriate timing of autologous BMMNC therapy in high-risk patients after AMI and percutaneous coronary intervention. (Am Heart J 2009; 158:356-63.) C1 [Traverse, Jay H.; Henry, Timothy D.; Olson, Rachel E.; Jorgenson, Beth C.] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Minneapolis, MN 55407 USA. [Traverse, Jay H.; Henry, Timothy D.; McKenna, David H.; Taylor, Doris A.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Vaughn, Douglas E.; Zhao, David X. M.; Hatzopoulos, Antonis K.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ellis, Stephen G.; Penn, Marc S.] Cleveland Clin, Cleveland, OH 44106 USA. [Pepine, Carl J.; Byrne, Barry J.; Forder, John R.; Cogle, Christopher R.] Univ Florida, Sch Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.; Moye, Lemuel A.] Texas Heart Inst, Houston, TX 77025 USA. [Piller, Linda B.; Sayre, Shelly L.; Vojvodic, Rachel W.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Gee, Adrian P.] Baylor Univ, Sch Med, Houston, TX 77030 USA. [Gordon, David J.; Skarlatos, Sonia I.] NHLBI, NIH, Bethesda, MD 20892 USA. [Simari, Robert D.] Mayo Clin, Rochester, MN USA. RP Traverse, JH (reprint author), Abbott NW Hosp, Minneapolis Heart Inst, 920 E 28th St,Suite 300, Minneapolis, MN 55407 USA. EM trave004@umn.edu RI Hatzopoulos, Antonis/D-2049-2010; Cogle, Christopher/H-1746-2016 OI Cogle, Christopher/0000-0001-5422-6863 FU NHLBI [U01 HL0873 18-01]; Production Assistance for Cellular Therapies [N01-HB-37164] FX This study is supported by the NHLBI (U01 HL0873 18-01) and by the Production Assistance for Cellular Therapies (N01-HB-37164). PTCA and quide catheters and wires were generously supplied by the Boston Scientific Corporation (Natick, MA). NR 23 TC 47 Z9 51 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2009 VL 158 IS 3 BP 356 EP 363 DI 10.1016/j.ahj.2009.06.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492FV UT WOS:000269641200006 PM 19699857 ER PT J AU Dham, N Ensing, G Minniti, C Campbell, A Arteta, M Rana, S Darbari, D Nouraie, M Onyekwere, O Lasota, M Kato, GJ Gladwin, MT Castro, O Gordeuk, V Sable, C AF Dham, Niti Ensing, Gregory Minniti, Caterina Campbell, Andrew Arteta, Manuel Rana, Sohail Darbari, Deepika Nouraie, Mehdi Onyekwere, Onyinye Lasota, Malgorzata Kato, Gregory J. Gladwin, Mark T. Castro, Oswaldo Gordeuk, Victor Sable, Craig TI Prospective Echocardiography Assessment of Pulmonary Hypertension and Its Potential Etiologies in Children With Sickle Cell Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID VENTRICULAR DIASTOLIC FUNCTION; SOCIETY-OF-ECHOCARDIOGRAPHY; REGURGITANT JET VELOCITY; DOPPLER-ECHOCARDIOGRAPHY; STANDARDS COMMITTEE; SYSTOLIC FUNCTION; ARTERY PRESSURES; RISK-FACTOR; TASK-FORCE; ADOLESCENTS AB Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle-cell disease (SCD), but its importance in children is less clear. The aim of this study was to define the incidence and causes of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54) were prospectively enrolled under basal conditions. Participants underwent echocardiography, pulse oximetry, 6-minute walk tests, and hematologic testing. Echocardiographic measures were compared between patients with SCD and control subjects before and after adjusting for hemoglobin. Correlations of echocardiographic and clinical parameters were determined. Tricuspid regurgitation velocity (TRV) was elevated compared to controls (2.28 vs 2.10 m/s, p <0.0001). Increased TRV was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial pressure. TRV remained elevated when controlling for, left ventricular diameter and left atrial pressure. Echocardiographically derived pulmonary resistance was not significantly different between patients with SCD and controls, although it was elevated in the SCD subgroup with elevated TRV. When controlling for hemoglobin, TRV was no longer statistically different, but pulmonary insufficiency velocity, septal wall thickness, and. estimated pulmonary resistance were statistically higher. TRV, pulmonary insufficiency end-diastolic velocity, and markers of increased cardiac output were correlated with indicators of adverse functional status, including history of acute chest syndrome, stroke, transfusions, and 6-minute walk distance. In conclusion, children with SCD had mildly increased TRV that was correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin-adjusted analysis also suggested a contribution of primary vascular changes. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:713-720) C1 [Dham, Niti; Lasota, Malgorzata; Sable, Craig] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [Ensing, Gregory] Univ Michigan, Div Pediat Cardiol, Dept Pediat, Ann Arbor, MI 48109 USA. [Campbell, Andrew] Univ Michigan, Div Hematol, Dept Pediat, Ann Arbor, MI 48109 USA. [Arteta, Manuel] Univ Michigan, Dept Pediat, Div Pulm, Ann Arbor, MI 48109 USA. [Minniti, Caterina; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Rana, Sohail] Howard Univ, Dept Pediat & Child Hlth, Washington, DC 20059 USA. [Nouraie, Mehdi; Onyekwere, Onyinye; Castro, Oswaldo; Gordeuk, Victor] Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC USA. [Darbari, Deepika] Childrens Natl Med Ctr, Dept Hematol, Washington, DC 20010 USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Dept Pulm Allergy & Crit Care Med & Hemostasis, Pittsburgh, PA USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Vasc Biol Res Inst, Pittsburgh, PA USA. RP Sable, C (reprint author), Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. EM csable@cnmc.org RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006016-02]; NCRR NIH HHS [M01 RR010284]; NHLBI NIH HHS [1 R01 HL079912-02, 2 R25 HL003679-08, R01 HL079912, R01 HL079912-02, R25 HL003679] NR 30 TC 32 Z9 35 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2009 VL 104 IS 5 BP 713 EP 720 DI 10.1016/j.amjcard.2009.04.034 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 493RW UT WOS:000269756600018 PM 19699350 ER PT J AU Ding, JZ Hsu, FC Harris, TB Liu, YM Kritchevsky, SB Szklo, M Ouyang, P Espeland, MA Lohman, KK Criqui, MH Allison, M Bluemke, DA Carr, JJ AF Ding, Jingzhong Hsu, Fang-Chi Harris, Tamara B. Liu, Yongmei Kritchevsky, Stephen B. Szklo, Moyses Ouyang, Pamela Espeland, Mark A. Lohman, Kurt K. Criqui, Michael H. Allison, Matthew Bluemke, David A. Carr, J. Jeffrey TI The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA) SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID EPICARDIAL ADIPOSE-TISSUE; ARTERY-DISEASE; RISK-FACTORS; IN-VIVO; MEN; CALCIFICATION; THICKNESS; OBESITY; PLAQUE; WOMEN AB Background: Pericardial fat (ie, fat around the heart) may have a direct role in the atherosclerotic process in coronary arteries through local release of inflammation-related cytokines. Cross-sectional studies suggest that pericardial fat is positively associated with coronary artery disease independent of total body fat. Objective: We investigated whether pericardial fat predicts future coronary heart disease events. Design: We conducted a case-cohort study in 998 individuals, who were randomly selected from 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants and 147 MESA participants (26 from those 998 individuals) who developed incident coronary heart disease from 2000 to 2005. The volume of pericardial fat was determined from cardiac computed tomography at baseline. Results: The age range of the subjects was 45-84 y (42% men, 45% white, 10% Asian American, 22% African American, and 23% Hispanic). Pericardial fat was positively correlated with both body mass index (correlation coefficient = 0.45, P < 0.0001) and waist circumference (correlation coefficient = 0.57, P < 0.0001). In un-adjusted analyses, pericardial fat (relative hazard per 1-SD increment: 1.33; 95% CI: 1.15, 1.54), but not body mass index (1.00; 0.84, 1.18), was associated with the risk of coronary heart disease. Waist circumference (1.14; 0.97, 1.34; P = 0.1) was marginally associated with the risk of coronary heart disease. The relation between pericardial fat and coronary heart disease remained significant after further adjustment for body mass index and other cardiovascular disease risk factors (1.26; 1.01, 1.59). The relation did not differ by sex. Conclusion: Pericardial fat predicts incident coronary heart disease independent of conventional risk factors, including body mass index. Am J Clin Nutr 2009;90:499-504. C1 [Ding, Jingzhong; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. [Hsu, Fang-Chi; Liu, Yongmei; Espeland, Mark A.; Lohman, Kurt K.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. [Szklo, Moyses] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Ouyang, Pamela] Johns Hopkins Univ, Div Cardiol, Sch Med, Baltimore, MD USA. [Criqui, Michael H.; Allison, Matthew] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Bluemke, David A.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC 27157 USA. RP Ding, JZ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jding@wfubmc.edu RI Inca, Inct/K-2204-2013; Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Kritchevsky, Stephen/0000-0003-3336-6781; Bluemke, David/0000-0002-8323-8086; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute, Wake Forest University [R01-HL-085323, N01-HC-95159, N01-HC-95165, N01-HC-95169]; Claude D Pepper Older Americans Independence Center [NIH P30-AG21332] FX Supported by grant R01-HL-085323 (to JD) from the National Heart, Lung, and Blood Institute, Wake Forest University; the Claude D Pepper Older Americans Independence Center (NIH P30-AG21332); and contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 28 TC 180 Z9 184 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 499 EP 504 DI 10.3945/ajcn.2008.27358 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300008 PM 19571212 ER PT J AU Agurs-Collins, T Rosenberg, L Makambi, K Palmer, JR Adams-Campbell, L AF Agurs-Collins, Tanya Rosenberg, Lynn Makambi, Kepher Palmer, Julie R. Adams-Campbell, Lucile TI Dietary patterns and breast cancer risk in women participating in the Black Women's Health Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID AFRICAN-AMERICAN WOMEN; POOLED ANALYSIS; NUTRITION-COHORT; GLYCEMIC INDEX; VEGETABLES; FRUITS; FOOD; FAT; PREMENOPAUSAL; SMOKING AB Background: No studies have examined dietary patterns and breast cancer risk in a large cohort of African American women. Objective: We investigated the association between dietary patterns and breast cancer risk in the Black Women's Health Study. Design: This is a prospective cohort study of 50,778 participants followed biennially from 1995 through 2007. During 443,742 person-years of follow-up, 1094 incident cases of breast cancer were identified. Factor analysis was used to derive food patterns based on 69 food variables. We used Cox regression models to obtain incident rate ratios (IRRs) for breast cancer in relation to quintiles of each of the 2 dietary patterns, with adjustment for other breast cancer risk factors. Results: Through factor analysis, we identified 2 dietary patterns: Western (refined grains, processed meat, and sweets) and prudent (whole grains, vegetables, fruit, and fish). The prudent diet was weakly associated with lower breast cancer risk overall; P for trend = 0.06. In analyses stratified by body mass index (BMI; in kg/m(2)), the prudent dietary pattern was associated with a significantly lower risk of breast cancer in women with a BMI <25 (IRR: 0.64; 95% CI: 0.43, 0.93; P for trend = 0.01). The prudent dietary pattern was also associated with a significantly lower risk of breast cancer in premenopausal women (IRR: 0.70; 95% CI: 0.52, 0.96; P for trend = 0.01), and we found a significant inverse association for the prudent dietary pattern and estrogen receptor-negative breast cancer (IRR: 0.52; 95% CI: 0.28, 0.94; P for trend <0.01). Conclusion: Our findings suggest that the prudent dietary pattern may protect against breast cancer in some black women. Am J Clin Nutr 2009;90:621-8. C1 [Agurs-Collins, Tanya] NCI, Bethesda, MD 20892 USA. [Agurs-Collins, Tanya; Makambi, Kepher; Adams-Campbell, Lucile] Howard Univ, Ctr Canc, Washington, DC 20059 USA. [Rosenberg, Lynn; Palmer, Julie R.] Boston Univ, Sch Med, Slone Epidemiol Ctr, Brookline, MA USA. [Makambi, Kepher; Adams-Campbell, Lucile] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Rosenberg, L (reprint author), Boston Univ, Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM collinsta@mail.nih.gov; lrosenberg@slone.bu.edu OI Palmer, Julie/0000-0002-6534-335X FU National Cancer Institute [CA58420] FX Supported by National Cancer Institute grant CA58420. NR 51 TC 51 Z9 52 U1 1 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 621 EP 628 DI 10.3945/ajcn.2009.27666 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300024 PM 19587089 ER PT J AU Kant, AK Graubard, BI Atchison, EA AF Kant, Ashima K. Graubard, Barry I. Atchison, Elizabeth A. TI Intakes of plain water, moisture in foods and beverages, and total water in the adult US population-nutritional, meal pattern, and body weight correlates: National Health and Nutrition Examination Surveys 1999-2006 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SUGAR-SWEETENED BEVERAGES; SOFT DRINK CONSUMPTION; INDUCED THERMOGENESIS; DIETARY DIVERSITY; UNITED-STATES; SALT INTAKE; ADOLESCENTS; CHILDREN; HUMANS; GAIN AB Background: There is a surprising paucity of studies that have systematically examined the correlates of water intake in the US population. Objective: The objective was to examine the association of contributors of water intake with dietary characteristics, meal consumption, and body weight in the US population. Design: We used 24-h dietary recall data from the National Health and Nutrition Examination Survey (NHANES) 1999 2004 (n = 12,283) and the NHANES 2005-2006 (n = 4112) to examine the independent association of intakes of plain water, beverage moisture, food moisture, and total water with sociodemographic factors, dietary characteristics (energy, nutrients, diet quality, and energy density), and meal patterns (number of eating episodes, mention of breakfast or snack) by using multiple regression methods. Results: In 2005-2006, American adults reported consuming 3.18 L of total water within the previous 24 h (in 1999-2004, estimated total water intake was 3.35 L), with plain water and beverages contributing 33% and 48% of the total, respectively. Plain water intake was unrelated to the intake of energy and body mass index but was positively related to dietary fiber and inversely related to beverages, sugars, and the energy density of foods; these associations were in the opposite direction for beverage moisture intake. Total water intake was inversely related to energy from fat and energy density but positively related to dietary fiber, caffeine, alcohol, and diet quality. The number of eating episodes predicted higher beverage and food moisture and total water intakes. A higher body mass index predicted higher intakes of beverage moisture and total water. Conclusion: Various contributors of total water intake differed in their association with dietary characteristics and body weight in the adult US population. Am J Clin Nutr 2009;90:655-63. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. [Atchison, Elizabeth A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remsen Hall,Room 306E, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU Department of Health and Human Services, National Cancer Institute, NIH FX Supported in part by the intramural research program of the Department of Health and Human Services, National Cancer Institute, NIH (BIG). NR 37 TC 65 Z9 75 U1 0 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 655 EP 663 DI 10.3945/ajcn.2009.27749 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300028 PM 19640962 ER PT J AU Park, Y Brinton, LA Subar, AF Hollenbeck, A Schatzkin, A AF Park, Yikyung Brinton, Louise A. Subar, Amy F. Hollenbeck, Albert Schatzkin, Arthur TI Dietary fiber intake and risk of breast cancer in postmenopausal women: the National Institutes of Health-AARP Diet and Health Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID PROGESTERONE-RECEPTOR STATUS; RETIRED-PERSONS DIET; GLYCEMIC INDEX; AMERICAN-ASSOCIATION; PROSPECTIVE COHORT; ESTROGEN; FAT; CARBOHYDRATE; NUTRITION; LOAD AB Background: Although dietary fiber has been hypothesized to lower risk of breast cancer by modulating estrogen metabolism, the association between dietary fiber intake and risk of breast cancer by hormone receptor status is unclear. Objective: The objective was to examine the relation of dietary fiber intake to breast cancer by hormone receptor status and histologic type among postmenopausal women in the National Institutes of Health-AARP Diet and Health Study (n = 185,598; mean age: 62 y). Design: Dietary intakes were assessed with a food-frequency questionnaire. Incident breast cancer cases were identified through linkage with state cancer registries. Cox proportional hazard models were used to estimate relative risks (RRs) and 2-sided 95% CIs. Results: During an average of 7 y of follow-up, 5461 breast cancer cases were identified, of which 3341 cases had estrogen receptor (ER) and progesterone receptor (PR) status. Dietary fiber intake was inversely associated with breast cancer risk [RR for the highest quintile (Q5) compared with the lowest quintile (Q1): 0.87; 95% CI: 0.77, 0.98; P for trend: 0.02]. The inverse association appeared to be stronger for ER-/PR- tumors (RRQ5vsQ1: 0.56; 95% CI: 0.35, 0.90; P for trend: 0.008; 366 cases) than for ER+/PR+ tumors (RRQ5vsQ1: 0.95; 95% CI: 0.76, 1.20; P for trend: 0.47; 1641 cases). The RRQ5vsQ1 of lobular tumors was 0.66 (95% CI: 0.44, 0.97; P for trend: 0.04), and the RRQ5vsQ1 of ductal tumors was 0.90 (95% CI: 0.77, 1.04; P for trend: 0.10). Fiber from grains, fruit, vegetables, and beans was not related to breast cancer. Conclusion: Our findings suggest that dietary fiber can play a role in preventing breast cancer through nonestrogen pathways among postmenopausal women. Am J Clin Nutr 2009;90:664-71. C1 [Park, Yikyung; Brinton, Louise A.; Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Park, Y (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM parkyik@mail.nih.gov RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health FX Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 41 TC 51 Z9 53 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 664 EP 671 DI 10.3945/ajcn.2009.27758 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300029 PM 19625685 ER PT J AU Looker, AC Lacher, DA Pfeiffer, CM Schleicher, RL Picciano, MF Yetley, EA AF Looker, Anne C. Lacher, David A. Pfeiffer, Christine M. Schleicher, Rosemary L. Picciano, Mary Frances Yetley, Elizabeth A. TI Data advisory with regard to NHANES serum 25-hydroxyvitamin D data SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 [Looker, Anne C.; Lacher, David A.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Pfeiffer, Christine M.; Schleicher, Rosemary L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Picciano, Mary Frances; Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Looker, AC (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM alooker@cdc.gov NR 2 TC 13 Z9 13 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 695 EP 695 DI 10.3945/ajcn.2009.28175 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300033 PM 19571227 ER PT J AU Laskey, HL Gopal, L Gallin, JI Holland, SM Heller, T AF Laskey, Heather L. Gopal, Lakshmi Gallin, John I. Holland, Steven M. Heller, Theo TI Twenty-Year Follow-Up of Esophageal Involvement in Chronic Granulomatous Disease SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter C1 [Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, NIH, Bethesda, MD 20892 USA. [Laskey, Heather L.] Univ Oklahoma, Sch Med, Norman, OK 73019 USA. [Gallin, John I.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Heller, T (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr MSC 1800, Bethesda, MD 20892 USA. EM Theller@nih.gov FU Intramural NIH HHS [ZIA DK075008-04]; NIDDK NIH HHS [Z01 DK075008-03 LDB, Z01 DK075008] NR 9 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD SEP PY 2009 VL 104 IS 9 BP 2368 EP 2370 DI 10.1038/ajg.2009.274 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 497AP UT WOS:000270024800049 PM 19727106 ER PT J AU Kelly, TN Rice, TK Gu, DF Hixson, JE Chen, J Liu, DP Jaquish, CE Bazzano, LA Hu, DS Ma, JX Gu, CC Huang, JF Hamm, LL He, J AF Kelly, Tanika N. Rice, Treva K. Gu, Dongfeng Hixson, James E. Chen, Jing Liu, Depei Jaquish, Cashell E. Bazzano, Lydia A. Hu, Dongsheng Ma, Jixiang Gu, C. Charles Huang, Jianfeng Hamm, L. Lee He, Jiang TI Novel Genetic Variants in the alpha-Adducin and Guanine Nucleotide Binding Protein beta-Polypeptide 3 Genes and Salt Sensitivity of Blood Pressure SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article ID ESSENTIAL-HYPERTENSION; C825T POLYMORPHISM; GLY460TRP POLYMORPHISM; SODIUM; ASSOCIATION; POPULATION; ACE AB BACKGROUND We examined the association between 12 single-nucleotide polymorphisms (SNPs) in the (alpha-adducin (ADD1) and guanine nucleotide binding protein (G protein) beta-polypeptide 3 (GNB3) genes and systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressure responses to salt intake. METHODS A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 Han participants from rural North China. Blood pressure (BP) measurements were obtained at baseline and at the end of each intervention period using a random-zero sphygmomanometer. RESULTS We identified a significant association between a rare ADD 1 variant rs17833172 and SBP, DBP, and MAP responses to high sodium (P values <0.0001) and DBP response to low sodium (P value = 0.002). Participants homozygous for the variant A allele of this marker had SBP, DBP, and MAP responses (95% confidence interval) to high salt of 1.6 (-1.8,4.9),-0.8 (-5.6,4.0), and -0.1 (-4.0, 3.9) mm Hg, respectively, vs. corresponding responses of 4.6 (2.5,6.6),1.7 (-0.2, 3.6), and 2.7 (0.9,4.4) mm Hg, respectively, for those who were heterozygous or homozygous for the G allele. In addition, participants with at least one copy of the A allele of SNP rs1129649 of the GNB3 gene had significantly decreased MAP response to low salt compared to homozygotes for the C allele (P value = 0.004) with responses of -3.4 (-3.8,-3.0) vs. -4.2 (-4.6,-3.8) mm Hg, respectively. CONCLUSIONS These data support a role for the ADDI and GNB3 genes in BP salt sensitivity. Future studies aimed at replicating these novel findings are warranted. Am J Hypertens 2009; 22:985-992 (C) 2009 American Journal of Hypertension, Ltd, C1 [Kelly, Tanika N.; Chen, Jing; Bazzano, Lydia A.; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. [Rice, Treva K.; Gu, C. Charles] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Rice, Treva K.] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100037, Peoples R China. [Rice, Treva K.] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100037, Peoples R China. [Gu, Dongfeng; Liu, Depei; Huang, Jianfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng; Huang, Jianfeng] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing, Peoples R China. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [Chen, Jing; Bazzano, Lydia A.; Hamm, L. Lee; He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Liu, Depei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Hu, Dongsheng] Shenzhen Univ, Sch Med, Dept Epidemiol, Shenzhen, Guangdong, Peoples R China. RP Kelly, TN (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. EM tkelly@tulane.edu RI Rice, Treva/D-1385-2009; Gu, Charles/A-7934-2010 OI Gu, Charles/0000-0002-8527-8145 FU National Heart, Lung, and Blood Institute [U01HL072507]; National Institutes of Health, Bethesda, Maryland. FX The Genetic Epidemiology Network of Salt Sensitivity is supported by a cooperative agreement project grant (U01HL072507) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. NR 38 TC 17 Z9 17 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD SEP PY 2009 VL 22 IS 9 BP 985 EP 992 DI 10.1038/ajh.2009.118 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 487PQ UT WOS:000269287600017 PM 19574959 ER PT J AU Gautam, P Valiathan, A Adhikari, R AF Gautam, Pawan Valiathan, Ashima Adhikari, Raviraj TI Maxillary protraction with and without maxillary expansion: A finite element analysis of sutural stresses SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID CRANIOFACIAL COMPLEX; FORCES AB Introduction: In this finite element study, we compared the stress patterns along the various craniofacial sutures with maxillary protraction with and without expansion. Methods: Two 3-dimensional analytic models were developed, 1 simulating maxillary protraction and the other simulating maxillary protraction with expansion. The model consisted of 108799 10 node solid 92 elements (tetrahedron), 193633 nodes, and 580899 degrees of freedom. Results: The overall stresses after maxillary protraction with maxillary expansion were significantly higher than with a facemask alone. The magnitude of stress on the craniofacial sutures with maxillary protraction alone was in the range of a few millinewtons per square millimeter, whereas, with maxillary protraction with maxillary expansion, the stresses ranged from a few newtons per square millimeter to a few hundred newtons per square millimeter. The pattern of stress distribution also differed with the 2 treatment modalities as did the sutures experiencing maximum and minimum stresses. Conclusions: The osteogenic potential of such low stresses after maxillary protraction can be questioned. High stresses generated in various craniofacial sutures after maxillary protraction with expansion are responsible for disrupting the circummaxillary sutural system and presumably facilitating the orthopedic effect of the facemask. (Am J Orthod Dentofacial Orthop 2009;136:361-6) C1 [Valiathan, Ashima] Manipal Coll Dent Sci, Dept Orthodont & Dentofacial Orthoped, Manipal, Karnataka, India. [Adhikari, Raviraj] Manipal Inst Technol, Dept Mech Engn, Manipal, Karnataka, India. RP Gautam, P (reprint author), NIDCR, CSDB, NIH, Bldg 10,Room 5N-102, Bethesda, MD 20892 USA. EM drgautampawan@rediffmail.com OI Adhikari, Dr. Raviraja/0000-0001-8409-6406 NR 23 TC 11 Z9 18 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0889-5406 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD SEP PY 2009 VL 136 IS 3 BP 361 EP 366 DI 10.1016/j.ajodo.2008.02.021 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 490RV UT WOS:000269522700023 PM 19732670 ER PT J AU Chen, GJ Han, GC Wang, JN Wang, RX Xu, RN Shen, BF Qian, JH Li, Y AF Chen, Guojiang Han, Gencheng Wang, Jianan Wang, Renxi Xu, Ruonan Shen, Beifen Qian, Jiahua Li, Yan TI Natural Killer Cells Modulate Overt Autoimmunity to Homeostasis in Nonobese Diabetic Mice after Anti-CD3 F(ab ')(2) Antibody Treatment through Secreting Transforming Growth Factor-beta SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID T-REGULATORY CELLS; BOUND TGF-BETA; NK CELLS; NOD MICE; SELF-TOLERANCE; IFN-GAMMA; IN-VITRO; INDUCTION; THERAPY; ACTIVATION AB Recently, the anti-CD3 antibody has been shown to be a promising candidate for the efficient treatment of overt autoimmunity. However, the mechanisms underlying this effect remain unclear. Our previous studies demonstrated that natural killer (NK)T cells and transforming growth factor (TGF)-beta were key elements in anti-CD3 F(ab')(2)-mediated re-establishment of glucose homeostasis and restoration of self tolerance to islets in type 1 diabetes. In this report, we further investigate the regulatory pathways involved, especially the cellular source of TGF-beta production. The treatment of new-onset nonobese diabetic mice with anti-CD3 F(ab')(2) resulted in a significant increase in the numbers of NK cells in spleen and pancreatic lymph nodes that secrete TGF-beta. Depletion of this cell population with a specific anti-AsGM1 antibody abrogated anti-CD3 F(ab')(2) therapeutic effects and splenic TGF-beta production. When fractionated from recovered mice after CD3 antibody therapy, these NK cells actively suppressed diabetogenic cell proliferation and prevented the cotransfer of diabetes into nonobese diabetic-severe combined immunodeficient mice in a TGF-beta-dependent manner. In addition, the regulatory NKT cells from remitting mice were capable of causing NK cells to exhibit a TGF-beta-producing phenotype by the secretion of the T helper 2 cytokines interleukins 4 and 10. overall, these data indicate that NK cells are the main source of TGF-beta production after anti-CD3 F(ab')(2) treatment, which are controlled by a population of T helper 2-like NKT cells. (Am JPathol 2009,175:1086-1094; DOI: 10.2353/ajpath.2009.080488) C1 [Chen, Guojiang; Han, Gencheng; Wang, Jianan; Wang, Renxi; Xu, Ruonan; Shen, Beifen; Li, Yan] Inst Basic Med Sci, Dept Mol Immunol, Beijing 100850, Peoples R China. [Qian, Jiahua] NCI, Vaccine Branch, Bethesda, MD 20892 USA. RP Li, Y (reprint author), Inst Basic Med Sci, Dept Mol Immunol, Taiping Rd 27, Beijing 100850, Peoples R China. EM liyan62033@yahoo.com.cn FU National Key Basic Research Program of China [2007CB512406]; National Natural Science Foundation of China [30801029] FX Supported by grants from the National Key Basic Research Program of China (2007CB512406) and the National Natural Science Foundation of China (30801029). NR 43 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2009 VL 175 IS 3 BP 1086 EP 1094 DI 10.2353/ajpath.2009.080488 PG 9 WC Pathology SC Pathology GA 491ZQ UT WOS:000269623300015 PM 19644014 ER PT J AU Katsifis, GE Rekka, S Moutsopoulos, NM Pillemer, S Wahl, SM AF Katsifis, Gikas E. Rekka, Sofia Moutsopoulos, Niki M. Pillemer, Stanley Wahl, Sharon M. TI Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjogren's Syndrome Immunopathogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID REGULATORY T-CELLS; GROWTH-FACTOR-BETA; MESSENGER-RNA EXPRESSION; ROR-GAMMA-T; TGF-BETA; PROINFLAMMATORY CYTOKINES; DENDRITIC CELLS; SALIVARY-GLANDS; CLINICAL-TRIAL; DOUBLE-BLIND AB Recently recognized as a distinct CD4(+) T helper (Th) lineage, Th17 cells have been implicated in host responses to infections and in pathogenesis associated with autoimmune diseases. This cytokine is implicated in primary Sjogren's syndrome (pSS) immunopathology because of the increased levels of circulating interleukin (IL)-17 in pSS. Plasma and minor salivary glands (MSGs) from patients with pSS were therefore evaluated for CD4(+) T cells, T regulatory cells, IL-17, and supporting cytokines by immunohistochemistry, RT-PCR, and microbead assays. MSGs from pSS patients contain IL-17-expressing cells as a dominant population within inflammatory lesions. IL-17 protein expression progressively increased with higher biopsy focus scores (P < 0.0001), in parallel with detection by RT-PCR. Transforming growth factor-beta, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues. Although transforming growth factor-beta is also a pivotal differentiation factor for immunosuppressive Foxp3(+) T regulatory cells (Tregs), an increase in Foxp3(+) Tregs was evident in biopsy specimens with mild and moderate inflammation but this increase was disproportionate to escalating pro-inflammatory Th17 populations in advanced disease. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 were significantly elevated in pSS plasma. These data identify a profusion of IL-17-generating cells and supporting cytokines within diseased pSS MSGs without a compensatory increase in immunomodulatory Tregs; this imbalance seems to foster a pathogenic milieu that may be causative and predictive of infiltrative injury and amenable to therapeutic intervention. (Am J Pathol 2009, 175:1167-1177; DOI: 10.2353/ajpath.2009.090319) C1 [Wahl, Sharon M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Sjogrens Syndrome Clin, NIH, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 320,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM smwahl@mail.nih.gov FU National Institutes of Health FX Supported in part by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 50 TC 128 Z9 143 U1 0 U2 5 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2009 VL 175 IS 3 BP 1167 EP 1177 DI 10.2353/ajpath.2009.090319 PG 11 WC Pathology SC Pathology GA 491ZQ UT WOS:000269623300023 PM 19700754 ER PT J AU Roilides, E Zaoutis, TE Katragkou, A Benjamin, DK Walsh, TJ AF Roilides, Emmanuel Zaoutis, Theoklis E. Katragkou, Aspasia Benjamin, Daniel K., Jr. Walsh, Thomas J. TI Zygomycosis in Neonates: An Uncommon but Life-threatening Infection SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Epidemiology; mucormycosis; outcome; Rhizopus spp.; gastrointestinal infection ID PRIMARY CUTANEOUS MUCORMYCOSIS; GASTROINTESTINAL MUCORMYCOSIS; NECROTIZING ENTEROCOLITIS; ABSIDIA-CORYMBIFERA; PREMATURE-INFANT; COLONIC MUCORMYCOSIS; RHIZOPUS INFECTION; PRETERM INFANT; NEWBORN INFANT; CHILDREN AB We systematically reviewed all published cases of zygomycosis, an increasingly important infection with high mortality, in neonates. We searched PubMed and individual references for English publications of single cases or case series of neonatal (0 to 1 month) zygomycosis. Cases were included if the), fulfilled prespecified criteria. Fifty-nine cases were published through July 2007. Most of the infants (77%) were premature. The most common sites of zygomycosis were gastrointestinal (54%) and cutaneous (36%) diseases. This pattern differs from sinopulmonary and rhinocerebral patterns of older children. Fifty-six percent of cases were diagnosed by histology only and 44% by histology, and Culture. Rhizopus spp. were isolated from 18/25 (72%) cases. Thirty-seven percent of patients received no antifungal therapy. Thirty-two (54%) neonates underwent surgery with (39%) or without (15%) antifungal agents. Overall mortality was 64%. A higher fraction of neonates treated with amphotericin B and surgery, survived than those who received no therapy (70% versus 5%). Zygomycosis is a life-threatening infection in neonates with a distinct pattern of gastrointestinal and cutaneous involvement and high mortality. Combination of amphotericin B and surgery was common management strategy in survivors. C1 [Roilides, Emmanuel; Katragkou, Aspasia] Aristotle Univ Thessaloniki, Dept Pediat 3, GR-54642 Thessaloniki, Greece. [Zaoutis, Theoklis E.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Zaoutis, Theoklis E.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Zaoutis, Theoklis E.] Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. [Benjamin, Daniel K., Jr.] Duke Univ, Dept Pediat, Duke Clin Res Inst, Durham, NC 27706 USA. [Roilides, Emmanuel; Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Roilides, E (reprint author), Aristotle Univ Thessaloniki, Sch Med, Dept Pediat 3, Hippokrat Hosp, Konstantinoupoleos 49, GR-54642 Thessaloniki, Greece. EM roilides@med.auth.gr NR 57 TC 16 Z9 18 U1 0 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD SEP PY 2009 VL 26 IS 8 BP 565 EP 573 DI 10.1055/s-0029-1220775 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 486RY UT WOS:000269216600004 PM 19391079 ER PT J AU Potenza, MA Gagliardi, S De Benedictis, L Zigrino, A Tiravanti, E Colantuono, G Federici, A Lorusso, L Benagiano, V Quon, MJ Montagnani, M AF Potenza, Maria A. Gagliardi, Sara De Benedictis, Leonarda Zigrino, Addolorata Tiravanti, Edy Colantuono, Giuseppe Federici, Antonio Lorusso, Loredana Benagiano, Vincenzo Quon, Michael J. Montagnani, Monica TI Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE oxidative stress ID ENHANCED SUPEROXIDE-PRODUCTION; ASSESSING INSULIN SENSITIVITY; ACTIVATED RECEPTOR-ALPHA; OXIDATIVE STRESS; ENDOTHELIAL DYSFUNCTION; METABOLIC SYNDROME; NITRIC-OXIDE; PPAR-GAMMA; IN-VIVO; BLOOD-PRESSURE AB Potenza MA, Gagliardi S, De Benedictis L, Zigrino A, Tiravanti E, Colantuono G, Federici A, Lorusso L, Benagiano V, Quon MJ, Montagnani M. Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature. Am J Physiol Endocrinol Metab 297: E685-E694, 2009. First published June 16, 2009; doi: 10.1152/ajpendo.00291.2009.-Oxidative stress contributes to cardiovascular complications of diabetes, in part, by reducing the bioavailability of nitric oxide (NO). We investigated the mechanisms whereby the insulin sensitizer rosiglitazone may ameliorate oxidative stress in the vasculature of spontaneously hypertensive rats (SHR). Nine-week-old SHR were treated by gavage for 7 wk with rosiglitazone (5 mg.kg(-1).day(-1)) or vehicle control. Treatment of SHR with rosiglitazone lowered systolic blood pressure, reduced fasting plasma insulin and asymmetrical dimethylarginine, and increased insulin sensitivity (when compared with vehicle treatment). In vessel homogenates and serum from rosiglitazone-treated SHR, SOD activity was enhanced, while 8-iso-PGF(2 alpha) (lipid peroxidation product) was reduced (when compared with samples from vehicle-treated SHR). Moreover, expression of p22phox (catalytic subunit of NADPH oxidase) as well as nitrotyrosine and superoxide content were all reduced in the aortas of rosiglitazone-treated SHR. In mesenteric vascular beds (MVB) isolated ex vivo from rosiglitazone-treated SHR, NO-dependent vasodilator actions of insulin were improved when compared with MVB from vehicle-treated SHR. Acute pretreatment of MVB from vehicle-treated SHR with apocynin (NADPH oxidase inhibitor) enhanced vasodilator actions of insulin (results comparable to those in MVB from rosiglitazone-treated SHR). In Langendorff heart preparations from rosiglitazone-treated SHR, ischemia/reperfusion injury caused infarcts 40% smaller than in hearts from vehicle-treated SHR. Acute pretreatment of hearts from vehicle-treated SHR with apocynin produced similar results. Finally, rosiglitazone treatment of endothelial cells in primary culture reduced superoxide induced by insulin-resistant conditions. We conclude that rosiglitazone therapy in SHR increases SOD activity and decreases p22phox expression in the vasculature to reduce oxidant stress leading to an improved cardiovascular phenotype. C1 [Montagnani, Monica] Univ Bari, Dept Pharmacol & Human Physiol, Pharmacol Sect, Sch Med, I-70124 Bari, Italy. [Tiravanti, Edy; Colantuono, Giuseppe] Univ Bari, Dept Emergency & Transplants, I-70124 Bari, Italy. [Lorusso, Loredana; Benagiano, Vincenzo] Univ Bari, Dept Human Anat & Histol, I-70124 Bari, Italy. [Quon, Michael J.] Natl Ctr Complementary & Alternat Med, Diabet Unit, NIH, Bethesda, MD USA. RP Montagnani, M (reprint author), Univ Bari, Dept Pharmacol & Human Physiol, Pharmacol Sect, Sch Med, Policlin Piazza G Cesare 11, I-70124 Bari, Italy. EM monica@farmacol.uniba.it OI Potenza, Maria Assunta/0000-0002-9995-1468; Quon , Michael /0000-0002-5289-3707; federici, antonio/0000-0001-5102-9995; Quon, Michael/0000-0002-9601-9915; BENAGIANO, VINCENZO/0000-0003-2579-9456; montagnani, monica/0000-0002-5697-8185 FU Italian Ministry for University and Research; Juvenile Diabetes Research Foundation [CDA 2-2006-32]; Intramural Research Program; National Center for Complementary and Alternative Medicine; National Institutes of Health FX This work was supported, in part, by research grant awards from the Italian Ministry for University and Research and the Juvenile Diabetes Research Foundation (CDA 2-2006-32 to M. Montagnani) and by the Intramural Research Program, National Center for Complementary and Alternative Medicine, National Institutes of Health (to M. J. Quon). NR 77 TC 36 Z9 38 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD SEP PY 2009 VL 297 IS 3 BP E685 EP E694 DI 10.1152/ajpendo.00291.2009 PG 10 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 484QW UT WOS:000269063000014 PM 19531637 ER PT J AU Ansari, HR Teng, BY Nadeem, A Roush, KP Martin, KH Schnermann, J Mustafa, SJ AF Ansari, Habib R. Teng, Bunyen Nadeem, Ahmed Roush, Kevin P. Martin, Karen H. Schnermann, J. Mustafa, S. Jamal TI A(1) adenosine receptor-mediated PKC and p42/p44 MAPK signaling in mouse coronary artery smooth muscle cells SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE A(1) adenosine receptor agonist; coronary artery smooth muscle; protein kinase C; mitogen-activated protein kinase signaling ID PROTEIN-KINASE-C; PHOSPHOLIPASE-C; P38 MAPK; CONTRACTION; ACTIVATION; MICE; MODULATION; RESISTANCE; MECHANISM; ANALOGS AB Ansari HR, Teng B, Nadeem A, Roush KP, Martin KH, Schnermann J, Mustafa SJ. A(1) adenosine receptor-mediated PKC and p42/p44 MAPK signaling in mouse coronary artery smooth muscle cells. Am J Physiol Heart Circ Physiol 297: H1032-H1039, 2009. First published July 10, 2009; doi: 10.1152/ajpheart.00374.2009.-The A(1) adenosine receptor (A(1)AR) is coupled to G(i)/G(o) proteins, but the downstream signaling pathways in smooth muscle cells are unclear. This study was performed in coronary artery smooth muscle cells (CASMCs) isolated from the mouse heart [A(1)AR wild type (A(1)WT) and A(1)AR knockout (A(1)KO)] to delineate A(1)AR signaling through the PKC pathway. In A(1)WT cells, treatment with (2S)-(N)6-(2-endo-norbornyl)adenosine (ENBA; 10(-5)M) increased A(1)AR expression by 150%, which was inhibited significantly by the A(1)AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (10(-6)M), but not in A(1)KO CASMCs. PKC isoforms were identified by Western blot analysis in the cytosolic and membrane fractions of cell homogenates of CASMCs. In A(1)WT and A(1)KO cells, significant levels of basal PKC-alpha were detected in the cytosolic fraction. Treatment with the A(1)AR agonist ENBA (10(-5)M) translocated PKC-alpha from the cytosolic to membrane fraction significantly in A(1)WT but not A(1)KO cells. Phospholipase C isoforms (beta I, beta III, and gamma(1)) were analyzed using specific antibodies where ENBA treatment led to the increased expression of PLC-beta III in A(1)WT CASMCs while having no effect in A(1)KO CASMCs. In A(1)WT cells, ENBA increased PKC-alpha expression and p42/p44 MAPK (ERK1/2) phospohorylation by 135% and 145%, respectively. These effects of ENBA were blocked by Go-6976 (PKC-alpha inhibitor) and PD-98059 (p42/p44 MAPK inhibitor). We conclude that A(1)AR stimulation by ENBA activates the PKC-alpha signaling pathway, leading to p42/p44 MAPK phosphorylation in CASMCs. C1 [Mustafa, S. Jamal] W Virginia Univ, Ctr Cardiovasc & Resp Sci, Dept Physiol & Pharmacol, Robert C Byrd Hlth Sci Ctr,Sch Med, Morgantown, WV 26506 USA. [Martin, Karen H.] W Virginia Univ, Robert C Byrd Hlth Sci Ctr, Microscope Imaging Facil, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. [Schnermann, J.] NIDDK, NIH, Bethesda, MD USA. RP Mustafa, SJ (reprint author), W Virginia Univ, Ctr Cardiovasc & Resp Sci, Dept Physiol & Pharmacol, Robert C Byrd Hlth Sci Ctr,Sch Med, Morgantown, WV 26506 USA. EM smustafa@hsc.wvu.edu FU National Heart, Lung, and Blood Institute [HL-027339, HL-094447] FX This work was supported by National Heart, Lung, and Blood Institute Grants HL-027339 and HL-094447. NR 34 TC 19 Z9 19 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2009 VL 297 IS 3 BP H1032 EP H1039 DI 10.1152/ajpheart.00374.2009 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 487WP UT WOS:000269308900016 PM 19592614 ER PT J AU Liu, Y Wen, H Gorman, RC Pilla, JJ Gorman, JH Buckberg, G Teague, SD Kassab, GS AF Liu, Yi Wen, Han Gorman, Robert C. Pilla, James J. Gorman, Joseph H., III Buckberg, Gerald Teague, Shawn D. Kassab, Ghassan S. TI Reconstruction of myocardial tissue motion and strain fields from displacement-encoded MR imaging SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE magnetic resonance imaging; displacement-encoding with stimulated echo; heart motion analysis; finite element ID 3-DIMENSIONAL STRAIN; HUMAN-HEART; MODEL; TRACKING; IMAGES; DEFORMATION; ANEURYSM; DENSE AB Liu Y, Wen H, Gorman RC, Pilla JJ, Gorman JH 3rd, Buckberg G, Teague SD, Kassab GS. Reconstruction of myocardial tissue motion and strain fields from displacement-encoded MR imaging. Am J Physiol Heart Circ Physiol 297: H1151-H1162, 2009. First published June 26, 2009; doi:10.1152/ajpheart.00074.2009.-A quantitative analysis of myocardial mechanics is fundamental to understanding cardiac function, diagnosis of heart disease, and assessment of therapeutic intervention. Displacement encoding with stimulated-echo ( DENSE) magnetic resonance imaging (MRI) technique was developed to track the three-dimensional (3D) displacement vector of discrete material grid points in the myocardial tissue. Despite the wealth of information gained from DENSE images, the current software only provides two-dimensional in-plane deformation. The objective of this study is to introduce a postprocessing method to reconstruct and visualize continuous dynamic 3D displacement and strain fields in the ventricular wall from DENSE data. An anatomically accurate hexagonal finite-element model of the left ventricle (LV) is reconstructed by fitting a prolate spheroidal primitive to contour points of the epi- and endocardial surfaces. The continuous displacement field in the model is described mathematically based on the discrete DENSE vectors using a minimization method with smoothness regularization. Based on the displacement, heart motion and myocardial stretch (or strain) are analyzed. Illustratory computations were conducted with DENSE data of three infarcted and one normal sheep ventricles. The full 3D results show stronger overall axial shortening, wall thickening, and twisting of the normal LV compared with the infarcted hearts. Local myocardial stretches show a dyskinetic LV in the apical region, dilation of apex in systole, and a compensatory increase in strain in the healthy basal region as a compensatory mechanism. We conclude that the proposed postprocessing method significantly extends the utility of DENSE MRI, which may provide a patient-specific 3D model of cardiac mechanics. C1 [Liu, Yi; Kassab, Ghassan S.] Indiana Univ Purdue Univ, Dept Biomed Engn, Indianapolis, IN 46202 USA. [Wen, Han] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Gorman, Robert C.; Pilla, James J.; Gorman, Joseph H., III] Hosp Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Pilla, James J.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Buckberg, Gerald] Univ Calif Los Angeles, Dept Cardiac Surg, Los Angeles, CA USA. [Teague, Shawn D.] Indiana Univ Purdue Univ, Dept Radiol, Indianapolis, IN 46202 USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ, Dept Surg, Indianapolis, IN 46202 USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. RP Kassab, GS (reprint author), Indiana Univ Purdue Univ, Dept Biomed Engn, SL 220,723 W Michigan St, Indianapolis, IN 46202 USA. EM gkassab@iupui.edu RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 NR 26 TC 16 Z9 16 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2009 VL 297 IS 3 BP H1151 EP H1162 DI 10.1152/ajpheart.00074.2009 PG 12 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 487WP UT WOS:000269308900029 PM 19561315 ER PT J AU Lyashkov, AE Vinogradova, TM Zahanich, I Li, Y Younes, A Nuss, HB Spurgeon, HA Maltsev, VA Lakatta, EG AF Lyashkov, Alexey E. Vinogradova, Tatiana M. Zahanich, Ihor Li, Yue Younes, Antoine Nuss, H. Bradley Spurgeon, Harold A. Maltsev, Victor A. Lakatta, Edward G. TI Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca2+ cycling and I-KACh SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE submembrane Ca2+ release; ion channels; protein kinase A phosphorylation; signal transduction ID CARDIAC-PACEMAKER CELLS; VAGAL NERVE-STIMULATION; MUSCARINIC K+ CHANNELS; ADENYLYL-CYCLASE; CALCIUM CURRENT; DIASTOLIC DEPOLARIZATION; RYANODINE RECEPTOR; G-PROTEIN; BEATING RATE; SINUS NODE AB Lyashkov AE, Vinogradova TM, Zahanich I, Li Y, Younes A, Nuss HB, Spurgeon HA, Maltsev VA, Lakatta EG. Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca2+ cycling and I-KACh. Am J Physiol Heart Circ Physiol 297: H949-H959, 2009. First published June 19, 2009; doi: 10.1152/ajpheart.01340.2008.-Prior studies indicate that cholinergic receptor (ChR) activation is linked to beating rate reduction (BRR) in sinoatrial nodal cells (SANC) via 1) a G(i)-coupled reduction in adenylyl cyclase (AC) activity, leading to a reduction of cAMP or protein kinase A (PKA) modulation of hyperpolarization-activated current (I-f) or L-type Ca2+ currents (I-Ca,I- L), respectively; and 2) direct G(i)-coupled activation of ACh-activated potassium current (I-KACh). More recent studies, however, have indicated that Ca2+ cycling by the sarcoplasmic reticulum within SANC (referred to as a Ca2+ clock) generates rhythmic, spontaneous local Ca2+ releases (LCR) that are AC-PKA dependent. LCRs activate Na+-Ca2+ exchange (NCX) current, which ignites the surface membrane ion channels to effect an AP. The purpose of the present study was to determine how ChR signaling initiated by a cholinergic agonist, carbachol (CCh), affects AC, cAMP, and PKA or sarcolemmal ion channels and LCRs and how these effects become integrated to generate the net response to a given intensity of ChR stimulation in single, isolated rabbit SANC. The threshold CCh concentration ([CCh]) for BRR was similar to 10 nM, half maximal inhibition (IC50) was achieved at 100 nM, and 1,000 nM stopped spontaneous beating. G(i) inhibition by pertussis toxin blocked all CCh effects on BRR. Using specific ion channel blockers, we established that I-f blockade did not affect BRR at any [CCh] and that I-KACh activation, evidenced by hyperpolarization, first became apparent at [CCh] > 30 nM. At IC50, CCh reduced cAMP and reduced PKA-dependent phospholamban (PLB) phosphorylation by similar to 50%. The dose response of BRR to CCh in the presence of I-KACh blockade by a specific inhibitor, tertiapin Q, mirrored that of CCh to reduced PLB phosphorylation. At IC50, CCh caused a time-dependent reduction in the number and size of LCRs and a time dependent increase in LCR period that paralleled coincident BRR. The phosphatase inhibitor calyculin A reversed the effect of IC50 CCh on SANC LCRs and BRR. Numerical model simulations demonstrated that Ca2+ cycling is integrated into the cholinergic modulation of BRR via LCR-induced activation of NCX current, providing theoretical support for the experimental findings. Thus ChR stimulation-induced BRR is entirely dependent on G(i) activation and the extent of G(i) coupling to Ca2+ cycling via PKA signaling or to I-KACh: at low [CCh], I-KACh activation is not evident and BRR is attributable to a suppression of cAMP-mediated, PKA-dependent Ca2+ signaling; as [CCh] increases beyond 30 nM, a tight coupling between suppression of PKA-dependent Ca2+ signaling and I-KACh activation underlies a more pronounced BRR. C1 [Lyashkov, Alexey E.; Vinogradova, Tatiana M.; Zahanich, Ihor; Li, Yue; Younes, Antoine; Nuss, H. Bradley; Spurgeon, Harold A.; Maltsev, Victor A.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lakattae@grc.nia.nih.gov FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 53 TC 25 Z9 25 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2009 VL 297 IS 3 BP H949 EP H959 DI 10.1152/ajpheart.01340.2008 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 487WP UT WOS:000269308900007 PM 19542482 ER PT J AU Ostbye, T Krause, KM Lovelady, CA Morey, MC Bastian, LA Peterson, BL Swamy, GK Brouwer, RJN McBride, CM AF Ostbye, Truis Krause, Katrina M. Lovelady, Cheryl A. Morey, Miriam C. Bastian, Lori A. Peterson, Bercedis L. Swamy, Geeta K. Brouwer, Rebecca J. N. McBride, Colleen M. TI Active Mothers Postpartum A Randomized Controlled Weight-Loss Intervention Trial SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; SOCIAL SUPPORT; MULTIPLE-PASS; RISK-FACTORS; RETENTION; WOMEN; DIET; PREGNANCY; MAINTENANCE; OVERWEIGHT AB Background: Pregnancy may contribute to overweight and obesity. Purpose: The primary objective of Active Mothers Postpartum was to promote a reduction in BMI through 24-months postpartum via Sustainable lifestyle changes. Design: Behavioral intervention RCT to enhance postpartum weight loss. Setting/ A total of 450 overweight or obese women, enrolled 6-weeks postpartum, were recruited participants: through obstetrics clinics and community posters in the Durham NC area. Intervention: Intervention participants were offered eight healthy-eating classes, ten physical-activity classes, and six telephone-counseling sessions over 9 months. Main outcome measures: Changes from baseline (6-weeks postpartum) to 1-month post-intervention (12-months postpartum) in: (1) diet (caloric intake, calories from fat, intake of certain foods); (2) physical activity (self-reported physical activity, television time); and (3) weight (collected 2004-2007, analyzed 2007-2008). Results: Mean weight loss was 0.90 kg (+/- 5.1 kg) in the intervention group and 0.36 kg (+/- 4.9 kg) in the control group; this difference was not significant. There were also no significant group differences in improvement of diet or increased physical activity. In secondary analyses, there was a positive bivariate relationship between classes attended and weight loss (p=0.01). Conclusions: There were no significant differences among the arms in diet, physical activity, or weight change. Home-based interventions via mail, telephone, or Internet/e-mail may be more feasible and Successful in this population. The postpartum period is an important phase in women's lives with regard to weight retention, but engaging them during this busy period remains a challenge. C1 [Ostbye, Truis; Krause, Katrina M.; Brouwer, Rebecca J. N.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Morey, Miriam C.; Bastian, Lori A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Peterson, Bercedis L.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Swamy, Geeta K.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Morey, Miriam C.; Bastian, Lori A.] Durham Vet Affairs Med Ctr, Durham, NC USA. [Ostbye, Truis; Lovelady, Cheryl A.] Univ N Carolina, Dept Nutr, Greensboro, NC 27412 USA. [Ostbye, Truis] Duke NUS Grad Med Sch, Singapore, Singapore. [McBride, Colleen M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ostbye, T (reprint author), Duke Univ, Med Ctr, Dept Community & Family Med, Box 104006, Durham, NC 27710 USA. EM truls.ostbye@duke.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK064986] FX This study was funded through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; R01 DK064986). NR 48 TC 83 Z9 86 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2009 VL 37 IS 3 BP 173 EP 180 DI 10.1016/j.amepre.2009.05.016 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 487RA UT WOS:000269291300001 PM 19595557 ER PT J AU Vitiello, B Towbin, K AF Vitiello, Benedetto Towbin, Kenneth TI Stimulant Treatment of ADHD and Risk of Sudden Death in Children SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DRUGS C1 [Vitiello, Benedetto] NIMH, Div Serv & Intervent Res & Mood, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, Div Serv & Intervent Res & Mood, Rm 7147,6001 Execut Blvd, Bethesda, MD 20892 USA. EM bvitiell@mail.nih.gov NR 14 TC 9 Z9 10 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2009 VL 166 IS 9 BP 955 EP 957 DI 10.1176/appi.ajp.2009.09050619 PG 3 WC Psychiatry SC Psychiatry GA 490FH UT WOS:000269483600001 PM 19528196 ER PT J AU Ducci, F Roy, A Shen, PH Yuan, QP Yuan, NP Hodgkinson, CA Goldman, LR Goldman, D AF Ducci, Francesca Roy, Alec Shen, Pei-Hong Yuan, Qiaoping Yuan, Nicole P. Hodgkinson, Colin A. Goldman, Lynn R. Goldman, David TI Association of Substance Use Disorders With Childhood Trauma but not African Genetic Heritage in an African American Cohort SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID NEIGHBORHOOD SOCIOECONOMIC-STATUS; GENOME-WIDE ASSOCIATION; SEXUAL-ABUSE; LINKAGE DISEQUILIBRIUM; DEPENDENT PATIENTS; HUMAN-POPULATIONS; ATTEMPT SUICIDE; DRUG-USE; COCAINE; ALCOHOL AB Objective: Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. Method: The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. Results: African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76-0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. Conclusions: These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities. C1 NIAAA, Neurogenet Lab, Bethesda, MD USA. [Ducci, Francesca] Inst Psychiat, Div Psychol Med, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ USA. Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Ducci, F (reprint author), Inst Psychiat, Div Psychol Med, Social Genet & Dev Psychiat Ctr, PO63,Crespigny Pk, London SE5 8AF, England. EM francesca.ducci@kcl.ac.uk RI Goldman, David/F-9772-2010; Goldman, Lynn/D-5372-2012 OI Goldman, David/0000-0002-1724-5405; FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [K23 AA-014606] FX Supported by the intramural research program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and by grant K23 AA-014606 from NIAAA to Dr. Nicole Yuan. NR 42 TC 33 Z9 33 U1 3 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2009 VL 166 IS 9 BP 1031 EP 1040 DI 10.1176/appi.ajp.2009.08071068 PG 10 WC Psychiatry SC Psychiatry GA 490FH UT WOS:000269483600014 PM 19605534 ER PT J AU Stringaris, A Cohen, P Pine, DS Leibenluft, E AF Stringaris, Argyris Cohen, Patricia Pine, Daniel S. Leibenluft, Ellen TI Adult Outcomes of Youth Irritability: A 20-Year Prospective Community-Based Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ANGER ATTACKS; AGGRESSION; DISORDERS; ADOLESCENCE; PREVALENCE; OPPOSITIONALITY; TEMPERAMENT; PERSONALITY; PREDICTORS; DEPRESSION AB Objective: Irritability is a widely occurring DSM-IV symptom in youths. However, little is known about the relationship between irritability in early life and its outcomes in mid-adulthood. This study examines the extent to which youth irritability is related to adult psychiatric outcomes by testing the hypothesis that it predicts depressive and generalized anxiety disorders. Method: The authors conducted a longitudinal community-based study of 631 participants whose parents were interviewed when participants were in early adolescence ( mean age=13.8 years [SD=2.6]) and who were themselves interviewed 20 years later ( mean age=33.2 years [SD=2.9]). Parent-reported irritability in adolescence was used to predict self-reported psychopathology, assessed by standardized diagnostic interview at 20-year follow-up. Results: Cross-sectionally, irritability in adolescence was widely associated with other psychiatric disorders. After adjustment for baseline emotional and behavioral disorders, irritability in adolescence predicted major depressive disorder (odds ratio=1.33, 95% confidence interval [CI]= 1.00-1.78]), generalized anxiety disorder ( odds ratio=1.72, 95% CI=1.04-2.87), and dysthymia (odds ratio=1.81, 95% CI=1.06-3.12) at 20-year follow-up. Youth irritability did not predict bipolar disorder or axis II disorders at follow-up. Conclusions: Youth irritability as reported by parents is a specific predictor of self-reported depressive and anxiety disorders 20 years later. The role of irritability in developmental psychiatry, and in the pathophysiology of mood and anxiety disorders specifically, should receive further study. C1 [Stringaris, Argyris] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Mood & Anxiety Program, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, Div Epidemiol, New York, NY 10032 USA. RP Stringaris, A (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Mood & Anxiety Program, NIMH Bldg 15K,MSC-2670, Bethesda, MD 20892 USA. EM stringarisa@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 35 TC 136 Z9 137 U1 3 U2 18 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2009 VL 166 IS 9 BP 1048 EP 1054 DI 10.1176/appi.ajp.2009.08121849 PG 7 WC Psychiatry SC Psychiatry GA 490FH UT WOS:000269483600016 PM 19570932 ER PT J AU Shah, S Elmer, S Grady, C AF Shah, Seema Elmer, Stacey Grady, Christine TI Planning for Posttrial Access to Antiretroviral Treatment for Research Participants in Developing Countries SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID INTERRUPTION; THERAPY AB Despite recognition of the importance of posttrial access to antiretroviral therapy (ART), the implementation process has not been studied. We examined whether the National Institutes of Health (NIH) guidance document was being implemented in NIH-funded ART trials conducted in developing countries between July 2005 and June 2007. All of the 18 studies we identified had posttrial access plans for trial participants. More than 70% had specific mechanisms for posttrial access, but none guaranteed long-term sponsor funding after the trials. The plans reflected variation in local contexts and the uncertainty of predicting local conditions in the long term. The strength of the NIH guidance document may be that it encourages investigators to formulate plans in advance and to work with other stakeholders to provide access to ART. (Am J Public Health. 2009;99:1556-1562. doi:10.2105/AJPH.2008.157982) C1 [Shah, Seema] NIH, Ctr Clin, Dept Bioeth, Sect Human Subjects Res, Bethesda, MD 20892 USA. [Shah, Seema] NIH, Henry Jackson Fdn, Liaison Off, Div Aids, Bethesda, MD 20892 USA. RP Shah, S (reprint author), NIH, Ctr Clin, Dept Bioeth, Sect Human Subjects Res, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU DAIDS Enterprise Information System [N01-AI-30060]; Department of the Army [W81XWH-04-2-0005]; US Army Medical Research Acquisition Activity FX This work was supported in part by the DAIDS Enterprise Information System (contract N01-AI-30060). Seema Shah was sponsored by the Department of the Army (cooperative agreement W81XWH-04-2-0005) through the US Army Medical Research Acquisition Activity. NR 15 TC 12 Z9 12 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2009 VL 99 IS 9 BP 1556 EP 1562 DI 10.2105/AJPH.2008.157982 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 488FL UT WOS:000269334500010 PM 19608940 ER PT J AU Hersh, CP Hansel, NN Barnes, KC Lomas, DA Pillai, SG Coxson, HO Mathias, RA Rafaels, NM Wise, RA Connett, JE Klanderman, BJ Jacobson, FL Gill, R Litonjua, AA Sparrow, D Reilly, JJ Silverman, EK AF Hersh, Craig P. Hansel, Nadia N. Barnes, Kathleen C. Lomas, David A. Pillai, Sreekumar G. Coxson, Harvey O. Mathias, Rasika A. Rafaels, Nicholas M. Wise, Robert A. Connett, John E. Klanderman, Barbara J. Jacobson, Francine L. Gill, Ritu Litonjua, Augusto A. Sparrow, David Reilly, John J. Silverman, Edwin K. CA ICGN Investigators TI Transforming Growth Factor-beta Receptor-3 Is Associated with Pulmonary Emphysema SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE betaglycan; chronic obstructive pulmonary disease; computed tomography; linkage; single nucleotide polymorphism ID GENOMEWIDE LINKAGE ANALYSIS; GLUTATHIONE-S-TRANSFERASE; VOLUME-REDUCTION SURGERY; AIR-FLOW OBSTRUCTION; CHRONIC-BRONCHITIS; EPOXIDE HYDROLASE; RANDOMIZED-TRIAL; SERPINE2 GENE; WIDE LINKAGE; DISEASE AB Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-beta receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV(1) (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3. C1 [Hersh, Craig P.; Klanderman, Barbara J.; Litonjua, Augusto A.; Silverman, Edwin K.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Hersh, Craig P.; Klanderman, Barbara J.; Litonjua, Augusto A.; Silverman, Edwin K.] Brigham & Womens Hosp, Ctr Genom Med, Boston, MA 02115 USA. [Jacobson, Francine L.; Gill, Ritu] Brigham & Womens Hosp, Div Thorac Radiol, Boston, MA 02115 USA. [Hersh, Craig P.; Klanderman, Barbara J.; Jacobson, Francine L.; Gill, Ritu; Litonjua, Augusto A.; Silverman, Edwin K.] Harvard Univ, Sch Med, Boston, MA USA. [Hansel, Nadia N.; Wise, Robert A.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Barnes, Kathleen C.; Rafaels, Nicholas M.] Johns Hopkins Univ, Div Clin Immunol & Allergy, Baltimore, MD USA. [Sparrow, David] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Sparrow, David] Boston Univ, Sch Med, Boston, MA 02118 USA. [Reilly, John J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Lomas, David A.] Univ Cambridge, Cambridge, England. [Pillai, Sreekumar G.] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. [Coxson, Harvey O.] Univ British Columbia, Dept Radiol, Vancouver, BC, Canada. [Mathias, Rasika A.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Connett, John E.] Univ Minnesota, Sch Publ Hlth, Div Biostat, St Paul, MN 55108 USA. RP Hersh, CP (reprint author), Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM craig.hersh@channing.harvard.edu RI Reilly, John/H-8755-2012; Coxson, Harvey/A-9861-2017; OI Coxson, Harvey/0000-0001-5750-9711; Vestbo, Jorgen/0000-0001-6355-6362; Wise, Robert/0000-0002-8353-2349; Litonjua, Augusto/0000-0003-0422-5875 FU National Institutes of Health [HL080242, HL71393, HL075478, U01 HL065899, P01 HL083069, HL076322, U01 HL 066583]; Alpha-1 Foundation; Flight Attendant Medical Research Institute; National Heart, Lung, and Blood Institute [N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119, N01HR46002, N01-HV-48195]; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; U.S. Department of Veterans Affairs; Mary Beryl Patch Turnbull Scholar Program; Johns Hopkins University under U.S. Federal Government; GlaxoSmithKline FX This work was supported by National Institutes of Health grants HL080242, HL71393, HL075478, U01 HL065899, P01 HL083069, HL076322, U01 HL 066583; the Alpha-1 Foundation; the Flight Attendant Medical Research Institute. The National Emphysema Treatment Trial was supported by the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119), Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston, MA. The Lung Health Study was supported by National Heart, Lung, and Blood Institute N01HR46002. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. Genotyping services on the Lung Health Study samples were provided by the Johns Hopkins University under U.S. Federal Government contract number N01-HV-48195 from the National Heart, Lung, and Blood Institute. The International COPD Genetics Network was supported by GlaxoSmithKline. NR 47 TC 21 Z9 21 U1 2 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD SEP PY 2009 VL 41 IS 3 BP 324 EP 331 DI 10.1165/rcmb.2008-0427OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 488JR UT WOS:000269346400009 PM 19131638 ER PT J AU Kurkjian, C Kummar, S AF Kurkjian, Carla Kummar, Shivaani TI Advances in the Treatment of Metastatic Colorectal Cancer SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Review DE colorectal; cancer; metastatic treatment ID GROWTH-FACTOR RECEPTOR; FLUOROURACIL PLUS LEUCOVORIN; III COLON-CANCER; MULTICENTER RANDOMIZED-TRIAL; HIGH-DOSE LEUCOVORIN; GENE COPY NUMBER; PHASE-III; CONTINUOUS-INFUSION; 1ST-LINE TREATMENT; ORAL CAPECITABINE AB The treatment of metastatic colorectal cancer has undergone major advances yielding significant improvements in survival over the past decade. These advances have evolved due to the benefits of combination chemotherapy and the incorporation of biologic therapy. However, as we struggle to provide optimum care while sparing patients ineffective therapy and undue cost, the importance of tailored therapy to maximize benefit will become increasingly important. This article reviews the major advances in the treatment of patients with metastatic colorectal cancer and the burgeoning developments in individualized therapy. C1 [Kummar, Shivaani] NCI, Med Oncol Branch, Clin Res Ctr, Bethesda, MD 20892 USA. [Kurkjian, Carla] Univ Oklahoma, Dept Hematol Oncol, Oklahoma City, OK USA. RP Kummar, S (reprint author), NCI, Med Oncol Branch, Clin Res Ctr, 10 Ctr Dr,10-12N226, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 69 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD SEP-OCT PY 2009 VL 16 IS 5 BP 412 EP 420 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 501KF UT WOS:000270379900008 PM 19955859 ER PT J AU Isogai, S Hitomi, J Yaniv, K Weinstein, BM AF Isogai, Sumio Hitomi, Jiro Yaniv, Karina Weinstein, Brant M. TI Zebrafish as a new animal model to study lymphangiogenesis SO ANATOMICAL SCIENCE INTERNATIONAL LA English DT Article; Proceedings Paper CT Satellite Symposium on Mechanisms Regulating Cardiovascular Development held at the 112th Japanese-Association-of-Anatomists Annual Meeting CY MAR 27-29, 2007 CL Osaka, JAPAN SP Japanese Assoc Anatomists DE Animal model; Lymphangiogenesis; Zebrafish ID VESSELS AB The lymphatic system is essential for fluid homeostasis, fat absorption and immune responses, and also plays key roles under pathological conditions, such as tumor metastasis, lymphoedema and inflammation. The main function of the lymphatic vascular system is to return excess interstitial fluid back to the blood vascular system. Lymph, including fluid, macromolecules, leukocytes and activated antigen-presenting cells, is transported from the blind-ended lymphatic capillaries toward the collecting lymphatic vessels; for there, it is returned to the blood circulation through lymphatico-venous junctions (Alitalo et al. in Nature 438:946-954, 2005). Despite its importance, lymphangiogenesis remains poorly understood. The lack of specific markers has complicated the identification of lymph vessels, and a small animal model that could be genetically manipulated to discover the function of novel lymphangiogenic candidates has only recently become available (Ny et al. in Nat Med 11(9):998-1004, 2005). Since 2004, we have worked to make the zebrafish a new genetic model for unraveling the function of candidate genes involved in lymphangiogenesis. We have demonstrated that zebrafish possess a lymphatic vascular system that shares the morphological, molecular and functional characteristics of the lymphatic vessels found in other vertebrates (Yaniv et al. in Nat Med 12(6):711-716, 2006). In this process, we realized that it was necessary to seek a common definition for the lymph system which would be applicable from fish to man. The aim of this article is to review classical, mainly morphological, studies in order to elucidate the nature of the lymphatic system. C1 [Isogai, Sumio; Hitomi, Jiro] Iwate Med Univ, Dept Anat, Sch Med, Morioka, Iwate 0208505, Japan. [Isogai, Sumio; Yaniv, Karina; Weinstein, Brant M.] NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Isogai, S (reprint author), Iwate Med Univ, Dept Anat, Sch Med, 19-1 Uchimaru, Morioka, Iwate 0208505, Japan. EM sisogai@iwate-med.ac.jp NR 13 TC 27 Z9 27 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1447-6959 J9 ANAT SCI INT JI Anat. Sci. Int. PD SEP PY 2009 VL 84 IS 3 BP 102 EP 111 DI 10.1007/s12565-009-0024-3 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 485EU UT WOS:000269104600006 PM 19288175 ER PT J AU Buvanendran, A Mitchell, K Kroin, JS Iadarola, MJ AF Buvanendran, Asokumar Mitchell, Kendall Kroin, Jeffrey S. Iadarola, Michael J. TI Cytokine Gene Expression After Total Hip Arthroplasty: Surgical Site versus Circulating Neutrophil Response SO ANESTHESIA AND ANALGESIA LA English DT Article ID MIGRATION INHIBITORY FACTOR; HUMAN INTERLEUKIN-8 RECEPTOR; RHEUMATOID-ARTHRITIS; PAIN; ANTAGONIST; TISSUE; ENDOMETRIOSIS; ANAKINRA; SURGERY; WOMEN AB BACKGROUND: After surgery, cytokines and chemokines are released at the surgical wound site, which can contribute to postoperative pain, local inflammation, and tissue repair. Multiple cell types are present that can release cytokines/chemokines at the wound site and, thus, the exact cellular source of these molecules is unclear. We sought to better understand the contribution of neutrophils to cytokine/chemokine gene expression at the surgical wound site during the initial postsurgery phase of total hip arthroplasty (THA). METHODS: Hip drain fluid was collected at 24 h postsurgery from six patients undergoing standardized THA. In addition, venous blood was collected presurgery and 24 h postsurgery. Neutrophils were isolated, total RNA extracted, and a biotinylated cRNA probe generated. The probes were hybridized with a cDNA microarray containing approximately 100 oligonucleotide sequences representing various human cytokines/chemokines or receptor genes. Changes in gene expression seen in the microarray were verified by reverse transcription polymerase chain reaction. RESULTS: In the microarray analysis of hip drain neutrophils, interleukin-1 receptor antagonist (IL1RN), interleukin-18 receptor 1 (IL18R1), macrophage migration inhibitory factor (MIF), and macrophage inflammatory protein 3 alpha (CCL20) were upregulated, whereas interleukin-8 receptor beta (IL8RB/CXCR2) was consistently downregulated, compared with presurgery blood neutrophils. All of these changes were confirmed by reverse transcription polymerase chain reaction. CONCLUSION: There is a distinct cytokine gene expression profile in neutrophils at the THA surgical wound site at 24 h postsurgery when compared with that found in presurgery circulating neutrophils. Understanding these changes may allow Lis to knowledgeably manipulate neutrophil activity to reduce postoperative pain and inflammation without impairing wound healing. (Anesth Analg 2009:109:959-64) C1 [Buvanendran, Asokumar; Kroin, Jeffrey S.] Rush Univ, Med Ctr, Dept Anesthesiol, Chicago, IL 60612 USA. [Mitchell, Kendall; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Bethesda, MD USA. RP Buvanendran, A (reprint author), Rush Univ, Med Ctr, Dept Anesthesiol, 1653 W Congress Pkwy, Chicago, IL 60612 USA. EM asokumar@aol.com FU Intramural Research Program; NIDCR; NIH; DHHS; University Anesthesiologists S.C., Chicago, IL FX Supported by the Intramural Research Program, NIDCR, NIH, DHHS, and University Anesthesiologists S.C., Chicago, IL. NR 31 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2009 VL 109 IS 3 BP 959 EP 964 DI 10.1213/ane.0b013e3181ac1746 PG 6 WC Anesthesiology SC Anesthesiology GA 488EB UT WOS:000269330800042 PM 19690273 ER PT J AU Arnaoutova, I George, J Kleinman, HK Benton, G AF Arnaoutova, Irina George, Jay Kleinman, Hynda K. Benton, Gabriel TI The endothelial cell tube formation assay on basement membrane turns 20: state of the science and the art SO ANGIOGENESIS LA English DT Review DE Angiogenesis; Basement membrane; Endothelial cell tubes; Morphological differentiation; Quantitative assay; High throughput screen ID CAPILLARY-LIKE STRUCTURES; IN-VITRO; EXTRACELLULAR-MATRIX; BIOLOGICAL-ACTIVITY; GENE-EXPRESSION; GROWTH-FACTORS; ANGIOGENESIS; LAMININ; TUMOR; DIFFERENTIATION AB It has been more than 20 years since it was first demonstrated that endothelial cells will rapidly form capillary-like structures in vitro when plated on top of a reconstituted basement membrane extracellular matrix (BME, Matrigel, EHS matrix, etc.). Subsequently, this morphological differentiation has been demonstrated with a variety of endothelial cells; with endothelial progenitor cells; and with transformed/immortalized endothelial cells. The differentiation process involves several steps in blood vessel formation, including cell adhesion, migration, alignment, protease secretion, and tubule formation. Because the formation of vessel structures is rapid and quantifiable, endothelial cell differentiation on basement membrane has found numerous applications in assays. Such differentiation has been used (1) to study angiogenic and antiangiogenic factors, (2) to define mechanisms and pathways involved in angiogenesis, and (3) to define endothelial cell populations. Further, the endothelial cell differentiation assay has been successfully used to study processes ranging from wound repair and reproduction to development and tumor growth. The assay is easy to perform and is the most widely used in vitro angiogenesis assay. C1 [Kleinman, Hynda K.] NIDCR, NIH, Bethesda, MD 20892 USA. [Arnaoutova, Irina; George, Jay; Kleinman, Hynda K.; Benton, Gabriel] Trevigen Inc, Gaithersburg, MD USA. RP Kleinman, HK (reprint author), NIDCR, NIH, 30 Convent Dr MSC 4370,Bldg 30,Room 400, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov OI Benton, Gabriel/0000-0003-4244-5764 NR 38 TC 180 Z9 181 U1 6 U2 46 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 J9 ANGIOGENESIS JI Angiogenesis PD SEP PY 2009 VL 12 IS 3 BP 267 EP 274 DI 10.1007/s10456-009-9146-4 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 500RT UT WOS:000270322900006 PM 19399631 ER PT J AU Kim, S Xi, YM Chen, MH AF Kim, Sungduk Xi, Yingmei Chen, Ming-Hui TI A NEW LATENT CURE RATE MARKER MODEL FOR SURVIVAL DATA SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Deviance Information Criterion (DIC); Markov chain Monte Carlo; logarithm of pseudomarginal likelihood (LPML); PSA recurrence ID BEAM RADIATION-THERAPY; TIME-TO-EVENT; BAYESIAN MODEL; PROSTATE-CANCER; RADICAL PROSTATECTOMY; JOINT ANALYSIS; LONG-TERM AB To address an important risk classification issue that arises in clinical practice, we propose a new mixture model via latent cure rate markers for survival data with a cure fraction. In the proposed model, the latent cure rate markers are modeled via a multinomial logistic regression and patients who share the same cure rate are classified into the same risk group. Compared to available cure rate models, the proposed model fits better to data from a prostate cancer clinical trial. In addition, the proposed model can be used to determine the number of risk groups and to develop a predictive classification algorithm. C1 [Kim, Sungduk] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Xi, Yingmei] Biogen Idec Inc, Cambridge, MA 02142 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. RP Kim, S (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. EM kims2@mail.nih.gov; yingmei.xi@biogenidec.com; mhchen@stat.uconn.edu FU NIH [CA 074015, GM 70335] FX Dr. Chen's research was supported in part by NIH Grants #CA 074015 and #GM 70335. NR 31 TC 6 Z9 6 U1 1 U2 1 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD SEP PY 2009 VL 3 IS 3 BP 1124 EP 1146 DI 10.1214/09-AOAS238 PG 23 WC Statistics & Probability SC Mathematics GA 522EF UT WOS:000271979900012 ER PT J AU Dart, RC Borron, SW Caravati, EM Cobaugh, DJ Curry, SC Falk, JL Goldfrank, L Gorman, SE Groft, S Heard, K Miller, K Olson, KR O'Malley, G Seger, D Seifert, SA Sivilotti, MLA Schaeffer, T Tomassoni, AJ Wise, R Bogdan, GM Alhelail, M Buchanan, J Hoppe, J Lavonas, E Mlynarchek, S Phua, DH Rhyee, S Varney, S Zosel, A AF Dart, Richard C. Borron, Stephen W. Caravati, E. Martin Cobaugh, Daniel J. Curry, Steven C. Falk, Jay L. Goldfrank, Lewis Gorman, Susan E. Groft, Stephen Heard, Kennon Miller, Ken Olson, Kent R. O'Malley, Gerald Seger, Donna Seifert, Steven A. Sivilotti, Marco L. A. Schaeffer, Tammi Tomassoni, Anthony J. Wise, Robert Bogdan, Gregory M. Alhelail, Mohammed Buchanan, Jennie Hoppe, Jason Lavonas, Eric Mlynarchek, Sara Phua, Dong-Haur Rhyee, Sean Varney, Shawn Zosel, Amy CA Antidote Summit Authorship Grp TI Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID POISONING ANTIDOTES; AVAILABILITY AB Study objective: We developed recommendations for antidote stocking at hospitals that provide emergency care. Methods: An expert panel representing diverse perspectives (clinical pharmacology, clinical toxicology, critical care medicine, clinical pharmacy, emergency medicine, internal medicine, pediatrics, poison centers, pulmonary medicine, and hospital accreditation) was formed to create recommendations for antidote stocking. Using a standardized summary of the medical literature, the primary reviewer for each antidote proposed guidelines for antidote stocking to the full panel. The panel used a formal iterative process to reach their recommendation for the quantity of an antidote that should be stocked and the acceptable period for delivery of each antidote. Results: The panel recommended consideration of 24 antidotes for stocking. The panel recommended that 12 of the antidotes be available for immediate administration on patient arrival. In most hospitals, this period requires that the antidote be stocked in the emergency department. Another 9 antidotes were recommended for availability within 1 hour of the decision to administer, allowing the antidote to be stocked in the hospital pharmacy if the hospital has a mechanism for prompt delivery of antidotes. The panel identified additional antidotes that should be stocked by the hospital but are not usually needed within the first hour of treatment. The panel recommended that each hospital perform a formal antidote hazard vulnerability assessment to determine the need for antidote stocking in that hospital. Conclusion: The antidote expert recommendations provide a tool to be used in creating practices for appropriate and adequate antidote stocking in hospitals that provide emergency care. [Ann Emerg Med. 2009;54:386-394.] C1 [Dart, Richard C.; Heard, Kennon; Schaeffer, Tammi; Bogdan, Gregory M.; Alhelail, Mohammed; Buchanan, Jennie; Hoppe, Jason; Lavonas, Eric; Mlynarchek, Sara; Phua, Dong-Haur; Rhyee, Sean; Varney, Shawn; Zosel, Amy] Rocky Mt Poison & Drug Ctr Denver Hlth, Denver, CO USA. [Borron, Stephen W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX 78229 USA. [Caravati, E. Martin] Univ Utah, Hlth Sci Ctr, Utah Poison Control Ctr, Div Emergency Med, Salt Lake City, UT USA. [Cobaugh, Daniel J.] ASHP Res & Educ Fdn, Bethesda, MD USA. [Curry, Steven C.] Banner Good Samaritan Med Ctr, Dept Med Toxicol, Phoenix, AZ USA. [Curry, Steven C.] Banner Good Samaritan Med Ctr, Banner Poison Control Ctr, Phoenix, AZ USA. [Falk, Jay L.] Univ Florida, Dept Emergency Med, Orlando Reg Med Ctr, Orlando, FL USA. [Goldfrank, Lewis] NYU, Sch Med, New York City Poison Ctr, New York, NY USA. [Gorman, Susan E.] Ctr Dis Control & Prevent, Div Strateg Natl Stockpile, Atlanta, GA USA. [Groft, Stephen] Off Rare Dis Res, Bethesda, MD USA. [Dart, Richard C.; Heard, Kennon; Schaeffer, Tammi; Lavonas, Eric] Univ Colorado Denver, Sch Med, Div Emergency Med, Aurora, CO USA. [Bogdan, Gregory M.] Univ Colorado Denver, Sch Pharm, Dept Pharmaceut Sci, Aurora, CO USA. [Miller, Ken] Orange Cty Fire Author & Orange Cty Hlth Care Agc, Emergency Med Serv, Irvine, CA USA. [Miller, Ken] Natl Assoc EMS Phys, Lenexa, KS USA. [Olson, Kent R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Olson, Kent R.] Calif Poison Control Syst, San Francisco Div, San Francisco, CA 94143 USA. [O'Malley, Gerald] Albert Einstein Med Ctr, Dept Emergency Med, Div Res, Philadelphia, PA 19141 USA. [Seger, Donna] Vanderbilt Univ, Div Clin Pharmacol, Dept Med, Tennessee Poison Ctr,Med Ctr, Nashville, TN USA. [Seifert, Steven A.] Univ New Mexico, Sch Med & Med Director, New Mexico Poison & Drug Informat Ctr, Albuquerque, NM 87131 USA. [Sivilotti, Marco L. A.] Queens Univ, Dept Emergency Med, Kingston, ON K7L 3N6, Canada. [Sivilotti, Marco L. A.] Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. [Tomassoni, Anthony J.] Yale Univ, Sch Med, Dept Surg, Sect Emergency Med, New Haven, CT 06510 USA. [Tomassoni, Anthony J.] Yale New Haven Ctr Emergency Preparedness & Disas, New Haven, CT USA. [Wise, Robert] Int Joint Commiss, Div Stand & Survey Methods, Oak Brook Terrace, IL USA. RP Dart, RC (reprint author), 777 Bannock St,Mailcode 0180, Denver, CO 80204 USA. EM rdart@rmpdc.org RI Siry, Bonnie/D-7189-2017 FU NIDA NIH HHS [K08 DA020573, K08 DA020573-03] NR 23 TC 39 Z9 44 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 BP 386 EP 394 DI 10.1016/j.annemergmed.2009.01.023 PG 9 WC Emergency Medicine SC Emergency Medicine GA 488JM UT WOS:000269345900016 PM 19406507 ER PT J AU Cohen, JI Kimura, H Nakamura, S Ko, YH Jaffe, ES AF Cohen, J. I. Kimura, H. Nakamura, S. Ko, Y. -H. Jaffe, E. S. TI Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008 SO ANNALS OF ONCOLOGY LA English DT Review DE chronic active EBV infection; diffuse large B-cell lymphoma; hemophagocytic syndrome; hydroa vacciniforme; immune senescence; senile EBV-positive lymphoproliferative disease; systemic EBV-positive lymphoproliferative disease ID STEM-CELL TRANSPLANTATION; ACTIVE EBV INFECTION; VACCINIFORME-LIKE ERUPTIONS; NATURAL-KILLER-CELLS; LYMPHOMATOID GRANULOMATOSIS; HEMOPHAGOCYTIC-SYNDROME; HYDROA VACCINIFORME; ELDERLY-PATIENTS; B-LYMPHOCYTES; T-CELLS AB Design: To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting. Results: The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas. Conclusion: The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs. C1 [Cohen, J. I.] NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Kimura, H.] Nagoya Univ, Dept Virol, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Nakamura, S.] Nagoya Univ Hosp, Dept Pathol, Showa Ku, Nagoya, Aichi, Japan. [Nakamura, S.] Nagoya Univ Hosp, Clin Labs, Showa Ku, Nagoya, Aichi, Japan. [Ko, Y. -H.] Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Jaffe, E. S.] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10 Room 2B 42,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov RI Ko, Young Hyeh/C-9651-2011; Nakamura, Shigeo/I-1571-2012; Kimura, Hiroshi/I-2246-2012 FU Center for Cancer Research: National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX Intramural Research Programs of the Center for Cancer Research: National Cancer Institute; National Institute of Allergy and Infectious Diseases; Office of Rare Diseases at the National Institutes of Health. NR 68 TC 119 Z9 144 U1 2 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2009 VL 20 IS 9 BP 1472 EP 1482 DI 10.1093/annonc/mdp064 PG 11 WC Oncology SC Oncology GA 496FS UT WOS:000269955700003 PM 19515747 ER PT J AU Hanauske, AR Lahn, M Musib, LC Weigang-Kohler, K Yilmaz, E Graefe, T Kuenen, B Thornton, D McNealy, P Giaccone, G AF Hanauske, A. -R. Lahn, M. Musib, L. C. Weigang-Koehler, K. Yilmaz, E. Graefe, T. Kuenen, B. Thornton, D. McNealy, P. Giaccone, G. TI Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-05, 2007 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) DE enzastaurin; pemetrexed; pharmacokinetics; phase I; safety ID KINASE-C-BETA; CELL LUNG-CANCER; INHIBITOR ENZASTAURIN; IN-VITRO; MULTITARGETED ANTIFOLATE; SELECTIVE INHIBITOR; DOSE-ESCALATION; ONCOLOGY TRIALS; THYROID-CANCER; SOLID TUMORS AB Patients and methods: Pemetrexed 500 mg/m(2) with folic acid and vitamin B-12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1-15 without initial loading dose and 250 mg b.i.d. on days 16-30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d. Results: Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (C-av,C-ss) decreased by similar to 25% in the presence of pemetrexed. Enzastaurin C-av,C-ss were similar to 40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST. Conclusions: Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer. C1 [Hanauske, A. -R.; Graefe, T.] Gen Hosp, Dept Med 1, Hamburg, Germany. [Lahn, M.; Musib, L. C.; Thornton, D.; McNealy, P.] Eli Lilly & Co, Early Phase Clin Oncol Dev, Indianapolis, IN 46285 USA. [Weigang-Koehler, K.] Clin Nurnberg Nord, Med Clin 5, Nurnberg, Germany. [Kuenen, B.; Giaccone, G.] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. RP Giaccone, G (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 43 TC 18 Z9 18 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2009 VL 20 IS 9 BP 1565 EP 1575 DI 10.1093/annonc/mdp049 PG 11 WC Oncology SC Oncology GA 496FS UT WOS:000269955700017 PM 19487488 ER PT J AU Song, HK Bavaria, JE Kindem, MW Holmes, KW Milewicz, DM Maslen, CL Pyeritz, RE Basson, CT Eagle, K Tolunay, HE Kroner, BL Dietz, H Menashe, V Devereux, RB Desvigne-Nickens, P Ravekes, W Weinsaft, JW Brambilla, D Stylianou, MP Hendershot, T Mitchell, MS LeMaire, SA AF Song, Howard K. Bavaria, Joseph E. Kindem, Mark W. Holmes, Kathryn W. Milewicz, Dianna M. Maslen, Cheryl L. Pyeritz, Reed E. Basson, Craig T. Eagle, Kim Tolunay, H. Eser Kroner, Barbara L. Dietz, Hal Menashe, Victor Devereux, Richard B. Desvigne-Nickens, Patrice Ravekes, William Weinsaft, Jonathan W. Brambilla, Donald Stylianou, Mario P. Hendershot, Tabitha Mitchell, Megan S. LeMaire, Scott A. CA Natl Registry Genetically Triggere TI Surgical Treatment of Patients Enrolled in the National Registry of Genetically Triggered Thoracic Aortic Conditions SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 26-28, 2009 CL San Francisco, CA SP Soc Thorac Surg ID MARFAN-SYNDROME; TURNER-SYNDROME; ANEURYSMS; DISSECTION; MUTATIONS; PATTERNS; CHILDREN; HETEROGENEITY; DILATATION; DILATION AB Background. Genetic disorders are an important cause of thoracic aortic aneurysms (TAAs) in young patients. Despite advances in the treatment of genetically triggered TAAs, the optimal syndrome-specific treatment approach remains undefined. We used data from the National Institutes of Health-funded, multicenter National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) to characterize the contemporary surgical treatment of patients with genetically triggered TAAs. Methods. GenTAC's aim is to collect longitudinal clinical data and banked biospecimens from 2800 patients with genetically triggered TAAs. We analyzed data from the 606 patients (mean age, 37.5 years) enrolled in GenTAC to date whose clinical data were available. Results. The patients' primary diagnoses included Marfan syndrome (35.8%), bicuspid aortic valve with aneurysm (29.2%), and familial TAAs and dissections (10.7%). Of these, 56.4% had undergone at least one operation; the most common indications were aneurysm (85.7%), valve dysfunction (65.8%), and dissection (25.4%). Surgical procedures included replacement of the aortic root (50.6%), ascending aorta (64.8%), aortic arch (27.9%), and descending or thoracoabdominal aorta (12.4%). Syndrome-specific differences in age, indications for operation, and procedure type were identified. Conclusions. Patients with genetically transmitted TAAs evaluated in tertiary care centers frequently undergo surgical repair. Aneurysm repairs most commonly involve the aortic root and ascending aorta; distal repairs are less common. Like TAAs themselves, complications of TAAs, including dissection and aortic valve dysfunction, are important indications for intervention. Future studies will focus on syndrome- and gene-specific phenotypes, biomarkers, treatments, and outcomes to improve the treatment of patients with TAAs. (Ann Thorac Surg 2009; 88: 781-8) (C) 2009 by The Society of Thoracic Surgeons C1 [Song, Howard K.] Oregon Hlth & Sci Univ, Div Cardiothorac Surg, Portland, OR 97239 USA. Univ Penn, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Baltimore, MD USA. RTI Int, Rockville, MD USA. NHLBI, Bethesda, MD 20892 USA. Univ Texas Houston, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. Weill Cornell Med Coll, New York, NY USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Song, HK (reprint author), Oregon Hlth & Sci Univ, Div Cardiothorac Surg, Mail Code L353,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM songh@ohsu.edu FU NCRR NIH HHS [UL1 RR024140, UL1 RR024996, UL1RR024996]; NHLBI NIH HHS [N01 HV068199, N01-HV-68199, N01HV68199] NR 27 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD SEP PY 2009 VL 88 IS 3 BP 781 EP 788 DI 10.1016/j.athoracsur.2009.04.034 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 485UO UT WOS:000269150500011 PM 19699898 ER PT J AU Maciag, AE Saavedra, JE Chakrapani, H AF Maciag, Anna E. Saavedra, Joseph E. Chakrapani, Harinath TI The Nitric Oxide Prodrug JS-K and Its Structural Analogues as Cancer Therapeutic Agents SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article ID GLUTATHIONE S-TRANSFERASES; IN-VITRO; ANTICANCER LEAD; ANTILEUKEMIC ACTIVITY; NITROGEN(II) OXIDE; KINASE PATHWAYS; CELLS; CHEMISTRY; DERIVATIVES; ACTIVATION AB Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O(2)-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O(2)-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K. C1 [Maciag, Anna E.; Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Chakrapani, Harinath] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Maciag, AE (reprint author), NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. EM amaciag@ncifcrf.gov; chakrah@ncifcrf.gov NR 35 TC 14 Z9 14 U1 0 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD SEP PY 2009 VL 9 IS 7 BP 798 EP 803 PG 6 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 513RG UT WOS:000271340300007 PM 19538173 ER PT J AU Monks, A Hose, CD Pezzoli, P Kondapaka, S Vansant, G Petersen, KD Sehested, M Monforte, J Shoemaker, RH AF Monks, Anne Hose, Curtis D. Pezzoli, Patrick Kondapaka, Sudhir Vansant, Gordon Petersen, Kamille Dumong Sehested, Maxwell Monforte, Joseph Shoemaker, Robert H. TI Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts SO ANTI-CANCER DRUGS LA English DT Article DE belinostat; gene signature; histone deacetylase inhibitor ID GROWTH IN-VITRO; SOLID TUMORS; CANCER; PXD101; ACETYLATION; TRANSCRIPTION; IDENTIFICATION; CYTOTOXICITY; THERAPY; VIVO AB Belinostat is a hydroxamate-type histone deactylase inhibitor (HDACi), which has recently entered phase I and 11 clinical trials. Microarray-based analysis of belinostat-treated cell lines showed an impact on genes associated with the G(2)/M phase of the cell cycle and downregulation of the aurora kinase pathway. Expression of 25 dysregulated genes was measured in eight differentially sensitive cell lines using a novel high-throughput assay that combines multiplex reverse transcriptase-PCR and fluorescence capillary electrophoresis. Sensitivity to belinostat and the magnitude of changes in overall gene modulation were significantly correlated. A belinostat-gene profile was specific for HDACi in three cell lines when compared with equipotent concentrations of four mechanistically different chemotherapeutic agents: 5-fluorouracil, cisplatin, paclitaxel, and thiotepa. Belinostat- and trichostatin A (HDACi)-induced gene responses were highly correlated with each other, but not with the limited changes in response to the other non-HDACi agents. Moreover, belinostat treatment of mice bearing human xenografts showed that the preponderance of selected genes were also modulated in vivo, more extensively in a drug-sensitive tumor than a more resistant model. We have demonstrated a gene signature that is selectively regulated by HDACi when compared with other clinical agents allowing us to distinguish HDACi responses from those related to other mechanisms. Anti-Cancer Drugs 20:682-692 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Pezzoli, Patrick; Vansant, Gordon; Monforte, Joseph] Althea Technol Inc, Express Pathway & Biomarker Grp, San Diego, CA USA. [Petersen, Kamille Dumong; Sehested, Maxwell] TopoTarget AS, Copenhagen, Denmark. [Petersen, Kamille Dumong; Sehested, Maxwell] Rigshosp, DK-2100 Copenhagen, Denmark. [Monks, Anne] NCI Frederick, SAIC Frederick Inc, STB Lab Funct Genom, Frederick, MD 21702 USA. [Kondapaka, Sudhir; Shoemaker, Robert H.] NCI Frederick, Screening Technol Branch, DTP, Frederick, MD 21702 USA. RP Monks, A (reprint author), NCI Frederick, SAIC Frederick Inc, STB Lab Funct Genom, POB B,1032 Boyles St, Frederick, MD 21702 USA. EM monksa@mail.nih.gov FU National Cancer Institute; National Institutes of Health [N01-CO-12400] 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 N01-CO-12400. 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 research was supported by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 38 TC 14 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD SEP PY 2009 VL 20 IS 8 BP 682 EP 692 DI 10.1097/CAD.0b013e32832e14e1 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 480KA UT WOS:000268732100006 PM 19606018 ER PT J AU Hattori, S Ide, K Nakata, H Harada, H Suzu, S Ashida, N Kohgo, S Hayakawa, H Mitsuya, H Okada, S AF Hattori, Shinichiro Ide, Kazuhiko Nakata, Hirotomo Harada, Hideki Suzu, Shinya Ashida, Noriyuki Kohgo, Satoru Hayakawa, Hiroyuki Mitsuya, Hiroaki Okada, Seiji TI Potent Activity of a Nucleoside Reverse Transcriptase Inhibitor, 4 '-Ethynyl-2-Fluoro-2 '-Deoxyadenosine, against Human Immunodeficiency Virus Type 1 Infection in a Model Using Human Peripheral Blood Mononuclear Cell-Transplanted NOD/SCID Janus Kinase 3 Knockout Mice SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PBL-SCID MICE; CENTRAL-NERVOUS-SYSTEM; ANTIRETROVIRAL THERAPY; MITOCHONDRIAL-DNA; IMMUNE-SYSTEMS; HIGHLY POTENT; CD34(+) CELLS; HIV-1; MOUSE; 2'-DEOXY-4'-C-ETHYNYL-2-FLUOROADENOSINE AB 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a recently discovered nucleoside reverse transcriptase inhibitor, exhibits activity against a wide spectrum of wild-type and multidrug-resistant clinical human immunodeficiency virus type 1 (HIV-1) isolates (50% effective concentration, 0.0001 to 0.001 mu M). In the present study, we used human peripheral blood mononuclear cell-transplanted, HIV-1-infected NOD/SCID/Janus kinase 3 knockout mice for in vivo evaluation of the anti-HIV activity of EFdA. Administration of EFdA decreased the replication and cytopathic effects of HIV-1 without identifiable adverse effects. In phosphate-buffered saline (PBS)-treated mice, the CD4(+)/CD8(+) cell ratio in the spleen was low (median, 0.04; range, 0.02 to 0.49), while that in mice receiving EFdA was increased (median, 0.65; range, 0.57 to 1.43). EFdA treatment significantly suppressed the amount of HIV-1 RNA (median of 9.0 x 10(2) copies/ml [range, 8.1 x 10(2) to 1.1 x 10(3) copies/ml] versus median of 9.9 x 10(4) copies/ml [range, 8.1 x 10(2) to 1.1 x 10(3) copies/ml]; P < 0.001), the p24 level in plasma (2.5 x 10(3) pg/ml [range, 8.2 x 10(2) to 5.6 x 10(3) pg/ml] versus 2.8 x 10(2) pg/ml [ range, 8.2 x 10(1) to 6.3 x 10(2) pg/ml]; P < 0.001), and the percentage of p24-expressing cells in the spleen (median of 1.90% [ range, 0.33% to 3.68%] versus median of 0.11% [range, 0.00% to 1.00%]; P = 0.003) in comparison with PBS-treated mice. These data suggest that EFdA is a promising candidate for a new age of HIV-1 chemotherapy and should be developed further as a potential therapy for individuals with multidrug-resistant HIV-1 variants. C1 [Hattori, Shinichiro; Harada, Hideki; Suzu, Shinya; Okada, Seiji] Kumamoto Univ, Ctr AIDS Res, Div Hematopoiesis, Grad Sch Med & Pharmaceut Sci, Kumamoto 8600811, Japan. [Ide, Kazuhiko; Mitsuya, Hiroaki] Kumamoto Univ, Dept Infect Dis, Grad Sch Med & Pharmaceut Sci, Kumamoto 8600811, Japan. [Ide, Kazuhiko; Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol, Grad Sch Med & Pharmaceut Sci, Kumamoto 8600811, Japan. [Ashida, Noriyuki; Kohgo, Satoru; Hayakawa, Hiroyuki] Yamasa Corp, Div Biochem, Chiba, Japan. [Nakata, Hirotomo; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Okada, S (reprint author), Kumamoto Univ, Ctr AIDS Res, Div Hematopoiesis, Grad Sch Med & Pharmaceut Sci, 2-2-1 Honjo, Kumamoto 8600811, Japan. EM okadas@kumamoto-u.ac.jp RI Suzu, Shinya/F-5786-2013; Okada, Seiji/F-5785-2013; Kumamoto University, CAIDS/G-8446-2013 FU Center for Cancer Research, National Cancer Institute; National Institutes of Health; Ministry of Health, Labor and Welfare of Japan; Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases; Global COE program; Ministry of Education, Culture, Sports, Science, and Technology of Japan FX This work was supported in part by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, by science research grants from the Ministry of Health, Labor and Welfare of Japan, by a grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases ( Renkei Jigyo, no. 78; Kumamoto University), and by grants from the Global COE program ( Education Unit and Global Education and Research Center Aiming at the Control of AIDS) of the Ministry of Education, Culture, Sports, Science, and Technology of Japan. NR 32 TC 25 Z9 25 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2009 VL 53 IS 9 BP 3887 EP 3893 DI 10.1128/AAC.00270-09 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 496XR UT WOS:000270014200036 PM 19546363 ER PT J AU Lindblad, AS Lloyd, PC Clemons, TE Gensler, GR Ferris, FL Klein, ML Armstrong, JR AF Lindblad, Anne S. Lloyd, Patricia C. Clemons, Traci E. Gensler, Gary R. Ferris, Frederick L., III Klein, Michael L. Armstrong, Jane R. CA AREDS Res Grp TI Change in Area of Geographic Atrophy in the Age-Related Eye Disease Study AREDS Report Number 26 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; FUNDUS AUTOFLUORESCENCE; NATURAL-HISTORY; CLINICAL-TRIALS; VISUAL-ACUITY; VISION LOSS; PROGRESSION; ENLARGEMENT; PERIMETRY AB Objective: To characterize progression of geographic atrophy (GA) associated with age-related macular degeneration in AREDS as measured by digitized fundus photographs. Methods: Fundus photographs from 181 of 4757 AREDS participants with a GA area of at least 0.5 disc areas at baseline or from participants who developed bilateral GA during follow-up were scanned, digitized, and evaluated longitudinally. Geographic atrophy area was determined using planimetry. Rates of progression from noncentral to central GA and of vision loss following development of central GA included the entire AREDS cohort. Results: Median initial lesion size was 4.3 mm(2). Average change in digital area of GA from baseline was 2.03 mm(2) standard error of the mean, 0.24 mm(2)) at 1 year, 3.78 mm(2) (0.24 mm(2)) at 2 years, 5.93 mm(2) (0.34 mm(2)) at 3 years, and 1.78 mm(2) (0.086 mm(2)) per year overall. Median time to developing central GA after any GA diagnosis was 2.5 years (95% confidence interval, 2.0-3.0). Average visual acuity decreased by 3.7 letters at first documentation of central GA, and by 22 letters at year 5. Conclusions: Growth of GA area can be reliably measured using standard fundus photographs that are digitized and subsequently graded at a reading center. Development of GA is associated with subsequent further growth of GA, development of central GA, and loss in central vision. C1 [Lindblad, Anne S.] EMMES Corp, AREDS Coordinating Ctr, Rockville, MD 20850 USA. [Ferris, Frederick L., III] NEI, Bethesda, MD 20892 USA. [Klein, Michael L.] Casey Eye Inst, Portland, OR USA. [Armstrong, Jane R.] Fundus Photograph Reading Ctr, Madison, WI USA. RP Lindblad, AS (reprint author), EMMES Corp, AREDS Coordinating Ctr, 401 N Washington St,Ste 700, Rockville, MD 20850 USA. EM aredspub@emmes.com FU National Eye Institute; National Institutes of Health; Department of Health and Human Services, Bethesda, Maryland FX This report was supported by contracts from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. NR 23 TC 76 Z9 76 U1 3 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2009 VL 127 IS 9 BP 1168 EP 1174 PG 7 WC Ophthalmology SC Ophthalmology GA 493VD UT WOS:000269765500008 PM 19752426 ER PT J AU Washington, MK Jessup, JM Compton, CC AF Washington, Mary Kay Jessup, J. Milburn Compton, Carolyn C. TI Protocol for the Examination of Specimens From Patients With Primary Carcinomas of the Colon and Rectum Reply SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Letter ID CANCER; INVOLVEMENT C1 [Washington, Mary Kay] Vanderbilt Univ, Dept Pathol, Ctr Med, Nashville, TN 37232 USA. [Jessup, J. Milburn] Natl Canc Inst, Diagnost Evaluat Branch, Canc Diag Program, Rockville, MD 20852 USA. [Compton, Carolyn C.] Natl Canc Inst, Off Biorepositories & Biospecimen Res, Bethesda, MD 20892 USA. RP Washington, MK (reprint author), Vanderbilt Univ, Dept Pathol, Ctr Med, Nashville, TN 37232 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD SEP PY 2009 VL 133 IS 9 BP 1360 EP 1361 PG 2 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 490GC UT WOS:000269486600002 ER PT J AU Freedman, DS Wang, J Thornton, JC Mei, ZG Sopher, AB Pierson, RN Dietz, WH Horlick, M AF Freedman, David S. Wang, Jack Thornton, John C. Mei, Zuguo Sopher, Aviva B. Pierson, Richard N., Jr. Dietz, William H. Horlick, Mary TI Classification of Body Fatness by Body Mass Index-for-Age Categories Among Children SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID X-RAY ABSORPTIOMETRY; CARDIOVASCULAR RISK-FACTORS; WHITE-CHILDREN; ADOLESCENT OVERWEIGHT; EXPERT COMMITTEE; AFRICAN-AMERICAN; BLOOD-PRESSURE; FOLLOW-UP; OBESITY; FAT AB Objective: To examine the ability of various body mass index (BMI)-for-age categories, including the Centers for Disease Control and Prevention's 85th to 94th percentiles, to correctly classify the body fatness of children and adolescents. Design: Cross-sectional. Setting: The New York Obesity Research Center at St Luke's-Roosevelt Hospital from 1995 to 2000. Participants: Healthy 5- to 18-year-old children and adolescents (N = 1196) were recruited in the New York City area through newspaper notices, announcements at schools and activity centers, and word of mouth. Main Outcome Measures: Percent body fat as determined by dual-energy x-ray absorptiometry. Body fatness cutoffs were chosen so that the number of children in each category (normal, moderate, and elevated fatness) would equal the number of children in the corresponding BMI-for-age category (<85th percentile, 85th-94th percentile, and >= 95th percentile, respectively). Results: About 77% of the children who had a BMI for age at or above the 95th percentile had an elevated body fatness, but levels of body fatness among children who had a BMI for age between the 85th and 94th percentiles (n = 200) were more variable; about one-half of these children had a moderate level of body fatness, but 30% had a normal body fatness and 20% had an elevated body fatness. The prevalence of normal levels of body fatness among these 200 children was highest among black children (50%) and among those within the 85th to 89th percentiles of BMI for age (40%). Conclusion: Body mass index is an appropriate screening test to identify children who should have further evaluation and follow-up, but it is not diagnostic of level of adiposity. C1 [Freedman, David S.; Mei, Zuguo; Dietz, William H.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Atlanta, GA 30341 USA. [Wang, Jack; Thornton, John C.; Sopher, Aviva B.; Pierson, Richard N., Jr.] Columbia Univ, St Lukes Roosevelt Hosp, Body Composit Unit, Dept Med,New York Obes Res Ctr,Med Ctr, New York, NY USA. [Sopher, Aviva B.] Columbia Univ, Dept Pediat, Morgan Stanley Childrens Hosp New York, Med Ctr, New York, NY 10027 USA. [Horlick, Mary] NIDDK, Bethesda, MD USA. RP Freedman, DS (reprint author), Ctr Dis Control & Prevent, Div Nutr & Phys Act, CDC Mailstop K-26,4770 Buford Hwy, Atlanta, GA 30341 USA. EM dfreedman@cdc.gov FU National Institutes of Health [DK37352] FX This study was supported by grant DK37352 from the National Institutes of Health. NR 41 TC 48 Z9 53 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD SEP PY 2009 VL 163 IS 9 BP 805 EP 811 PG 7 WC Pediatrics SC Pediatrics GA 491PC UT WOS:000269590300005 PM 19736333 ER PT J AU Lopez, MF Compton, WM Volkow, ND AF Lopez, Marsha F. Compton, Wilson M. Volkow, Nora D. TI Changes in Cigarette and Illicit Drug Use Among US Teenagers SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Editorial Material C1 [Lopez, Marsha F.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Lopez, MF (reprint author), Natl Inst Drug Abuse, NIH, 6001 Execut Blvd,Ste 5185, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 DA999999] NR 4 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD SEP PY 2009 VL 163 IS 9 BP 869 EP 870 PG 2 WC Pediatrics SC Pediatrics GA 491PC UT WOS:000269590300018 PM 19736345 ER PT J AU Delay, ML Turner, MJ Klenk, EI Smith, JA Sowders, DP Colbert, RA AF Delay, Monica L. Turner, Matthew J. Klenk, Erin I. Smith, Judith A. Sowders, Dawn P. Colbert, Robert A. TI HLA-B27 Misfolding and the Unfolded Protein Response Augment Interleukin-23 Production and Are Associated With Th17 Activation in Transgenic Rats SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; T-CELLS; ANKYLOSING-SPONDYLITIS; HLA-B27-TRANSGENIC RATS; AUTOIMMUNE INFLAMMATION; INTESTINAL INFLAMMATION; INTERFERON-GAMMA; CHRONIC COLITIS; IFN-GAMMA; ARTHRITIS AB Objective. To determine whether HLA-B27 misfolding and the unfolded protein response (UPR) result in cytokine dysregulation and whether this is associated with Th1 and/or Th17 activation in HLA-B27/human beta(2)-microglobulin (Hu beta(2)m)-transgenic rats, an animal model of spondylarthritis. Methods. Cytokine expression in lipopolysaccharide (LPS)-stimulated macrophages was analyzed in the presence and absence of a UPR induced by chemical agents or by HLA-B27 up-regulation. Cytokine expression in colon tissue and in cells purified from the lamina propria was determined by real-time reverse transcription-polymerase chain reaction analysis, and differences in Th1 and Th17 CD4+ T cell populations were quantified after intracellular cytokine staining. Results. Interleukin-23 (IL-23) was found to be synergistically up-regulated by LPS in macrophages undergoing a UPR induced by pharmacologic agents or by HLA-B27 misfolding. IL-23 was also increased in the colon tissue from B27/Hu beta(2)m-transgenic rats concurrently with the development of intestinal inflammation, and IL-17, a downstream target of IL-23, exhibited robust up-regulation in a similar temporal pattern. IL-23 and IL-17 transcripts were localized to CD11+ antigen-presenting cells and CD4+ T cells, respectively, from the colonic lamina propria. Colitis was associated with a 6-fold expansion of CD4+ IL-17-expressing T cells. Conclusion. The IL-23/IL-17 axis is strongly activated in the colon of B27/Hu beta(2)m-transgenic rats with spondylarthritis-like disease. HLA-B27 misfolding and UPR activation in macrophages can result in enhanced induction of the pro-Th17 cytokine IL-23. These results suggest a possible link between HLA-B27 misfolding and immune dysregulation in this animal model, with implications for human disease. C1 Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Colbert, RA (reprint author), NIAMSD, NIH, Bldg 10,CRC,Room 1-5142, Bethesda, MD 20892 USA. EM colbertra@mac.com RI Turner, Matthew/J-2642-2013 OI Turner, Matthew/0000-0002-5394-0923 FU NIH [R01-AR-46177, AR-48372, T32-AR-07594]; University of Cincinnati College of Medicine; University of Cincinnati College of Medicine Physician Scientist Training Program; Arthritis Foundation FX Supported by NIH grants R01-AR-46177 and AR-48372. Dr. Turner is recipient of a Functional Genomics Fellowship from the University of Cincinnati College of Medicine and was supported by the University of Cincinnati College of Medicine Physician Scientist Training Program. Drs. Smith and Sowder's work was supported by NIH training grant T32-AR-07594, and Dr. Smith is recipient of an Arthritis Foundation Postdoctoral Fellowship. NR 47 TC 133 Z9 142 U1 1 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2009 VL 60 IS 9 BP 2633 EP 2643 DI 10.1002/art.24763 PG 11 WC Rheumatology SC Rheumatology GA 497JI UT WOS:000270054900013 PM 19714651 ER PT J AU Wang, D Larder, B Revell, A Montaner, J Harrigan, R De Wolf, F Lange, J Wegner, S Ruiz, L Perez-Elias, MJ Emery, S Gatell, J Monforte, AD Torti, C Zazzi, M Lane, C AF Wang, Dechao Larder, Brendan Revell, Andrew Montaner, Julio Harrigan, Richard De Wolf, Frank Lange, Joep Wegner, Scott Ruiz, Lidia Jesus Perez-Elias, Maria Emery, Sean Gatell, Jose Monforte, Antonella D'Arminio Torti, Carlo Zazzi, Maurizio Lane, Clifford TI A comparison of three computational modelling methods for the prediction of virological response to combination HIV therapy SO ARTIFICIAL INTELLIGENCE IN MEDICINE LA English DT Article DE HIV; Artificial neural networks; Support vector machines; Random forests; Treatment decision support techniques; Antiretroviral treatment; Antiviral drug resistance ID ARTIFICIAL NEURAL-NETWORKS; DRUG-RESISTANCE; GENOTYPE; SUSCEPTIBILITY; PHENOTYPE; SYSTEMS AB Objective: HIV treatment failure is commonly associated with drug resistance and the selection of a new regimen is often guided by genotypic resistance testing. The interpretation of complex genotypic data poses a major challenge. We have developed artificial neural network (ANN) models that predict virological response to therapy from HIV genotype and other clinical information. Here we compare the accuracy of ANN with alternative modelling methodologies, random forests (RF) and support vector machines (SVM). Methods: Data from 1204 treatment change episodes (TCEs) were identified from the HIV Resistance Response Database Initiative (RDI) database and partitioned at random into a training set of 1154 and a test set of 50. The training set was then partitioned using an L-cross (L = 10 in this study) validation scheme for training individual computational models. Seventy six input variables were used for training the models: 55 baseline genotype mutations; the 14 potential drugs in the new treatment regimen; four treatment history variables; baseline viral toad; CD4 count and time to follow-up viral toad. The output variable was follow-up viral toad. Performance was evaluated in terms of the correlations and absolute differences between the individual models' predictions and the actual Delta VL values. Results: The correlations (r(2)) between predicted and actual Delta VL varied from 0.318 to 0.546 for ANN, 0.590 to 0.751 for RF and 0.300 to 0.720 for SVM. The mean absolute differences varied from 0.677 to 0.903 for ANN, 0.494 to 0.644 for RF and 0.500 to 0.790 for SVM. ANN models were significantly inferior to RF and SVM models. The predictions of the ANN, RF and SVM committees all correlated highly significantly with the actual Delta VL of the independent test TCEs, producing r(2) values of 0.689, 0.707 and 0.620, respectively. The mean absolute differences were 0.543, 0.600 and 0.607 log(10) copies/ml for ANN, RF and SVM, respectively. There were no statistically significant differences between the three committees. Combining the committees' outputs improved correlations between predicted and actual virological responses. The combination of all three committees gave a correlation of r(2) = 0.728. The mean absolute differences followed a similar pattern. Conclusions: RF and SVM models can produce predictions of virological response to HIV treatment that are comparable in accuracy to a committee of ANN models. Combining the predictions of different models improves their accuracy somewhat. This approach has potential as a future clinical toot and a combination of ANN and RF models is being taken forward for clinical evaluation. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wang, Dechao; Larder, Brendan; Revell, Andrew] HIV Resistance Response Database Initiat RDI, London, England. [Montaner, Julio; Harrigan, Richard] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [De Wolf, Frank] Netherlands HIV Monitoring Fdn, Amsterdam, Netherlands. [Lange, Joep] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Wegner, Scott] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Ruiz, Lidia] Fundacio IrsiCaixa, Badalona, Spain. [Jesus Perez-Elias, Maria] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Emery, Sean] Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. [Gatell, Jose] Hosp Clin Barcelona, Barcelona, Spain. [Monforte, Antonella D'Arminio] Univ Milan, Milan, Italy. [Torti, Carlo] Univ Brescia, Inst Infect & Trop Dis, Brescia, Italy. [Zazzi, Maurizio] Univ Siena, I-53100 Siena, Italy. [Lane, Clifford] NIAID, Bethesda, MD 20892 USA. RP Revell, A (reprint author), HIV Resistance Response Database Initiat RDI, 14 Union Sq, London, England. EM andrewrevell@hivrdi.org OI Zazzi, Maurizio/0000-0002-0344-6281 FU National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This research has been funded with Federal Funds from the National Cancer Institute, National Institutes of Health, under contract No. NO1-CO-12400. NR 33 TC 22 Z9 22 U1 3 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0933-3657 J9 ARTIF INTELL MED JI Artif. Intell. Med. PD SEP PY 2009 VL 47 IS 1 BP 63 EP 74 DI 10.1016/j.artmed.2009.05.002 PG 12 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 495JY UT WOS:000269888600005 PM 19524413 ER PT J AU De Fruyt, F De Bolle, M McCrae, RR Terracciano, A Costa, PT AF De Fruyt, Filip De Bolle, Marleen McCrae, Robert R. Terracciano, Antonio Costa, Paul T., Jr. CA Collaborators Adolescent Personali TI Assessing the Universal Structure of Personality in Early Adolescence The NEO-PI-R and NEO-PI-3 in 24 Cultures SO ASSESSMENT LA English DT Article DE adolescence; Five-Factor Model; cross-cultural; personality; observer ratings ID CHILD-PERSONALITY; AGE-DIFFERENCES; 5-FACTOR MODEL; TRAITS; INVENTORY; BIG-5 AB The structure and psychometric characteristics of the NEO Personality Inventory-3 (NEO-PI-3), a more readable version of the Revised NEO Personality Inventory (NEO-PI-R), are examined and compared with NEO-PI-R characteristics using data from college student observer ratings of 5,109 adolescents aged 12 to 17 years from 24 cultures. Replacement items in the PI-3 showed on average stronger item-total correlations and slightly improved facet reliabilities compared with the NEO-PI-R in both English- and non-English-speaking samples. NEO-PI-3 replacement items did not substantially affect scale means compared with the original scales. Analyses across and within cultures confirmed the intended factor structure of both versions when used to describe young adolescents. The authors discuss implications of these cross-cultural findings for the advancement of studies in adolescence and personality development across the lifespan. C1 [De Fruyt, Filip] Univ Ghent, Dept Dev Personal & Social Psychol, B-9000 Ghent, Belgium. [McCrae, Robert R.; Terracciano, Antonio; Costa, Paul T., Jr.] NIA, Bethesda, MD 20892 USA. RP De Fruyt, F (reprint author), Univ Ghent, Dept Dev Personal & Social Psychol, H Dunantlaan 2, B-9000 Ghent, Belgium. EM Filip.DeFruyt@ugent.be RI De Fruyt, Filip/A-3083-2009; terracciano, antonio/B-1884-2008; Allik, Juri/D-5609-2009; Realo, Anu/M-9524-2016; OI Allik, Juri/0000-0002-8358-4747; Shakespeare-Finch, Jane/0000-0003-4237-1320; Costa, Paul/0000-0003-4375-1712; Reategui, Norma/0000-0003-0484-9936; Loeckenhoff, Corinna/0000-0003-1605-1323 FU Intramural NIH HHS [ZIA AG000183-22, Z99 AG999999, ZIA AG000180-25, ZIA AG000180-26, ZIA AG000183-23] NR 24 TC 41 Z9 42 U1 9 U2 56 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 J9 ASSESSMENT JI Assessment PD SEP PY 2009 VL 16 IS 3 BP 301 EP 311 DI 10.1177/1073191109333760 PG 11 WC Psychology, Clinical SC Psychology GA 482YS UT WOS:000268927400007 PM 19419953 ER PT J AU Shamir, L Nemiroff, RJ AF Shamir, Lior Nemiroff, Robert J. TI FREQUENCY LIMITS ON NAKED-EYE OPTICAL TRANSIENTS LASTING FROM MINUTES TO YEARS SO ASTRONOMICAL JOURNAL LA English DT Article DE methods: data analysis; methods: statistical ID LOGIC-BASED ALGORITHM; MICROLENSING EVENTS; SKY; TELESCOPE; PERSEUS; SYSTEM; REJECTION; FLASHES; IMAGES; GALAXY AB How often do bright optical transients occur on the sky but go unreported? To constrain the bright end of the astronomical transient function, a systematic search for transients that become bright enough to be noticed by the unaided eye was conducted using the all-sky monitors of the Night Sky Live network. Two fisheye CONtinuous CAMeras operating over three years created a database that was searched for transients that appeared in time-contiguous CCD frames. Although a single candidate transient was found, the lack of more transients is used here to deduce upper limits to the general frequency of bright transients. To be detected, a transient must have increased by over three visual magnitudes to become brighter than visual magnitude 5.5 on the timescale of minutes to years. It is concluded that, on the average, fewer than 0.0040 (t(dur)/60 s) transients with duration t(dur) between minutes and hours, occur anywhere on the sky at any one time. For transients on the order of months to years, fewer than 160 (t(dur)/1 year) occur, while for transients on the order of years to millennia, fewer than 50 (t(dur)/1 year)(2) occur. C1 [Shamir, Lior] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Nemiroff, Robert J.] Michigan Technol Univ, Dept Phys, Houghton, MI 49931 USA. RP Shamir, L (reprint author), NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. EM shamirl@mail.nih.gov; nemiroff@mtu.edu NR 50 TC 1 Z9 1 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0004-6256 J9 ASTRON J JI Astron. J. PD SEP PY 2009 VL 138 IS 3 BP 956 EP 962 DI 10.1088/0004-6256/138/3/956 PG 7 WC Astronomy & Astrophysics SC Astronomy & Astrophysics GA 490OF UT WOS:000269509700022 ER PT J AU Lin, JP Schwaiger, JP Cupples, LA O'Donnell, CJ Zheng, G Schoenborn, V Hunt, SC Joo, J Kronenberg, F AF Lin, Jing-Ping Schwaiger, Johannes P. Cupples, L. Adrienne O'Donnell, Christopher J. Zheng, Gang Schoenborn, Veit Hunt, Steven C. Joo, Jungnam Kronenberg, Florian TI Conditional linkage and genome-wide association studies identify UGT1A1 as a major gene for anti-atherogenic serum bilirubin levels-The Framingham Heart Study SO ATHEROSCLEROSIS LA English DT Article DE Bilirubin; UGT1A1; Linkage analysis; Genome-wide association study ID CORONARY-ARTERY-DISEASE; UGT1A1-ASTERISK-28 ALLELE; GILBERTS-SYNDROME; RISK; POLYMORPHISMS; PROMOTER; HYPERBILIRUBINEMIA; METABOLISM; PEDIGREES; FAMILY AB Objective and methods: Low bilirubin levels are significantly associated with cardiovascular diseases (CVD). in previous genome-wide linkage studies we identified a major locus on chromosome 2q harboring the candidate gene UDP-glucuronosyltransferase (UGT1A1). The activity of this enzyme is significantly influenced by a TA-repeat polymorphism in the promoter of the gene. In a prospective study individuals with genotype (TA)7/(TA)7 had significantly higher bilirubin levels and approximately one-third the risk of CVD as carriers of the wildtype (TA)6 allele. In the present study we performed a conditional linkage study to investigate whether this polymorphism explains the observed linkage peak and extended our analysis by a genome-wide association study on bilirubin levels in 1345 individuals. Results: After adjustment for the bilirubin variance explained by this polymorphism, the LOD score on chromosome 2q dropped from 3.8 to 0.4, demonstrating that this polymorphism explains the previous linkage result. For the genome-wide association study, the closest marker to UGT1A1 was in the top ranking SNPs. The association became even stronger when we considered the TA-repeat polymorphism in the analysis (p = 2.68 x 10(-53)). Five other SNPs in other regions reached genome-wide significance without obvious connection to bilirubin metabolism. Conclusions: Our studies suggest that UGT1A1 may be the major gene with strong effects on bilirubin levels and the TA-repeat polymorphism might be the key polymorphism within the gene controlling bilirubin levels. Since this polymorphism has a high frequency and a substantial impact on the development of CVD, the gene might be an important drug target. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Lin, Jing-Ping] NHLBI, Off Biostat Res, Div Prevent & Populat Sci, NIH,Dept Populat & Publ Sci, Bethesda, MD 20892 USA. [Schwaiger, Johannes P.; Schoenborn, Veit; Kronenberg, Florian] Innsbruck Med Univ, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, A-6020 Innsbruck, Austria. [Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, NIH, Bethesda, MD 20892 USA. [Hunt, Steven C.] Univ Utah, Sch Med, Cardiovasc Genet Div, Salt Lake City, UT USA. RP Lin, JP (reprint author), NHLBI, Off Biostat Res, Div Prevent & Populat Sci, NIH,Dept Populat & Publ Sci, 6701 Rockledge Dr,Suite 9196, Bethesda, MD 20892 USA. EM linj@nhlbi.nih.gov; Florian.Kronenberg@i-med.ac.at RI Kronenberg, Florian/B-1736-2008; OI Kronenberg, Florian/0000-0003-2229-1120; Cupples, L. Adrienne/0000-0003-0273-7965; Schwaiger, Johannes/0000-0003-1960-0631 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [NOI-HC-25195] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. NOI-HC-25195). This work was also supported by grants to Florian Kronenberg from the "Tiroler Wi sse nscha fts fonds" (Project 404/505), the "Austrian Nationalbank" (Project 9331) and the "Genomics of Lipidassociated Disorders-GOLD" of the "Austrian Genome Research Programme GEN-AU", Schoepfstr. 41, A-6020 Innsbruck. NR 34 TC 31 Z9 31 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2009 VL 206 IS 1 BP 228 EP 233 DI 10.1016/j.atherosclerosis.2009.02.039 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 496TR UT WOS:000270002000036 PM 19389676 ER PT J AU Yerys, BE Wallace, GL Harrison, B Celano, MJ Giedd, JN Kenworthy, LE AF Yerys, Benjamin E. Wallace, Gregory L. Harrison, Bryan Celano, Mark J. Giedd, Jay N. Kenworthy, Lauren E. TI Set-shifting in children with autism spectrum disorders Reversal shifting deficits on the Intradimensional/Extradimensional Shift Test correlate with repetitive behaviors SO AUTISM LA English DT Article DE attention; autism; ID/ED shift task; set-shifting ID HIGH-FUNCTIONING AUTISM; EXECUTIVE FUNCTIONS; DEVELOPMENTAL DISORDERS; REPETITIVE BEHAVIORS; DIAGNOSTIC INTERVIEW; AUTOMATED BATTERY; PERFORMANCE; CORTEX; DYSFUNCTION; EXCELLENCE AB Research examining set-shifting has revealed significant difficulties for adults with autism spectrum disorders (ASDs). However, research with high-functioning children with ASDs has yielded mixed results. The current study tested 6- to 13-year-old high-functioning children with ASD and typically developing controls matched on age, gender, and IQ using the Intradimensional/Extradimensional (ID/ED) Shift Test from the Cambridge Neuropsychological Test Automated Battery. Children with ASDs completed as many ED shifts and reversal ED shifts as controls; however, they made significantly more errors than controls while completing the ED reversal shifts. Analyses on a subset of cases revealed a significant positive correlation between ED reversal errors and the number of repetitive behavior symptoms in the ASD group. These findings suggest that high-functioning children with ASDs require additional feedback to shift successfully. In addition, the relationship between set-shifting and non-social symptoms suggests its utility as a potentially informative intermediate phenotype in ASDs. C1 [Yerys, Benjamin E.] Childrens Natl Med Ctr, Childrens Res Inst Neurosci, Washington, DC 20009 USA. [Wallace, Gregory L.; Celano, Mark J.; Giedd, Jay N.] NIMH, Bethesda, MD 20892 USA. RP Yerys, BE (reprint author), Childrens Natl Med Ctr, Childrens Res Inst Neurosci, 111 Michigan Ave NW, Washington, DC 20009 USA. EM byerys@cnmc.org RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [Z99 MH999999]; NICHD NIH HHS [T32 HD046388-01A2, P30 HD040677, P30HD40677, T32 HD046388, T32HD046388]; NIMH NIH HHS [U54 MH066417, U54 MH066417-01A1, U54 MH066417-05] NR 36 TC 58 Z9 58 U1 5 U2 23 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1362-3613 J9 AUTISM JI Autism PD SEP PY 2009 VL 13 IS 5 BP 523 EP 538 DI 10.1177/1362361309335716 PG 16 WC Psychology, Developmental SC Psychology GA 494FZ UT WOS:000269798500005 PM 19759065 ER PT J AU Burbelo, PD Leahy, HP Issa, AT Groot, S Baraniuk, JN Nikolov, NP Illei, GG Iadarola, MJ AF Burbelo, Peter D. Leahy, Hannah P. Issa, Alexandra T. Groot, Sandra Baraniuk, James N. Nikolov, Nikolay P. Illei, Gabor G. Iadarola, Michael J. TI Sensitive and robust luminescent profiling of anti-La and other autoantibodies in Sjogren's syndrome SO AUTOIMMUNITY LA English DT Article DE Autoantibodies; Autoantigen; Diagnosis Sjogren's syndrome; SSA; SSB ID LUCIFERASE IMMUNOPRECIPITATION SYSTEMS; THYROID-DISEASE; RO52; AUTOANTIGEN; ASSAY; INFECTION; DIAGNOSIS; MARKER AB Sjogren's syndrome (SjS) patients often have a variety of extraglandular manifestations including neurological and gastrointestinal involvement. In this study we evaluated the diagnostic performance of luciferase immunoprecipitation system (LIPS) that employs mammalian cell-produced recombinant antigens for analyzing SjS autoantibody responses. LIPS testing of mammalian cell-produced La, Ro60 and Ro52 recombinant antigens with defined commercial antibodies demonstrated highly specific immunoprecitation of each antigen without cross-reactivity. Next, sera from 57 SjS and 25 volunteers were evaluated by LIPS against a panel of human autoantigens. LIPS detected robust anti-La. antibody levels in 43/57 SjS patients (75% sensitivity) and markedly outperformed an ELISA (46% sensitivity). Profiling of other SjS-associated autoantigens revealed the presence of anti-Ro60, anti-Ro52 in 63% and 61%, of SjS patients, respectively. Interestingly, a C-terminal fragment of Ro52 (Ro52-Delta 2), a protein fragment not previously found to be antigenic by ELISA, also showed positive immunoreactivity in 42/57 SjS patients (65% sensitivity). Additional profiling of other autoantigens revealed that certain SjS patients also showed positive immunoreactivity with thyroid peroxidase (14%), AQP-4 (12%) and the H(+)/K(+) gastric ATPase (16%) suggesting potential autoantibody attack of thyroid, neuronal and gastric parietal cells, respectively. These heterogeneous autoantibody responses detected by LIPS in SjS will likely be useful for diagnosis and for evaluating extraglandular manifestations. C1 [Burbelo, Peter D.; Leahy, Hannah P.; Issa, Alexandra T.; Groot, Sandra; Iadarola, Michael J.] Natl Inst Dent & Cranioacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Baraniuk, James N.] Georgetown Univ, Div Rheumatol Immunol & Rheumatol, Washington, DC USA. [Nikolov, Nikolay P.; Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Burbelo, PD (reprint author), Bldg 49,Room 1C38,49 Convent Dr, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU NIDCR; NIH FX We are grateful to Jason Keller for his technical assistance. We also acknowledge Dr. Kathryn Ching, Dr. Kendall Mitchell, and Brian Bates for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIDCR and, in part, by a Bench to Bedside award from the NIH Clinical Research Center. NR 35 TC 23 Z9 23 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0891-6934 J9 AUTOIMMUNITY JI Autoimmunity PD SEP PY 2009 VL 42 IS 6 BP 515 EP 524 DI 10.1080/08916930902911738 PG 10 WC Immunology SC Immunology GA 499ND UT WOS:000270227200006 PM 19657778 ER PT J AU Sosa, MS Lewin, NE Choi, SH Blumberg, PM Kazanietz, MG AF Sosa, Maria Soledad Lewin, Nancy E. Choi, Sung-Hee Blumberg, Peter M. Kazanietz, Marcelo G. TI Biochemical Characterization of Hyperactive beta 2-Chimaerin Mutants Revealed an Enhanced Exposure of C1 and Rac-GAP Domains SO BIOCHEMISTRY LA English DT Article ID ESTER TUMOR PROMOTERS; SUBCELLULAR-LOCALIZATION; PHORBOL ESTERS; C2 DOMAIN; ACTIVATION; BINDING; DIACYLGLYCEROL; RECEPTOR; ALPHA-2-CHIMAERIN; PHOSPHORYLATION AB Recent studies established that the Rac-GAP beta 2-chimaerin plays important roles in development, neuritogenesis, and cancer progression. A unique feature of beta 2-chimaerin is that it can be activated by phorbol esters and the lipid second messenger diacylglycerol (DAG), which bind with high affinity to its C1 domain and promote beta 2-chimaerin translocation to membranes, leading to the inactivation of the small G-protein Rac. Crystallographic evidence and cellular studies suggest that beta 2-chimaerin remains in an Inactive conformation in the cytosol with the Cl domain inaccessible to ligands. We developed a series of' beta 2-chimaerin point mutants in Which intramolecular contacts that occlude the C1 domain have been disrupted. These mutants showed enhanced translocation in response to phorbol 12-myristate 13-acetate (PMA) in cells. Binding assays using [(3)H]phorbol 12,13-dibutyrate ([(3)H]PDBu) revealed that internal contact mutants have a reduced acidic phospholipid requirement for phorbol ester binding. Moreover, disruption of intramolecular contacts enhances binding of beta 2-chimaerin to acidic phospholipid vesicles and confers enhanced Rac-GAP activity in vitro. These Studies Suggest that beta 2-chimaerin Must undergo a conformational rearrangement in order to expose its lipid binding sites and become activated. C1 [Sosa, Maria Soledad; Kazanietz, Marcelo G.] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. [Lewin, Nancy E.; Choi, Sung-Hee; Blumberg, Peter M.] NCI, Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kazanietz, MG (reprint author), Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. EM marcelog@upenn.edu FU NIH [R01-CA74197]; NIH, Center for Cancer Research, National Cancer Institute FX This work is supported by Grant R01-CA74197 from the NIH to M. G.K. and in part by the Intramural Program of the NIH, Center for Cancer Research, National Cancer Institute. NR 31 TC 7 Z9 7 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 1 PY 2009 VL 48 IS 34 BP 8171 EP 8178 DI 10.1021/bi9010623 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 485SR UT WOS:000269144900010 PM 19618918 ER PT J AU Puri, N Gaur, M Sharma, M Shukla, S Ambudkar, SV Prasad, R AF Puri, Nidhi Gaur, Manisha Sharma, Monika Shukla, Suneet Ambudkar, Suresh V. Prasad, Rajendra TI The amino acid residues of transmembrane helix 5 of multidrug resistance protein CaCdr1p of Candida albicans are involved in substrate specificity and drug transport SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Candida albicans; Cdr1p; ABC transporter; Multidrug resistance; Fungal transporter; Alanine scanning ID ABC ANTIFUNGAL EFFLUX; P-GLYCOPROTEIN; BINDING; YEAST; PDR5P; GENE; CDR1P; IDENTIFICATION; EXPRESSION; PUMP AB In view of the importance of Candida Drug Resistance Protein (Cdr1p) of pathogenic Candida albicans in azole resistance, we have characterized its ability to efflux variety of substrates by subjecting its entire transmembrane segment (TMS) 5 to site directed mutagenesis. All the mutant variants of putative 21 amino acids of TMS 5 and native CaCdr1p were over expressed as a GFP-tagged protein in a heterologous host Saccharomyces cerevisiae. Based on the drug susceptibility pattern, the mutant variants could be grouped into two categories. The variants belonging to first category were susceptible to all the tested drugs, as compared to those belonging to second category which exhibited resistance to selective drugs. The mutant variants of both the categories were analyzed for their ATP catalysis and drug efflux properties. Irrespective of the categories, most of the mutant variants of TMS 5 showed an uncoupling between ATP hydrolysis and drug efflux. The mutant variants such as M667A, F673A, I675A and P678A were an exception since they reflected a sharp reduction in both K(m) and V(max) values of ATPase activity when compared with WT CaCdr1p-GFP. Based on the competition experiments, we could identify TMS 5 residues which are specific to interact with select drugs. TMS 5 residues of CaCdr1p thus not only impart substrate specificity but also selectively act as a communication link between ATP hydrolysis and drug transport. (C) 2009 Elsevier B.V. All rights reserved. C1 [Puri, Nidhi; Gaur, Manisha; Sharma, Monika; Prasad, Rajendra] Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Prasad, R (reprint author), Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. EM rp47jnu@gmail.com RI shukla, suneet/B-4626-2012 FU Intramural NIH HHS [Z01 BC010030-12] NR 38 TC 12 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD SEP PY 2009 VL 1788 IS 9 BP 1752 EP 1761 DI 10.1016/j.bbamem.2009.04.009 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 494ZS UT WOS:000269859400007 PM 19393219 ER PT J AU Botos, I Liu, L Wang, Y Segal, DM Davies, DR AF Botos, Istvan Liu, Lin Wang, Yan Segal, David M. Davies, David R. TI The Toll-like receptor 3:dsRNA signaling complex SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE Toll-like receptor; Innate immunity; Inflammation; Leucine-rich repeat; dsRNA; Pattern recognition receptor ID DOUBLE-STRANDED-RNA; VARIABLE LYMPHOCYTE RECEPTORS; CRYSTAL-STRUCTURE; PATHOGEN RECOGNITION; FUNCTIONAL ANALYSES; TLR4-MD-2 COMPLEX; STRUCTURAL BASIS; BINDING-SITE; TLR3; ECTODOMAIN AB Toll-like receptors (TLRs) recognize conserved molecular patterns in invading pathogens and trigger innate immune responses. TLR3 recognizes dsRNA, a molecular signature of most viruses via its ectodomain (ECD). The TLR3-ECD structure consists of a 23 turn coil bent into the shape of a horseshoe with specialized domains capping the N and C-terminal ends of the coil. TLR3-ECDs bind as dimeric units to dsRNA oligonucleotides of at least 45 bp in length, the minimal length required for signal transduction. X-ray analysis has shown that each TLR3-ECD of a dimer binds dsRNA at two sites located at opposite ends of the TLR3 "horseshoe" on the one lateral face that lacks Winked glycans. Intermolecular contacts between the C-terminal domains of two TLR3-ECDs stabilize the dimer and position the C-terminal residues within 20-25 angstrom of each other, which is thought to be essential for transducing a signal across the plasma membrane in intact TLR3 molecules. Interestingly, in TLRs 1, 2 and 4, which bind lipid ligands using very different interactions from TLR3, the ligands nevertheless promote the formation of a dimer in which the same two lateral surfaces as in the TLR3-ECD:dsRNA complex face each other, bringing their C-termini in close proximity. Thus, a pattern is emerging in which pathogen-derived substances bind to TLR-ECDs, thereby promoting the formation of a dimer in which the glycan-free ligand binding surfaces face each other and the two C-termini are brought in close proximity for signal transduction. Published by Elsevier B.V. C1 [Botos, Istvan; Liu, Lin; Davies, David R.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yan; Segal, David M.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Davies, DR (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM david.davies@nih.gov FU Intramural NIH HHS [Z01 DK034002-42, Z01 BC009254-33] NR 29 TC 42 Z9 45 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD SEP-OCT PY 2009 VL 1789 IS 9-10 BP 667 EP 674 DI 10.1016/j.bbagrm.2009.06.005 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 523KE UT WOS:000272071200015 PM 19595807 ER PT J AU Roth, TL Lubin, FD Sodhi, M Kleinman, JE AF Roth, Tania L. Lubin, Farah D. Sodhi, Monsheel Kleinman, Joel E. TI Epigenetic mechanisms in schizophrenia SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Schizophrenia; Environment; Epigenetic; DNA methylation; Histone; HDAC; DNMT; Cognition ID CATECHOL-O-METHYLTRANSFERASE; 5-HT2A RECEPTOR GENE; MAJOR PSYCHIATRIC-DISORDERS; GENOME-WIDE ASSOCIATION; DNA-METHYLATION CHANGES; PREFRONTAL CORTEX; BIPOLAR DISORDER; MESSENGER-RNA; OBSTETRIC COMPLICATIONS; HUMAN BRAIN AB Epidemiological research suggests that both an individual's genes and the environment underlie the pathophysiology of schizophrenia. Molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. Recent work indicates that epigenetic mechanisms, or the chemical markings of the DNA and the surrounding histone proteins. remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. In this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where 'nature' is considered to be inherited or genetic vulnerability to schizophrenia, and 'nurture' is proposed to exert its effects through epigenetic mechanisms. Second, we define DNA methylation and discuss the evidence for its role in schizophrenia. Third, we define posttranslational histone modifications and discuss their place in schizophrenia. This research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia. (C) 2009 Elsevier B.V. All rights reserved. C1 [Roth, Tania L.; Lubin, Farah D.; Sodhi, Monsheel] Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA. [Roth, Tania L.; Lubin, Farah D.; Sodhi, Monsheel] Univ Alabama, Evelyn McKnight Brain Inst, Birmingham, AL 35294 USA. [Sodhi, Monsheel] Univ Alabama, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. [Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Sodhi, M (reprint author), Univ Alabama, Dept Neurobiol, 1720 7th Ave Sth,CIRC Rm 590C, Birmingham, AL 35294 USA. OI Sodhi, Monsheel/0000-0002-8261-3040 FU National Institutes of Health; National Alliance for Research on Schizophrenia and Depression; Civitan International; Evelyn F. McKnight Brain Research Foundation FX This work was funded by grants from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression, Civitan International, and the Evelyn F. McKnight Brain Research Foundation. NR 168 TC 74 Z9 76 U1 3 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD SEP PY 2009 VL 1790 IS 9 BP 869 EP 877 DI 10.1016/j.bbagen.2009.06.009 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 493YN UT WOS:000269775800004 PM 19559755 ER PT J AU Donaldson, JG AF Donaldson, Julie G. TI Phospholipase D in endocytosis and endosomal recycling pathways SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE Arf6; Endocytosis; Recycling; Membrane traffic; Phospholipase D ID CLATHRIN-INDEPENDENT ENDOCYTOSIS; ADP-RIBOSYLATION FACTOR; PLASMA-MEMBRANE; PHOSPHATIDIC-ACID; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; RECEPTOR ENDOCYTOSIS; DOWNSTREAM EFFECTOR; UNIQUE PLATFORM; ARF6; CELL AB The discovery that Arf GTPases, mediators of membrane traffic, activate phospholipase D (PLD) raised the possibility that Arfs could facilitate membrane traffic by altering membrane lipid composition. PLD hydrolyzes phosphatidylcholine to generate phosphatidic acid (PA), a lipid that favors membranes with negative curvature and thus can facilitate both membrane fission and fusion. This review examines studies that have reported a role for PLD in endocytosis and membrane recycling from endocytic pathways. Published by Elsevier B.V. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2503, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov FU Intramural NIH HHS [Z01 HL000517-12] NR 52 TC 48 Z9 49 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD SEP PY 2009 VL 1791 IS 9 BP 845 EP 849 DI 10.1016/j.bbalip.2009.05.011 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 495DA UT WOS:000269868900003 PM 19540357 ER PT J AU Huizing, M Krasnewich, DM AF Huizing, Marjan Krasnewich, Donna M. TI Hereditary Inclusion Body Myopathy: A decade of progress SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Muscular dystrophy; Sialic acid synthesis; UDP-GlcNAc 2-epimerase/ManNAc kinase; Hyposialylation; HIBM mouse model; ManNAc therapy; GNE mutation ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; SIALIC-ACID BIOSYNTHESIS; RIMMED VACUOLES DMRV; DISTAL MYOPATHY; GNE GENE; IRANIAN JEWS; UDP-N-ACETYLGLUCOSAMINE-2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; N-ACETYLMANNOSAMINE; ALPHA-DYSTROGLYCAN; GLCNAC 2-EPIMERASE AB Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive. quadriceps sparing type commonly referred to as HIBM but also termed h-IBM or Inclusion Body Myopathy 2 (IBM2). The clinical manifestations begin with muscle weakness progressing over the next 10-20 years uniquely sparing the quadriceps until the most advanced stage of the disease. Histopathology of an HIBM muscle biopsy shows rimmed vacuoles on Comori's trichrome stain, small fibers in groups and tubulofilaments without evidence of inflammation. In affected individuals distinct mutations have been identified in the GNE gene, which encodes the bifunctional enzyme uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetyl-mannosamine (ManNAc) kinase (GNE/MNK). GNE/MNK catalyzes the first two committed steps in the biosynthesis of acetylneuraminic acid (Neu5Ac), an abundant and functionally important sugar. The generation of HIBM animal models has led to novel insights into both the disease and the role of GNE/MNK in pathophysiology. Recent advances in therapeutic approaches for HIBM, including administration of N-acetyl-mannosamine (ManNAc), a precursor of Neu5Ac will be discussed. Published by Elsevier B.V. C1 [Krasnewich, Donna M.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Huizing, Marjan] NHGRI, Cell Biol Metab Disorders Unit, NIH, Bethesda, MD 20892 USA. RP Krasnewich, DM (reprint author), NHGRI, Off Clin Director, NIH, Bldg 10,CRC Room 3-2551,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkras@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. NR 78 TC 43 Z9 46 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD SEP PY 2009 VL 1792 IS 9 BP 881 EP 887 DI 10.1016/j.bbadis.2009.07.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 502OH UT WOS:000270469300012 PM 19596068 ER PT J AU Han, LY Wang, YL Bryant, SH AF Han, Lianyi Wang, Yanli Bryant, Stephen H. TI A survey of across-target bioactivity results of small molecules in PubChem SO BIOINFORMATICS LA English DT Article ID PROMISCUOUS INHIBITORS; DRUG DISCOVERY; MYRICETIN; HTS AB This work provides an anlysis of across-target bioactivity results in the screening data deposited in PubChem. Two alternative approaches for grouping-related targets are used to examine a compound's across-target bioactivity. This analysis identifies compounds that are selectively active against groups of protein targets that are identical or similar in sequence. This analysis also identifies compounds that are bioactive across unrelated targets. Statistical distributions of compounds' across-target selectivity provide a survey to evaluate target specficity of compounds by deriving and analyzing bioactivity profile across a wide range of biological targets for tested small molecules in PubChem. This work enables one to select target specific inhibitors, identify promiscuous compounds and better understand the biological mechanisms of target-small molecule interations. C1 [Han, Lianyi; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Han, Lianyi/D-1499-2009 FU National Institutes of Health, National Library of Medicine FX Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 20 TC 23 Z9 24 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP 1 PY 2009 VL 25 IS 17 BP 2251 EP 2255 DI 10.1093/bioinformatics/btp380 PG 5 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 486KX UT WOS:000269196000016 PM 19549631 ER PT J AU Roiser, JP Levy, J Fromm, SJ Nugent, AC Talagala, SL Hasler, G Henn, FA Sahakian, BJ Drevets, WC AF Roiser, Jonathan P. Levy, Jamey Fromm, Stephen J. Nugent, Allison C. Talagala, S. Lalith Hasler, Gregor Henn, Fritz A. Sahakian, Barbara J. Drevets, Wayne C. TI The Effects of Tryptophan Depletion on Neural Responses to Emotional Words in Remitted Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Acute tryptophan depletion; Affective Go/No-go (AGNG); depression; emotional processing; functional magnetic resonance imaging (fMRI); serotonin ID POSITRON-EMISSION-TOMOGRAPHY; MEDIAL PREFRONTAL CORTEX; VENTRAL TEGMENTAL AREA; LATERAL HABENULA; HEALTHY-VOLUNTEERS; BEHAVIORAL-RESPONSES; UNMEDICATED PATIENTS; MONOAMINE DEPLETION; SEROTONIN FUNCTION; PLASMA TRYPTOPHAN AB Background: Major depressive disorder (MDD) has been associated with both dysfunction of the central serotonergic system and abnormal responses to emotional stimuli. We used acute tryptophan depletion (ATD) to investigate the effect of temporarily reducing brain serotonin synthesis on neural and behavioral responses to emotional stimuli in remitted MDD subjects (rMDD) and healthy control subjects. Methods: Twenty control subjects and 23 rMDD subjects who had been unmedicated and in remission for >= 3 months completed the study. Following tryptophan or sham depletion, participants performed an emotional-processing task during functional magnetic resonance imaging. In addition, resting state regional blood flow was measured using arterial spin labeling. Results: Neither group exhibited significant mood change following ATD. However, tryptophan depletion differentially affected the groups in terms of hemodynamic responses to emotional words in a number of structures implicated in the pathophysiology of MDD, including medial thalamus and caudate. These interactions were driven by increased responses to emotional words in the control subjects, with little effect in the patients under the ATD condition. Following ATD, habenula blood flow increased significantly in the rMDD subjects relative to the control subjects, and increasing amygdala blood flow was associated with more negative emotional bias score across both groups. Conclusions: These data provide evidence for elevated habenula blood flow and alterations in the neural processing of emotional stimuli following ATD in rMDD subjects, even in the absence of overt mood change. However, further studies are required to determine whether these findings represent mechanisms of resilience or vulnerability to MDD. C1 [Roiser, Jonathan P.] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Roiser, Jonathan P.; Levy, Jamey; Fromm, Stephen J.; Nugent, Allison C.; Hasler, Gregor; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Talagala, S. Lalith] NINDS, NIH, MRI Res Facil, Bethesda, MD 20892 USA. [Henn, Fritz A.] Brookhaven Natl Lab, Upton, NY 11973 USA. [Roiser, Jonathan P.; Sahakian, Barbara J.] Univ Cambridge, Addenbrookes Hosp, Dept Psychiat, Cambridge CB2 2QQ, England. [Sahakian, Barbara J.] Wellcome Trust Behav & Clin Neurosci Inst, MRC, Cambridge, England. RP Roiser, JP (reprint author), UCL, Inst Cognit Neurosci, 17 Queen Sq, London WC1N 3AR, England. EM j.roiser@ucl.ac.uk RI Roiser, Jonathan/A-1791-2010; Hasler, Gregor/E-4845-2012; OI Hasler, Gregor/0000-0002-8311-0138; Nugent, Allison/0000-0003-2569-2480; Levy, Jamey/0000-0002-7434-7213 FU National Institute of Mental Health (NIMH); National Institutes of Health (NIH) FX Supplementary material cited in this article is available online. NR 62 TC 64 Z9 68 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2009 VL 66 IS 5 BP 441 EP 450 DI 10.1016/j.biopsych.2009.05.002 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 488EC UT WOS:000269330900006 PM 19539268 ER PT J AU Le Blanc, K Barrett, AJ Schaffer, M Hagglund, H Ljungman, P Ringden, O Remberger, M AF Le Blanc, Katarina Barrett, A. John Schaffer, Marie Hagglund, Hans Ljungman, Per Ringden, Olle Remberger, Mats TI Lymphocyte Recovery Is a Major Determinant of Outcome after Matched Unrelated Myeloablative Transplantation for Myelogenous Malignancies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hematopoietic stem cell transplantation (HSCT); Lymphocytes; Relapse-free survival (RFS); Graft-versus-host disease (GVHD) ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; MYELOID LEUKEMIAS; HLA-B; GRAFT; FAILURE; ALLOREACTIVITY; METHOTREXATE; CHEMOTHERAPY AB A higher absolute lymphocyte count I month (LC30) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with better outcome in patients transplanted from a matched sibling. We studied 102 SCT patients with unrelated donor and matched unrelated donors and the relationship between LC30 and outcome in patients with myelogenous leukemia. Conditioning was myeloablative using cyclophosphamide (Cy) with busulfan (Bu; n = 61) or total body irradiation (TBI; n = 41). LC30 was low (<0.2 x 10(9)/L) in 18 patients, intermediate (0.2-1.0 x 10(9)L) in 67, and high (>1.0 x 10(9)/L) in 17 patients. In multivariate analysis, independent factors associated with high relapse-free survival (RFS) were high LC30, high CD34 cell-dose, and absence of acute graft-versus-host disease (aGVHD) grades II-IV. When analyzed as a continuous variable in multivariate analysis, a higher LC30 was associated with a lower transplant-related mortality (TRM; relative hazard [RH] = 0.87, P < .05), higher relapse-free survival (RH = 3.42, P = .036), and improved survival (RH = 4.53, P = .016, excluding GVHD). In patients with high, intermediate, and low LC30, overall survival (OS) was 91% versus 60%, versus 36% (P = .02 and .001, respectively). This significant relationship was maintained in patients who did not develop GVHD by day 30. Significant risk factors to develop low LC30 was chronic myelogenous leukemia (CML; hazard ratio [HR] 0.73, P = .001), prophylaxis with granulocyte colony-stimulating factor (G-CSF; HR 0.81, P = .02) and aGVHD (HR 0.84, P = .05). These results indicate that LC30 is an independent prognostic factor for transplant outcome in matched unrelated SCT for myelogenous malignancies. Biol Blood Marrow Transplant 15: 1108-1115 (2009) (C) 2009 Elsevier Inc. All rights reserved. C1 [Le Blanc, Katarina; Schaffer, Marie; Ringden, Olle; Remberger, Mats] Karolinska Inst, Div Clin Immunol & Transfus Med, Stockholm, Sweden. [Le Blanc, Katarina; Hagglund, Hans; Ljungman, Per] Karolinska Univ Hosp Huddinge, Hematol Ctr, Stockholm, Sweden. [Barrett, A. John] NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hagglund, Hans; Ljungman, Per] Karolinska Inst, Div Hematol, Stockholm, Sweden. [Ringden, Olle] Karolinska Univ Hosp Huddinge, Ctr Allogene Stem Cell Res, Stockholm, Sweden. RP Le Blanc, K (reprint author), Karolinska Univ Hosp, Div Clin Immunol & Transfus Med, F79, SE-14186 Stockholm, Sweden. EM katarina.leblanc@ki.se FU Swedish Cancer Society [07 0132, 07 0529, 07 0117]; Children's Cancer Foundation [05/007, 06/094]; Swedish Research Council [K2006-32X-14716-04-1, K2005-32P-15457-01A, K2008-64X-20742-01-3, K2008-64X-05971-28-3, K2008-64P-15457-04-3]; Tobias Foundation; Cancer Society in Stockholm; Swedish Society of Medicine; Stockholm County Council; Sven and Ebba-Christina Hagbergs Foundation; Cancer and Allergy Foundation; Karolinska Institutet FX The study was supported by grants from the Swedish Cancer Society (07 0132, 07 0529, 07 0117), the Children's Cancer Foundation (05/007, 06/094), the Swedish Research Council (K2006-32X-14716-04-1, K2005-32P-15457-01A, K2008-64X-20742-01-3, K2008-64X-05971-28-3, K2008-64P-15457-04-3), the Tobias Foundation, the Cancer Society in Stockholm, the Swedish Society of Medicine, the Stockholm County Council, the Sven and Ebba-Christina Hagbergs Foundation, the Cancer and Allergy Foundation, and the Karolinska Institutet. NR 33 TC 38 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2009 VL 15 IS 9 BP 1108 EP 1115 DI 10.1016/j.bbmt.2009.05.015 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 486EK UT WOS:000269178400012 PM 19660724 ER PT J AU Boukari, H Brichacek, B Stratton, P Mahoney, SF Lifson, JD Margolis, L Nossal, R AF Boukari, Hacene Brichacek, Beda Stratton, Pamela Mahoney, Sheila F. Lifson, Jeffrey D. Margolis, Leonid Nossal, Ralph TI Movements of HIV-Virions in Human Cervical Mucus SO BIOMACROMOLECULES LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; IMMUNODEFICIENCY-VIRUS TYPE-1; MUC5B MUCIN; GLYCOPROTEINS; TRANSMISSION; DIFFUSION; TRANSPORT; CHARGE; SPERM; STAGE AB Time-resolved confocal microscopy and fluorescence correlation spectroscopy were used to examine the movements of fluorescently labeled HIV-virions (similar to 100 nm) added to samples of human cervical mucus. Particle-tracking analysis indicates that the motion of most virions is decreased 200-fold compared to that in aqueous solution and is not driven by typical diffusion. Rather, the time-dependence of their en semble-averaged mean-square displacements is proportional to tau(alpha) + v(2)tau(2), describing a combination of anomalous diffusion (alpha similar to 0.3) and flow-like behavior, with tau being the lag time. We attribute the flow-like behavior to slowly relaxing mucus matrix that follows mechanical perturbations such as stretching and twisting of the sample. Further analysis of the tracks and displacements of individual virions indicates differences in the local movements among the virions, including constrained motion and infrequent jumps, perhaps due to abrupt changes in matrix structure. Changes in the microenvironments due to slow structural changes may facilitate movement of the virions, allowing them to reach the epithelial layer. C1 [Boukari, Hacene; Brichacek, Beda; Margolis, Leonid; Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD 20892 USA. [Stratton, Pamela; Mahoney, Sheila F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Lifson, Jeffrey D.] NCI, SAIC Frederick, Frederick, MD 21702 USA. RP Boukari, H (reprint author), Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10467 USA. EM hboukari@aecom.yu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health FX We acknowledge fruitful discussions with Richard Cone, Rama Bansil, and Dan Sackett, and we thank Allie Muthukurnar and Nadia Ouhib for their help during their summer internships in our laboratories. We also thank Julian Bess, Jr. and Elena Chertova from the AIDS and Cancer Virus Program, SAIC Frederick Inc., NCI Frederick, for preparation and characterization of the labeled HIV-virions, and Vien Vanderhoof and Barbara Stegmann, of the Gynecology Consult Service, NICHD. This work was supported by intramural funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health. NR 47 TC 25 Z9 25 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD SEP PY 2009 VL 10 IS 9 BP 2482 EP 2488 DI 10.1021/bm900344q PG 7 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 492PO UT WOS:000269671200013 PM 19711976 ER PT J AU Chen, RJ Khormaee, S Eccleston, ME Slater, NKH AF Chen, Rongjun Khormaee, Sariah Eccleston, Mark E. Slater, Nigel K. H. TI Effect of L-Leucine Graft Content on Aqueous Solution Behavior and Membrane-Lytic Activity of a pH-Responsive Pseudopeptide SO BIOMACROMOLECULES LA English DT Article ID PSEUDO-PEPTIDES; POLY(L-LYSINE ISO-PHTHALAMIDE); PHOSPHOLIPID-VESICLES; DISRUPTIVE ACTIVITY; SYNTHETIC-POLYMERS; CELL-MEMBRANES; SIDE-CHAINS; FLUORESCENCE; COPOLYMERS; SYSTEMS AB A series of pH-responsive polymers have been synthesized by grafting L-leucine onto the pendant carboxylic acid groups of the linear pseudopeptide, poly(L-lysine iso-phthalamide). The effect of the degree of grafting on aqueous solution properties, cell membrane-disruptive activity, and in vitro cytotoxicity was examined by UV-visible and fluorescence spectroscopy, hemolysis, alamar blue staining, and propidium iodide fluorescence assays. Modification of poly(L-lysine iso-phthalamide) with <= 23.6 mol % L-leucine caused a marginal effect on the pH-mediated hydrophobic association and hemolytic activity. Increasing the degree of grafting from 31.9 to 61.2 mol % resulted in polymers with progressively enhanced hydrophobic association and cell membrane disruption, thus confirming that the pH responsiveness and the extent of hydrophobic association and membrane disruption of the polymers can be modulated by varying the degree of grafting with hydrophobic amino acids. The pH responses were demonstrated to be concentration-dependent. At certain degrees of leucine grafting, the polymers were nonmembrane-lytic at physiological pH but mediated considerable membrane lysis at endosomal pH values (5.0-6.8), a feature critical for potential drug delivery applications. C1 [Chen, Rongjun; Khormaee, Sariah; Slater, Nigel K. H.] Univ Cambridge, Dept Chem Engn & Biotechnol, Cambridge CB2 3RA, England. [Khormaee, Sariah] Natl Inst Neurol Disorders & Stroke, NIH, Surg & Mol Neurooncol Unit, Bethesda, MD 20892 USA. [Eccleston, Mark E.] Vivamer Ltd, Cambridge CB3 0FD, England. RP Slater, NKH (reprint author), Univ Cambridge, Dept Chem Engn & Biotechnol, Pembroke St, Cambridge CB2 3RA, England. EM nkhs2@cam.ac.uk OI Chen, Rongjun/0000-0002-8133-5472 FU Gates Cambridge Trust; Universities UK organizations; National Institute of Neurological Disorders and Stroke, National Institutes of Health; Marshall Aid Commemoration Commission FX Rongjun Chen wishes to thank the Gates Cambridge Trust and the Universities UK organizations for the financial support that enabled this work to be carried out. S.K. is grateful for the support of the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and the Marshall Aid Commemoration Commission. NR 41 TC 9 Z9 9 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD SEP PY 2009 VL 10 IS 9 BP 2601 EP 2608 DI 10.1021/bm900534j PG 8 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 492PO UT WOS:000269671200027 PM 19642668 ER PT J AU Follmann, D Fay, MP Proschan, M AF Follmann, Dean Fay, Michael P. Proschan, Michael TI Chop-Lump Tests for Vaccine Trials SO BIOMETRICS LA English DT Article DE Lachenbruch's test; Permutation; Principal stratification; Rank tests; Semicontinuous data; Sensitivity analysis ID RECOMBINANT GLYCOPROTEIN-120 VACCINE; VIRAL LOAD; EFFICACY; RANDOMIZATION; MALARIA; MODELS; HIV-1; AIDS AB P>This article proposes new tests to compare the vaccine and placebo groups in randomized vaccine trials when a small fraction of volunteers become infected. A simple approach that is consistent with the intent-to-treat principle is to assign a score, say W, equal to 0 for the uninfecteds and some postinfection outcome X > 0 for the infecteds. One can then test the equality of this skewed distribution of W between the two groups. This burden of illness (BOI) test was introduced by Chang, Guess, and Heyse (1994, Statistics in Medicine 13, 1807-1814). If infections are rare, the massive number of 0s in each group tends to dilute the vaccine effect and this test can have poor power, particularly if the X's are not close to zero. Comparing X in just the infecteds is no longer a comparison of randomized groups and can produce misleading conclusions. Gilbert, Bosch, and Hudgens (2003, Biometrics 59, 531-541) and Hudgens, Hoering, and Self (2003, Statistics in Medicine 22, 2281-2298) introduced tests of the equality of X in a subgroup-the principal stratum of those "doomed" to be infected under either randomization assignment. This can be more powerful than the BOI approach, but requires unexaminable assumptions. We suggest new "chop-lump" Wilcoxon and t-tests (CLW and CLT) that can be more powerful than the BOI tests in certain situations. When the number of volunteers in each group are equal, the chop-lump tests remove an equal number of zeros from both groups and then perform a test on the remaining W's, which are mostly > 0. A permutation approach provides a null distribution. We show that under local alternatives, the CLW test is always more powerful than the usual Wilcoxon test provided the true vaccine and placebo infection rates are the same. We also identify the crucial role of the "gap" between 0 and the X's on power for the t-tests. The chop-lump tests are compared to established tests via simulation for planned HIV and malaria vaccine trials. A reanalysis of the first phase III HIV vaccine trial is used to illustrate the method. C1 [Follmann, Dean; Fay, Michael P.; Proschan, Michael] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Follmann, D (reprint author), NIAID, Biostat Res Branch, 6700B Rockledge Dr,MSC 7609, Bethesda, MD 20892 USA. EM dfollmann@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 NR 23 TC 11 Z9 11 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2009 VL 65 IS 3 BP 885 EP 893 DI 10.1111/j.1541-0420.2008.01131.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 494HC UT WOS:000269801400026 PM 19210727 ER PT J AU Luo, S Crainiceanu, CM Louis, TA Chatterjee, N AF Luo, Sheng Crainiceanu, Ciprian M. Louis, Thomas A. Chatterjee, Nilanjan TI Bayesian Inference for Smoking Cessation with a Latent Cure State SO BIOMETRICS LA English DT Article DE Cure model; MCMC; Mixed-effects model; Prediction; Recurrent events; Smoking cessation ID RELAPSE; SURVIVAL; DISEASES; MODEL AB P>We present a Bayesian approach to modeling dynamic smoking addiction behavior processes when cure is not directly observed due to censoring. Subject-specific probabilities model the stochastic transitions among three behavioral states: smoking, transient quitting, and permanent quitting (absorbent state). A multivariate normal distribution for random effects is used to account for the potential correlation among the subject-specific transition probabilities. Inference is conducted using a Bayesian framework via Markov chain Monte Carlo simulation. This framework provides various measures of subject-specific predictions, which are useful for policy-making, intervention development, and evaluation. Simulations are used to validate our Bayesian methodology and assess its frequentist properties. Our methods are motivated by, and applied to, the Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention study, a large (29,133 individuals) longitudinal cohort study of smokers from Finland. C1 [Luo, Sheng] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Biostat, Houston, TX 77459 USA. [Crainiceanu, Ciprian M.; Louis, Thomas A.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Luo, S (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Biostat, 1200 Pressler St, Houston, TX 77459 USA. EM sheng.t.luo@uth.tmc.edu FU National Cancer Institute, National Institutes of Health; [R01 DK061662] FX This work was supported by a predoctoral fellowship to SL from the National Cancer Institute, National Institutes of Health. Support was provided to TAL by grant R01 DK061662. NR 21 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2009 VL 65 IS 3 BP 970 EP 978 DI 10.1111/j.1541-0420.2008.01167.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 494HC UT WOS:000269801400036 PM 19173701 ER PT J AU Worthen, DR Bence, AK Stables, JP Crooks, PA AF Worthen, David R. Bence, Aimee K. Stables, James P. Crooks, Peter A. TI In vivo evaluation of diaminodiphenyls: Anticonvulsant agents with minimal acute neurotoxicity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Diaminodiphenyl analogs; Epilepsy; Anti-seizure drugs; In vivo evaluation; Neurotoxicity; Mouse; Rat ID EPILEPSY; SEIZURES AB Several diaminodiphenyl analogs were assessed in vivo for their capacity to inhibit seizure induction and propagation in rodents. Both 3,4'- and 4,4'-diaminodiphenyl compounds prevented seizures for as long as 4 h after maximal electric shock induction. 4,4'-Diphenyl compounds bridged by a methylene, sulfide, or carbonyl linker also attenuated focal seizure acquisition in a kindling model. Of these analogs, based upon data generated in two rodent species, 4,4'-thiodianiline (1) was identified as the most active compound, significantly reducing seizure staging scores and after-discharge duration for several hours after systemic administration. All compounds were devoid of acute in vivo neurotoxicity at doses well above those required for anticonvulsant activity. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Worthen, David R.; Bence, Aimee K.; Crooks, Peter A.] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA. [Stables, James P.] NIH, Antiepilept Drug Dev Program, Epilepsy Branch, Rockville, MD USA. RP Crooks, PA (reprint author), Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Rose St, Lexington, KY 40536 USA. EM pcrooks@email.uky.edu NR 19 TC 4 Z9 4 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 1 PY 2009 VL 19 IS 17 BP 5012 EP 5015 DI 10.1016/j.bmcl.2009.07.059 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 482DH UT WOS:000268863800026 PM 19632831 ER PT J AU Bharate, SB Guo, LL Reeves, TE Cerasoli, DM Thompson, CM AF Bharate, Sandip B. Guo, Lilu Reeves, Tony E. Cerasoli, Douglas M. Thompson, Charles M. TI New series of monoquaternary pyridinium oximes: Synthesis and reactivation potency for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Organophosphorus; Acetylcholinesterase; Reactivators; Monoquaternary pyridinium oximes; Pralidoxime; 2-PAM ID BISPYRIDINIUM COMPOUNDS BEARING; (E)-BUT-2-ENE LINKER; XYLENE LINKER; NERVE AGENTS; GUINEA-PIG; TABUN; SARIN; CHOLINESTERASE; KINETICS; DESIGN AB The preparation of a series of monoquaternary pyridinium oximes bearing either a heterocyclic side chain or a functionalized aliphatic side chain and the corresponding in vitro evaluation for reactivation of paraoxon-inhibited electric eel acetylcholinesterase (EeAChE) and recombinant human acetylcholinesterase (rHuAChE) are reported. Several newly synthesized compounds efficiently reactivated inhibited EeAChE, but were poor reactivators of inhibited rHuAChE. Compounds bearing a thiophene ring in the side chain (20, 23, 26 and 29) showed better reactivation (24-37% for EeAChE and 5-9% for rHuAChE) compared to compounds with furan and isoxazole heterocycles (0-8% for EeAChE and 2-3% for rHuAChE) at 10(-5) M. The N-pyridyl-CH(2)COOH analog 8 reactivated EeAChE (36%) and rHuAChE (15%) at 10(-4) M with a kr value better than 2-pyridine aldoxime methiodide (2-PAM) for rHuAChE. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Bharate, Sandip B.; Thompson, Charles M.] Univ Montana, Dept Biomed & Pharmaceut Sci, Ctr Struct & Funct Neurosci, NIH,COBRE, Missoula, MT 59812 USA. [Guo, Lilu; Thompson, Charles M.] ATERIS Technol LLC, Missoula, MT 59802 USA. [Reeves, Tony E.; Cerasoli, Douglas M.] USAMRICD, Div Res, Physiol & Immunol Branch, Aberdeen Proving Ground, MD 21010 USA. RP Thompson, CM (reprint author), Univ Montana, Dept Biomed & Pharmaceut Sci, Ctr Struct & Funct Neurosci, NIH,COBRE, Missoula, MT 59812 USA. EM charles.thompson@umontana.edu FU NIH [UO1ES016102, P30-NS055022, P20RR015583]; SBIR [R43 ES016392 U44 NS058229] FX The research in this study was supported by NIH UO1ES016102 (CMT) and SBIR grants to ATERIS Technologies LLC (R43 ES016392 U44 NS058229). Support from the Core Laboratory for Neuromolecular Production (NIH P30-NS055022) and the Center for Structural and Functional Neuroscience (NIH P20RR015583) is appreciated. NR 41 TC 14 Z9 14 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 1 PY 2009 VL 19 IS 17 BP 5101 EP 5104 DI 10.1016/j.bmcl.2009.07.035 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 482DH UT WOS:000268863800047 PM 19640713 ER PT J AU Vaught, J Kelly, A Hewitt, R AF Vaught, Jim Kelly, Andrea Hewitt, Robert TI A Review of International Biobanks and Networks: Success Factors and Key Benchmarks SO BIOPRESERVATION AND BIOBANKING LA English DT Review AB Biobanks and biobanking networks are involved in varying degrees in the collection, processing, storage, and dissemination of biological specimens. This review outlines the approaches that 16 of the largest biobanks and biobanking networks in Europe, North America, Australia, and Asia have taken to collecting and distributing human research specimens and managing scientific initiatives while covering operating costs. Many are small operations that exist as either a single or a few freezers in a research laboratory, hospital clinical laboratory, or pathology suite. Larger academic and commercial biobanks operate to support large clinical and epidemiological studies. Operational and business models depend on the medical and research missions of their institutions and home countries. Some national biobanks operate with a centralized physical biobank that accepts samples from multiple locations. Others operate under a "federated" model where each institution maintains its own collections but agrees to list them on a central shared database. Some collections are "project-driven" meaning that specimens are collected and distributed to answer specific research questions. "General" collections are those that exist to establish a reference collection, that is, not to meet particular research goals but to be available to respond to multiple requests for an assortment of research uses. These individual and networked biobanking systems operate under a variety of business models, usually incorporating some form of partial cost recovery, while requiring at least partial public or government funding. Each has a well-defined biospecimen-access policy in place that specifies requirements that must be met-such as ethical clearance and the expertise to perform the proposed experiments-to obtain samples for research. The success of all of these biobanking models depends on a variety of factors including well-defined goals, a solid business plan, and specimen collections that are developed according to strict quality and operational controls. C1 [Vaught, Jim] NCI, OBBR, NIH, Bethesda, MD 20892 USA. [Kelly, Andrea] Rose Li & Associates Inc, Bethesda, MD USA. [Hewitt, Robert] Integrated Biobank Luxembourg, Luxembourg, Luxembourg. RP Vaught, J (reprint author), NCI, OBBR, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM vaughtj@mail.nih.gov FU US National Cancer Institute [N01-CO-12400]; National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part by Federal funds from the US National Cancer Institute and National Institutes of Health, under Contract Nos. N01-CO-12400 and HHSN261200800001E, respectively. 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. We thank Candice Nulsen for very helpful discussions of this manuscript. NR 7 TC 30 Z9 33 U1 1 U2 15 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD SEP PY 2009 VL 7 IS 3 BP 143 EP 150 DI 10.1089/bio.2010.0003 PG 8 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA 591IX UT WOS:000277294900003 PM 24835880 ER PT J AU Hopkins, RF Esposito, D AF Hopkins, Ralph F. Esposito, Dominic TI A rapid method for titrating baculovirus stocks using the Sf-9 Easy Titer cell line SO BIOTECHNIQUES LA English DT Article DE baculovirus; titrating; green fluorescent protein; GFP; Sf-9 cell line; method ID EXPRESSION VECTORS; INSECT CELLS; PROTEIN; ASSAY; VIRUS AB A new rapid method for titrating baculovirus stocks has been developed using a novel cell line Sf-9 Easy Titer (Sf-9ET). The Sf-9ET cell line has been transfected with plasmid DNA containing the enhanced green fluorescent protein (eGFP) gene under the control of the baculovirus polyhedrin promoter. When used in the titration assay, the Sf-9ET cells turn green when they are infected with baculovirus due to the activation of the polyhedrin promoter/eGFP complex by baculovirus gene products expressed during the infection. Using a 96-well plate format end-point dilution assay, baculovirus titers can be determined in three days using a fluorescence microscope. C1 [Hopkins, Ralph F.; Esposito, Dominic] NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Hopkins, RF (reprint author), NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick, POB B, Frederick, MD 21702 USA. EM hopkinsrf@mail.nih.gov FU National Cancer Institute (NCI) [NO1-CO-12400] FX We are grateful to Veronica Roberts and Cammi Bittner for their technical assistance. This research has been funded in whole or in part by federal funds from the National Cancer Institute (NCI; contract no. NO1-CO-12400). The content of this paper 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. NR 17 TC 30 Z9 30 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD SEP PY 2009 VL 47 IS 3 BP 785 EP 787 DI 10.2144/000113238 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 594ST UT WOS:000277558600010 PM 19852765 ER PT J AU Westerhoff, HV Kell, DB AF Westerhoff, Hans V. Kell, Douglas B. TI Matrix Method for Determining Steps Most Rate-Limiting to Metabolic Fluxes in Biotechnological Processes SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article AB The metabolic control theory developed by Kacser, Burns, Heinrich, and Rapoport is briefly outlined, extended, and transformed so as optimally to address some biotechnological questions. The extensions include (i) a new theorem that relates the control of metabolite concentrations by enzyme activities to flux ratios at branches in metabolic pathways; (ii) a new theorem that does the same for the control of the distribution of the flux over two branches; (iii) a method that expresses these controls into properties (the so-called elasticity coefficients) of the enzymes in the pathway; and (iv) a theorem that relates the effects of changes in metabolite concentrations on reaction rates to the effects of changes in enzyme properties on the same rates. Matrix equations relating the flux control and concentration control coefficients to the elasticity coefficients of enzymes in simple linear and branched pathways incorporating feedback are given, together with their general solutions and a numerical example. These equations allow one to develop rigorous criteria by which to decide the optimal strategy for the improvement of a microbial process. We show how this could be used in deciding which property of which enzyme should be changed in order to obtain the maximal concentration of a metabolite or the maximal metabolic flux. C1 [Westerhoff, Hans V.] NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. [Kell, Douglas B.] Univ Coll Wales, Dept Bot & Microbiol, Aberystwyth SY23 3DA, Dyfed, Wales. RP Westerhoff, HV (reprint author), NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RI Kell, Douglas/E-8318-2011; Westerhoff, Hans/I-5762-2012 OI Kell, Douglas/0000-0001-5838-7963; Westerhoff, Hans/0000-0002-0443-6114 FU Biotechnology Directorate of the Science and Engineering Research Council, U.K. FX D. B. K. thanks the Biotechnology Directorate of the Science and Engineering Research Council, U.K., for financial support. We thank Ms. Mary Lou Miller for the expert typing of the manuscript. NR 12 TC 2 Z9 2 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD SEP 1 PY 2009 VL 104 IS 1 BP 3 EP 9 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 485BZ UT WOS:000269096800002 ER PT J AU Beesdo, K Hofler, M Leibenluft, E Lieb, R Bauer, M Pfennig, A AF Beesdo, Katja Hoefler, Michael Leibenluft, Ellen Lieb, Roselind Bauer, Michael Pfennig, Andrea TI Mood episodes and mood disorders: patterns of incidence and conversion in the first three decades of life SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; community study; conversion; epidemiology; mood episode ID MENTAL-HEALTH SURVEY; COMORBIDITY SURVEY REPLICATION; EARLY DEVELOPMENTAL-STAGES; OF-ONSET DISTRIBUTIONS; GENERAL-POPULATION; BIPOLAR DISORDERS; YOUNG ADULTHOOD; CLINICAL-FEATURES; COMMUNITY SAMPLE; UNIPOLAR MANIA AB Objectives: Significant questions remain regarding both the incidence patterns of mood episodes in adolescents and young adults from the community and the conversion rate from unipolar to bipolar disorders. We addressed these issues by examining data from a prospective longitudinal community study to (i) determine the cumulative incidence of mood episodes and disorders in the first three decades of life; (ii) determine the risk for first onset of depression among individuals with a previous history of hypomanic/manic episodes and vice versa; and (iii) determine the clinical and treatment characteristics of these subjects. Methods: Using the Munich-Composite International Diagnostic Interview, clinically trained interviewers assessed mood episodes and mental disorders in 3,021 community subjects (aged 14-24 at baseline and 21-34 at third follow-up). Results: The estimated cumulative incidence at age 33 was 2.9% for manic, 4.0% for hypomanic, 29.4% for major depressive, and 19.0% for minor depressive episodes; overall, 26.0% had unipolar major depression, 4.0% bipolar depression, 1.5% unipolar mania, and 3.6% unipolar hypomania (no major depression). Overall, 0.6% and 1.8% had unipolar mania or hypomania, respectively, without indication for even minor depression. A total of 3.6% of the initial unipolar major depression cases subsequently developed (hypo)mania, with particularly high rates in adolescent onset depression (< 17 years: 9%). A total of 49.6% of the initial unipolar mania cases subsequently developed major depression and 75.6% major or minor depression. While bipolar cases had more adverse clinical and course depression characteristics and higher treatment rates than unipolar depressed cases, bipolar cases did not significantly differ in mania characteristics from unipolar mania cases. Conclusions: Unipolar and bipolar mood disorders are more frequent than previously thought in adolescence and young adulthood, a time period when both the recognition and the intervention rates by the healthcare system are rather low. 'Conversion' to bipolar disorder is limited in initial unipolar depression, but common in initial unipolar mania. The remaining unipolar mania cases appear to be significant in terms of clinical and course characteristics and thus require more research attention to replicate these findings. C1 [Beesdo, Katja; Hoefler, Michael; Pfennig, Andrea] Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, D-01187 Dresden, Germany. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lieb, Roselind] Max Planck Inst Psychiat, Clin Psychol & Epidemiol, D-80804 Munich, Germany. [Lieb, Roselind] Univ Basel, Basel, Switzerland. [Bauer, Michael; Pfennig, Andrea] Univ Hosp Dresden, Dept Psychiat & Psychotherapy, Dresden, Germany. RP Beesdo, K (reprint author), Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, Chemnitzer Str 46, D-01187 Dresden, Germany. EM beesdo@psychologie.tu-dresden.de RI Beesdo-Baum, Katja/A-5793-2012 FU German Federal Ministry of Education and Research [01EB9405/6, 01EB 9901/6, EB01016200, 01EB0140, 01EB0440]; Deutsche Forschungsgemeinschaft [LA1148/1-1, WI2246/1-1, WI709/7-1, WI709/8-1] FX This work is part of the Early Developmental Stages of Psychopathology (EDSP) study which, is funded by the German Federal Ministry of Education and Research (BMBF; project no. 01EB9405/6, 01EB 9901/6, EB01016200, 01EB0140, and 01EB0440). Part of the field work and analyses were also additionally supported by grants of the Deutsche Forschungsgemeinschaft (DFG; project no. LA1148/1-1, WI2246/1-1, WI709/7-1, and WI709/8-1).Principal investigators of the EDSP study are Hans-Ulrich Wittchen and Roselind Lieb. Both take responsibility for the integrity of the study data. All authors and coauthors had full access to all study data. Data analysis and manuscript preparation were completed by the authors and coauthors of this article, who take responsibility for its accuracy and content. Core staff members of the EDSP group are: Kirsten von Sydow, Gabriele Lachner, Axel Perkonigg, Peter Schuster, Michael Hofler, Holger Sonntag, Tanja Bruckl, Elzbieta Garczynski, Barbara Isensee, Agnes Nocon, Chris Nelson, Hildegard Pfister, Victoria Reed, Barbara Spiegel, Andrea Schreier, Ursula Wunderlich, Petra Zimmermann, Katja Beesdo, and Antje Bittner. Scientific advisors are Jules Angst (Zurich), Jurgen Margraf (Basel), Gunther Esser (Potsdam), Kathleen Merikangas (NIMH, Bethesda), Ron Kessler (Harvard, Boston), and Jim van Os (Maastricht).We thank Hans-Ulrich Wittchen for his helpful comments on earlier versions of this manuscript. NR 41 TC 61 Z9 61 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD SEP PY 2009 VL 11 IS 6 BP 637 EP 649 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 481ZE UT WOS:000268851800006 PM 19689506 ER PT J AU Driver, EC Kelley, MW AF Driver, Elizabeth C. Kelley, Matthew W. TI Specification of Cell Fate in the Mammalian Cochlea SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE Atoh1; haircells; inner ear; auditory system; notch signalling; FGF signalling; hedgehog signalling ID MOUSE INNER-EAR; AUDITORY SENSORY EPITHELIUM; HAIR-CELLS; NOTCH LIGANDS; PROSENSORY DOMAIN; PLACODE INDUCTION; ORGAN DEVELOPMENT; LUNATIC-FRINGE; OTIC PLACODE; CORTI AB Mammalian auditory sensation is mediated by the organ of Corti, a specialized sensory epithelium found in the cochlea of the inner ear. Proper auditory function requires that the many different cell types found in the sensory epithelium be precisely ordered within an exquisitely patterned cellular mosaic. The development of this mosaic depends on a series of cell fate decisions that transform the initially nearly uniform cochlear epithelium into the complex structure of the mature organ of Corti. The prosensory domain, which contains the progenitors of both the mechanosensory hair cells and their associated supporting cells, first becomes distinct from both the neural and the nonsensory domains. Further cell fate decisions subdivide prosensory cells into populations of inner and outer hair cells, and several different types of supporting cells. A number of different signaling pathways and transcription factors are known to be necessary for these developmental processes; in this review, we will summarize these results with an emphasis on recent findings. Birth Defects Research (Part C) 87:212-221, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Driver, Elizabeth C.; Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Driver, EC (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM DriverE@nidcd.nih.gov; Kelleymt@nidcd.nih.gov OI Driver, Elizabeth/0000-0002-5618-1053 FU Intramural NIH HHS [Z01 DC000059-08, Z01 DC000070-01, Z99 DC999999] NR 71 TC 28 Z9 28 U1 2 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-975X J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD SEP PY 2009 VL 87 IS 3 BP 212 EP 221 DI 10.1002/bdrc.20154 PG 10 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 502DZ UT WOS:000270436500002 PM 19750520 ER PT J AU Butler, MG Isogai, S Weinstein, BM AF Butler, Matthew G. Isogai, Sumio Weinstein, Brant M. TI Lymphatic Development SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE Lymphatic; lymphangiogeneis; lymphedema; zebrafish ID LYMPHEDEMA-DISTICHIASIS SYNDROME; GROWTH-FACTOR-D; ENDOTHELIAL-CELLS; VASCULAR DEVELOPMENT; TRANSCRIPTION FACTOR; IN-VIVO; VEGF-C; LYMPHENDOTHELIAL CHARACTERISTICS; EMBRYONIC LYMPHANGIOGENESIS; HEREDITARY LYMPHEDEMA AB The lymphatic system is essential for fluid homeostasis, immune responses, and fat absorption, and is involved in many pathological processes, including tumor metastasis and lymphedema. Despite its importance, progress in understanding the origins and early development of this system has been hampered by lack of defining molecular markers and difficulties in observing lymphatic cells in vivo and performing genetic and experimental manipulation of the lymphatic system. Recent identification of new molecular markers, new genes with important functional roles in lymphatic development, and new experimental models for studying lymphangiogenesis has begun to yield important insights into the emergence and assembly of this important tissue. This review focuses on the mechanisms regulating development of the lymphatic vasculature during embryogenesis. Birth Defects Research (Part C) 87:222-231, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Butler, Matthew G.; Weinstein, Brant M.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Isogai, Sumio] Iwate Med Univ, Dept Anat, Sch Med, Morioka, Iwate 0208505, Japan. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. EM bw96w@nih.gov FU Intramural NIH HHS [Z01 HD008808-01] NR 84 TC 25 Z9 27 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-975X J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD SEP PY 2009 VL 87 IS 3 BP 222 EP 231 DI 10.1002/bdrc.20155 PG 10 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 502DZ UT WOS:000270436500003 PM 19750516 ER PT J AU Duverger, O Morasso, MI AF Duverger, Olivier Morasso, Maria I. TI Epidermal Patterning and Induction of Different Hair Types During Mouse Embryonic Development SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE mouse development; epidermal patterning; hair placode induction; hair shaft development; guard; awl; auchene; zigzag ID HYPOHIDROTIC ECTODERMAL DYSPLASIA; FOLLICLE DEVELOPMENT; ECTODYSPLASIN-A; UNEXPECTED ROLE; TAIL EPIDERMIS; SHH EXPRESSION; BETA-CATENIN; GROWTH CYCLE; EDA GENE; MICE AB An intriguing question in developmental biology is how epidermal pattern formation processes are established and what are the molecular mechanisms involved in these events. The establishment of the pattern is concomitant with the formation of ectodermal appendages, which involves complex interactions between the epithelium and the underlying mesenchyme. Among ectodermal appendages, hair follicles are the "mini organs" that produce hair shafts. Several developmental and structural features are common to all hair follicles and to the hair shaft they produce. However, many different hair types are produced in a single organism. Also, different characteristics can be observed depending on the part of the body where the hair follicle is formed. Here, we review the mechanisms involved in the patterning of different hair types during mouse embryonic development as well as the influence of the body axes on hair patterning. Birth Defects Research (Part C) 87:263-272, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Morasso, Maria I.] NIAMSD, Dev Skin Biol Unit, NIH, Dev Skin Biol Sect, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), NIAMSD, Dev Skin Biol Unit, NIH, Dev Skin Biol Sect, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU National Institute of Arthritis; Musculoskeletal and Skin Diseases at the NIH FX Grant sponsors: Intramural Research Program of the National Institute of Arthritis; Musculoskeletal and Skin Diseases at the NIH NR 66 TC 25 Z9 27 U1 2 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-975X J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD SEP PY 2009 VL 87 IS 3 BP 263 EP 272 DI 10.1002/bdrc.20158 PG 10 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 502DZ UT WOS:000270436500006 PM 19750518 ER PT J AU Li, WJ Kornak, J Harris, TB Keyak, J Li, CX Lu, Y Cheng, XG Lang, T AF Li, Wenjun Kornak, John Harris, Tamara B. Keyak, Joyce Li, Caixia Lu, Ying Cheng, Xiaoguang Lang, Thomas TI Bone fracture risk estimation based on image similarity SO BONE LA English DT Article DE Osteoporosis; Proximal femur; QCT; Mutual information; Image registration ID QUANTITATIVE COMPUTED-TOMOGRAPHY; OSTEOPOROSIS-RELATED FRACTURES; FINITE-ELEMENT MODELS; POSTMENOPAUSAL WOMEN; PROXIMAL FEMUR; HIP FRACTURE; PARATHYROID-HORMONE; MINERAL DENSITY; UNITED-STATES; REGISTRATION AB We propose a fracture risk estimation technique based on image similarity. We employ image similarity indices to determine how images are similar to each other in their 3D bone mineral density distributions. Our premise for fracture risk estimation is that if a given scan is more similar to scans of subjects known to have fractures than to scans of control subjects, this subject is likely to have a higher degree of fracture risk. To test this hypothesis, we analyzed hip QCT scans of 37 patients with hip fractures and 38 age-matched controls. We divided the scans randomly into two groups: the Model Group and the Test Group. For each scan in the Test Group, the difference between the mean value of its image similarities to the Model fracture group and the mean value of its image similarities to the Model control group was used as index of fracture risk. We then used the estimated fracture risk indices to discriminate the fractured patients and controls in the Test Group. A test scan with a larger mean value of image similarities with respect to the Model fracture group was classified as a scan from a fractured patient, otherwise it was classified as a scan from a control subject. Based on ROC analysis, we compared the discrimination performances using image similarity measures with that obtained by using bone mineral density (BMD). When using BMD measured in the femoral neck, with the optimal BMD cutoff, the sensitivity and specificity were 86.5% and 73.7%. For the image similarity measures, the sensitivity ranged between 86.5% and 100%, and specificity ranged between 63.2% and 76.3%. By combining BMD with image similarity measures, the sensitivity and specificity reached 94.6% and 76.3% using linear discriminant analysis (LDA) algorithm, or 91.9% and 81.6% using recursive partitioning and regression trees (RPART) algorithm. In the RPART approach, the AUC value of the ROC curve was 0.923, higher than the AUC value of 0.835 when using BMD alone (p-value: 0.0046). Our results showed that combining BMD with image similarity measures resulted in improved hip fracture risk estimation. (C) 2009 Elsevier Inc. All rights reserved. C1 [Li, Wenjun; Kornak, John; Li, Caixia; Lu, Ying; Lang, Thomas] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Kornak, John; Lu, Ying] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Keyak, Joyce] Univ Calif Irvine, Dept Orthopaed, Irvine, CA 92697 USA. [Cheng, Xiaoguang] Beijing Ji Shui Tan Hosp, Dept Radiol, Beijing, Peoples R China. RP Li, WJ (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. EM wenjun.li@radiology.ucsf.edu RI Lang, Thomas/B-2685-2012 OI Lang, Thomas/0000-0002-3720-8038 FU NASA [NNJ04HF78G]; NIH [NIH-R42-AR45713]; Eli Lilly FX Development of the analytic technique was supported by NASA Grant NNJ04HF78G and NIH grant NIH-R42-AR45713. Acquisition of patients was supported by a grant from Eli Lilly. NR 32 TC 9 Z9 9 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD SEP PY 2009 VL 45 IS 3 BP 560 EP 567 DI 10.1016/j.bone.2009.04.250 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 488VK UT WOS:000269378200023 PM 19414074 ER PT J AU Yu, SJ Kaneko, Y Bae, E Stahl, CE Wang, Y van Loveren, H Sanberg, PR Borlongan, CV AF Yu, Seongjin Kaneko, Yuji Bae, Eunkyung Stahl, Christine E. Wang, Yun van Loveren, Harry Sanberg, Paul R. Borlongan, Cesar V. TI Severity of controlled cortical impact traumatic brain injury in rats and mice dictates degree of behavioral deficits SO BRAIN RESEARCH LA English DT Article DE Head injury; Cortical damage; Locomotor and cognitive behaviors; Animal model ID NEURAL STEM-CELLS; THERAPEUTIC STRATEGY; UNITED-STATES; TRANSPLANTATION; STROKE; RECEPTOR; VOLUME; DEATH AB The clinical presentation of traumatic brain injury (TBI) involves either mild, moderate, or severe injury to the head resulting in long-term and even permanent disability. The recapitulation of this clinical scenario in animal models should allow examination of the pathophysiology of the trauma and its treatment. To date, only a few studies have demonstrated TBI animal models encompassing the three levels of trauma severity. Thus, in the present study we characterized in mice and rats both brain histopathologic and behavioral alterations across a range of injury magnitudes arising from mild, moderate, and severe TBI produced by controlled cortical impact injury technique. Here, we replicated the previously observed TBI severity-dependent brain damage as revealed by 2,3,5-triphenyltetrazolium chloride staining (severe > moderate > mild) in rats, but also extended this pattern of histopathologic changes in mice. Moreover, we showed severity-dependent abnormalities in locomotor and cognitive behaviors in TBI-exposed rats and mice. Taken together, these results support the use of rodent models of TBI as a sensitive platform for investigations of the injury-induced neurostructural and behavioral deficits, which should serve as key outcome parameters for testing experimental therapeutics. (C) 2009 Elsevier B.V. All rights reserved. C1 [van Loveren, Harry; Sanberg, Paul R.; Borlongan, Cesar V.] Univ S Florida, Dept Neurosurg, Tampa, FL 33612 USA. [Yu, Seongjin; Kaneko, Yuji; Bae, Eunkyung; Borlongan, Cesar V.] Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. [Stahl, Christine E.] Dwight D Eisenhower Army Med Ctr, Dept Internal Med, Augusta, GA 30905 USA. [Wang, Yun] NIDA, Neural Protect & Regenerat Sect, NIH, Baltimore, MD 21224 USA. RP Borlongan, CV (reprint author), Univ S Florida, Dept Neurosurg, Tampa, FL 33612 USA. EM cborlong@health.usf.edu RI Kaneko, Yuji/J-6447-2012; OI Borlongan, Cesar/0000-0002-2966-9782 NR 31 TC 64 Z9 65 U1 4 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 1 PY 2009 VL 1287 BP 157 EP 163 DI 10.1016/j.brainres.2009.06.067 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 489XR UT WOS:000269460100016 PM 19573519 ER PT J AU Wayne, SJ Neuhouser, ML Koprowski, C Ulrich, CM Wiggins, C Gilliland, F Baumgartner, KB Baumgartner, RN McTiernan, A Bernstein, L Ballard-Barbash, R AF Wayne, Sharon J. Neuhouser, Marian L. Koprowski, Carol Ulrich, Cornelia M. Wiggins, Charles Gilliland, Frank Baumgartner, Kathy B. Baumgartner, Richard N. McTiernan, Anne Bernstein, Leslie Ballard-Barbash, Rachel TI Breast cancer survivors who use estrogenic botanical supplements have lower serum estrogen levels than non users SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Estrogenic botanical supplements; Serum sex hormones ID POSTMENOPAUSAL CHINESE WOMEN; PHYSICAL-ACTIVITY LEVELS; BLACK COHOSH; ALTERNATIVE MEDICINE; MENOPAUSAL SYMPTOMS; DIETARY ISOFLAVONES; RANDOMIZED-TRIAL; SOY; PHYTOESTROGENS; COMPLEMENTARY AB To measure the association between use of estrogenic botanical supplements and serum sex hormones in postmenopausal breast cancer survivors, a total 502 postmenopausal women were queried 2-3 years after breast cancer diagnosis about their use of botanical supplements, and supplements were categorized according to their estrogenic properties. Concurrently, a fasting blood sample was obtained for assay of estrone, estradiol, free estradiol, testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin. Adjusted means of the serum hormones were calculated by use of estrogenic supplements. Women reporting use of any estrogenic botanical supplement had significantly lower levels of estrone (20.8 vs. 23.6 pg/ml), estradiol (12.8 vs. 14.7 pg/ml), free estradiol (0.29 vs. 0.35 pg/ml), and DHEAS (47.7 vs. 56.2 A mu g/dl) compared to women reporting no use. Data from this cross-sectional study suggest the use of estrogenic botanical supplements may be associated with sex hormone concentrations in breast cancer survivors. Considering the high use of these supplements among breast cancer patients, further research is needed to clarify the relative estrogenicity/antiestrogenicity of these compounds and their relation with prognosis. C1 [Wayne, Sharon J.; Wiggins, Charles] Univ New Mexico, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. [Neuhouser, Marian L.; Ulrich, Cornelia M.; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Koprowski, Carol; Gilliland, Frank] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Baumgartner, Kathy B.; Baumgartner, Richard N.] Univ Louisville, Dept Epidemiol & Populat Hlth, Louisville, KY 40202 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, Bethesda, MD 20892 USA. RP Wayne, SJ (reprint author), Univ New Mexico, New Mexico Tumor Registry, MSC 11 620,1, Albuquerque, NM 87131 USA. EM swayne@salud.unm.edu FU National Cancer Institute [N01-CN-75036-20, N01-CN-05228, N01-PC-67010, N01-PC-35139, N01-PC-67007, N01-PC-35138, N01-PC-67009, N01-PC-35142, T32 CA09661, P30-CA118100]; NIH [M01-RR-00037]; National Institute of Child Health and Human Development [N01-HD-3-3175]; California Department of Health Services [050Q-8709-S1528] FX National Cancer Institute contracts N01-CN-75036-20, N01-CN-05228, N01-PC-67010/N01-PC-35139, N01-PC-67007/N01-PC-35138 and N01-PC-67009/N01-PC-35142, and training grant T32 CA09661. A portion of this work was conducted through the Clinical Research Center at the University of Washington and supported by the NIH grant M01-RR-00037. Data collection for the Women's Contraceptive and Reproductive Experiences Study at the University of Southern California was supported by the National Institute of Child Health and Human Development contract N01-HD-3-3175. Patient identification was supported in part by the California Department of Health Services grant 050Q-8709-S1528. Preparation of this manuscript was supported, in part, by the University of New Mexico Cancer Center, a recipient of NCI Cancer Support Grant P30-CA118100. NR 48 TC 4 Z9 4 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2009 VL 117 IS 1 BP 111 EP 119 DI 10.1007/s10549-008-0224-x PG 9 WC Oncology SC Oncology GA 483XC UT WOS:000269005400014 PM 18931907 ER PT J AU Cronin, KA Ravdin, PM Edwards, BK AF Cronin, Kathleen A. Ravdin, Peter M. Edwards, Brenda K. TI Sustained lower rates of breast cancer in the United States SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Letter ID ESTROGEN; DECREASE; THERAPY C1 [Ravdin, Peter M.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Cronin, Kathleen A.; Edwards, Brenda K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Ravdin, PM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. EM cronink@mail.nih.gov; pmravdin@aol.com NR 5 TC 19 Z9 20 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2009 VL 117 IS 1 BP 223 EP 224 DI 10.1007/s10549-008-0226-8 PG 2 WC Oncology SC Oncology GA 483XC UT WOS:000269005400030 PM 18979196 ER PT J AU Dorjgochoo, T Gao, YT Chow, WH Shu, XO Li, HL Yang, G Cai, QY Rothman, N Cai, H Franke, AA Zheng, W Dai, Q AF Dorjgochoo, Tsogzolmaa Gao, Yu-Tang Chow, Wong-Ho Shu, Xiao-Ou Li, Honglan Yang, Gong Cai, Qiuyin Rothman, Nathaniel Cai, Hui Franke, Adrian A. Zheng, Wei Dai, Qi TI Plasma carotenoids, tocopherols, retinol and breast cancer risk: results from the Shanghai Women Health Study (SWHS) SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Lipophilic antioxidants; Breast cancer; Plasma ID VITAMIN-E; BETA-CAROTENE; SERUM CAROTENOIDS; VEGETABLE CONSUMPTION; UNITED-STATES; DIETARY; LYCOPENE; COHORT; FRUITS; MICRONUTRIENTS AB Evidence from some previous studies suggests that lipophilic antioxidants, particularly carotenoids, may reduce the risk of breast cancer. We prospectively investigated the associations of plasma levels of tocopherols, retinol, carotenoids with the risk of developing breast cancer among Chinese women. We conducted a study of 365 incident breast cancer cases and 726 individually matched controls nested within a large cohort study of women aged 40-70 years at baseline. We observed no associations between breast cancer risk and any of the tocopherols, retinol, and most carotenoids. However, high levels of plasma lycopene other than trans, 5- and 7-cis or trans alpha-cryptoxanthin were inversely associated with the risk of developing breast cancer. Our results do not support an overall protective effect of lipophilic antioxidants on breast cancer risk. The few inverse associations observed for subtype of carotenoids may need to be confirmed in future studies. C1 [Dorjgochoo, Tsogzolmaa; Shu, Xiao-Ou; Yang, Gong; Cai, Qiuyin; Cai, Hui; Zheng, Wei; Dai, Qi] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Chow, Wong-Ho; Rothman, Nathaniel] NCI, US Dept HHS, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gao, Yu-Tang; Li, Honglan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Franke, Adrian A.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Dai, Qi] Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Nashville, TN 37203 USA. RP Dai, Q (reprint author), Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, 6th Floor,Suite 600,2525 W End Ave, Nashville, TN 37203 USA. EM qi.dai@vanderbilt.edu FU USPHS [R01CA106591, R01CA70867]; NIH [N02 CP1101066] FX The authors would like to thank the study participants and Brandy Sue Venuti for technical assistance in the preparation of this manuscript. The authors also thank Cynthia Morrison for the skillful performance of HPLC assays and thank Dr. Bob Cooney for his helpful comments. This study was supported by USPHS grant R01CA106591 as well as USPHS grant R01CA70867 and NIH intramural program (N02 CP1101066) for the parent study. NR 38 TC 16 Z9 16 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2009 VL 117 IS 2 BP 381 EP 389 DI 10.1007/s10549-008-0270-4 PG 9 WC Oncology SC Oncology GA 483XD UT WOS:000269005500019 PM 19096929 ER PT J AU Adams-Campbell, LL Makambi, KH Frederick, WAI Gaskins, M DeWitty, RL McCaskill-Stevens, W AF Adams-Campbell, Lucile L. Makambi, Kepher H. Frederick, Wayne A. I. Gaskins, Melvin DeWitty, Robert L. McCaskill-Stevens, Worta TI Breast Cancer Risk Assessments Comparing Gail and CARE Models in African-American Women SO BREAST JOURNAL LA English DT Article DE breast cancer; chemoprevention; risk assessment ID INDIVIDUALIZED PROBABILITIES; FAMILY-HISTORY; VALIDATION; TAMOXIFEN AB The Gail model has been used to predict invasive breast cancer risk in women using risk factors of age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of previous benign breast biopsies. However, this model underestimates breast cancer risk in African-American women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in African-American women. In a sample of 883 women who participated in the breast cancer screening program at Howard University Cancer Center, we compared the breast cancer risk estimates from the Gail model and the CARE model. The mean 5-year breast cancer risk was 0.88% (Range: 0.18-6.60%) for the Gail model and 1.29% (Range: 0.20-4.50%) for the CARE model. Using the usual cutoff-point of 1.67% or above for elevated risk, there is a significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar's test, p < 0.0001). For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank-sum test, p < 0.0001). Our results confirm the need for validation of the Gail model in African-Americans and diversity in research. Although these findings are not perfect and perhaps not definitive, they are additive in the discussions during counseling and risk assessment in African-Americans. Furthermore, these findings will be complemented by new technologies such as genomics in refining our ability to assess risk. C1 [Adams-Campbell, Lucile L.; Makambi, Kepher H.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20057 USA. [Adams-Campbell, Lucile L.; Makambi, Kepher H.; Frederick, Wayne A. I.; Gaskins, Melvin; DeWitty, Robert L.] Howard Univ, Ctr Canc, Washington, DC 20059 USA. [Frederick, Wayne A. I.; DeWitty, Robert L.] Howard Univ, Coll Med, Dept Surg, Washington, DC USA. [McCaskill-Stevens, Worta] NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Adams-Campbell, LL (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Med Ctr, 3970 Reservoir Rd NW,E501,Res Bldg, Washington, DC 20057 USA. EM lla9@georgetown.edu FU Minority Based Community Clinical Oncology Program [U10-CA09110] FX This research was supported by the Minority Based Community Clinical Oncology Program grant (U10-CA09110) awarded to Dr. Lucile Adams-Campbell. NR 12 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1075-122X J9 BREAST J JI Breast J. PD SEP-OCT PY 2009 VL 15 BP S72 EP S75 DI 10.1111/j.1524-4741.2009.00824.x PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 498IB UT WOS:000270130000011 PM 19775333 ER PT J AU Chae, JJ Aksentijevich, I Kastner, DL AF Chae, Jae J. Aksentijevich, Ivona Kastner, Daniel L. TI Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE inflammation; genetic disorders; molecular pathogenesis; neutrophils; macrophages ID NF-KAPPA-B; MULTISYSTEM INFLAMMATORY DISEASE; COLD AUTOINFLAMMATORY SYNDROME; RILONACEPT INTERLEUKIN-1 TRAP; CONTAINING APAF1-LIKE PROTEIN; MUCKLE-WELLS-SYNDROME; DEATH-DOMAIN-FOLD; INTERFERON-ALPHA; PYRIN DOMAIN; GENETIC-HETEROGENEITY AB P>Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder characterized by seemingly unprovoked recurrent episodes of fever and serosal, synovial, or cutaneous inflammation. FMF is caused by recessively inherited mutations in MEFV, which encodes pyrin, and most of the mutations are present in the C-terminal end of the protein encoding B30.2 domain. The FMF carrier frequencies are extremely high in several eastern Mediterranean populations. Pyrin is expressed in granulocytes, monocytes, dendritic cells, and synovial fibroblasts. Pyrin regulates caspase-1 activation and consequently interleukin-1 beta production through the interactions of its N-terminal PYRIN domain and C-terminal B30.2 domain with an adaptor protein, apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC) and caspase-1 respectively. Pyrin is cleaved by caspase-1 and the cleaved N-terminal fragment translocates to nucleus and enhances ASC-independent nuclear factor (NF)-kappa B activation through interactions with p65 NF-kappa B and I kappa B-alpha. In addition to the regulatory role of pyrin for caspase-1, the cleavage of pyrin provides an important clue not only in understanding the molecular pathogenesis of FMF but also in developing new therapeutic targets for FMF. C1 [Chae, Jae J.] NIAMSD, Clin Invest Lab, Genet & Genom Branch, Bethesda, MD 20892 USA. RP Chae, JJ (reprint author), NIAMSD, Clin Invest Lab, Genet & Genom Branch, 10 Ctr Dr MSC 1849,Bldg 10,Room 10C211, Bethesda, MD 20892 USA. EM chaej@exchange.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 105 TC 98 Z9 98 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2009 VL 146 IS 5 BP 467 EP 478 DI 10.1111/j.1365-2141.2009.07733.x PG 12 WC Hematology SC Hematology GA 482XK UT WOS:000268923700001 PM 19466978 ER PT J AU Vogiatzi, MG Macklin, EA Trachtenberg, FL Fung, EB Cheung, AM Vichinsky, E Olivieri, N Kirby, M Kwiatkowski, JL Cunningham, M Holm, IA Fleisher, M Grady, RW Peterson, CM Giardina, PJ AF Vogiatzi, Maria G. Macklin, Eric A. Trachtenberg, Felicia L. Fung, Ellen B. Cheung, Angela M. Vichinsky, Elliott Olivieri, Nancy Kirby, Melody Kwiatkowski, Janet L. Cunningham, Melody Holm, Ingrid A. Fleisher, Martin Grady, Robert W. Peterson, Charles M. Giardina, Patricia J. CA Thalassemia Clinical Res Network TI Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE thalassemia; short stature; hypogonadism; endocrinopathies; vitamin D; hypercalciuria ID BETA-THALASSEMIA; IRON OVERLOAD; FINAL HEIGHT; D DEFICIENCY; COMPLICATIONS; INTERMEDIA; ADULTS; HYPOPARATHYROIDISM; POPULATION; SURVIVAL AB P>This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23 center dot 2 years (range 6 center dot 1-75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = -0 center dot 73 +/- 1 center dot 24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12 center dot 8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents. C1 [Vogiatzi, Maria G.; Grady, Robert W.; Giardina, Patricia J.] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Macklin, Eric A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Trachtenberg, Felicia L.] New England Res Inst, Watertown, MA 02172 USA. [Fung, Ellen B.; Vichinsky, Elliott] Childrens Hosp Oakland, Oakland, CA USA. [Cheung, Angela M.; Olivieri, Nancy] Toronto Gen Hosp, Dept Med, Univ Hlth Network, Toronto, ON M5G 1L7, Canada. [Kirby, Melody] Toronto Hosp Sick Children, Toronto, ON, Canada. [Kwiatkowski, Janet L.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Kwiatkowski, Janet L.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Cunningham, Melody; Holm, Ingrid A.] Childrens Hosp Boston, Div Hematol & Oncol, Boston, MA USA. [Fleisher, Martin] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Peterson, Charles M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Vogiatzi, MG (reprint author), Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, 525 E 68th St,Box 103, New York, NY 10065 USA. EM mvogiatz@med.cornell.edu RI Vichinsky, Elliott/F-8541-2011; Macklin, Eric/E-2955-2013; OI Vichinsky, Elliott/0000-0002-0500-9579; Macklin, Eric/0000-0003-1618-3502; Quinn, Charles/0000-0002-2372-2175 FU National Heart, Lung, and Blood Institute; National Institutes of Health [U01-HL-65232, U01-HL-65233, U01-HL-65239, U01-HL-65244, U01-HL-65260, U01-HL-65238, 5K24HL004184-08]; Weill Medical College of Cornell University [K08 HL088231]; NIH-NCRR [UL1-RR024134, M01-RR02172] FX Supported by a cooperative agreement with the National Heart, Lung, and Blood Institute, National Institutes of Health (U01-HL-65232 to Children's Hospital of Philadelphia, U01-HL-65233 to University Health Network Toronto General Hospital, U01-HL-65239 to Children's Hospital and Research Center at Oakland, U01-HL-65244 to Weill Medical College of Cornell University, U01-HL-65260 to Children's Hospital Boston, and U01-HL-65238 to New England Research Institutes). The study was also supported, in part, at Weill Medical College of Cornell University grant K08 HL088231 awarded to Maria G. Vogiatzi, at Children's Hospital of Philadelphia by NIH-NCRR grant UL1-RR024134, and at Children's Hospital Boston by NIH-NCRR grant M01-RR02172 and NIH grant 5K24HL004184-08 to Ellis Neufeld. NR 25 TC 50 Z9 51 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2009 VL 146 IS 5 BP 546 EP 556 DI 10.1111/j.1365-2141.2009.07793.x PG 11 WC Hematology SC Hematology GA 482XK UT WOS:000268923700009 PM 19604241 ER PT J AU Gerecitano, J Portlock, C Moskowitz, C Hamlin, P Straus, D Zelenetz, AD Zhang, ZG Dumitrescu, O Sarasohn, D Lin, D Pappanicholaou, J Cortelli, BM Neylon, E Hamelers, R Wright, J O'Connor, OA AF Gerecitano, John Portlock, Carol Moskowitz, Craig Hamlin, Paul Straus, David Zelenetz, Andrew D. Zhang, Zhigang Dumitrescu, Otilia Sarasohn, Debra Lin, Dorothy Pappanicholaou, Jennifer Cortelli, Barbara M. Neylon, Ellen Hamelers, Rachel Wright, John O'Connor, Owen A. TI Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE bortezomib; follicular lymphoma; mantle cell lymphoma; non-Hodgkin lymphoma; proteasome inhibitor ID PROTEASOME INHIBITOR BORTEZOMIB; NON-HODGKINS-LYMPHOMA; IN-VITRO; CANCER; TRIAL AB P>Twice-weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, P = 0 center dot 02) with no complete remissions (CR) (compared with 18% CR for the twice-weekly schedule). Progression-free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice-weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients. C1 [Gerecitano, John; Portlock, Carol; Moskowitz, Craig; Hamlin, Paul; Straus, David; Zelenetz, Andrew D.; Lin, Dorothy; Pappanicholaou, Jennifer] Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, New York, NY 10021 USA. [Zhang, Zhigang] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Dumitrescu, Otilia; Sarasohn, Debra] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Cortelli, Barbara M.; Neylon, Ellen; Hamelers, Rachel; O'Connor, Owen A.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Wright, John] Natl Canc Inst, Drug Dev Branch, CTEP, Washington Dc, WA USA. [O'Connor, Owen A.] Columbia Univ, Coll Phys & Surg, New York Presbyterian Hosp, Med Ctr, New York, NY USA. RP Gerecitano, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, 1275 York Ave, New York, NY 10021 USA. EM gerecitj@mskcc.org RI Sarasohn, Debra/A-1863-2010; OI Hamelers, Rachel/0000-0003-4448-605X; Sarasohn, Debra/0000-0002-8790-5528; Zelenetz, Andrew/0000-0003-1403-6883 FU NCI Phase II [UO1 CA 69913]; CTEP; Lymphoma Research Foundation for Mantle Cell Lymphoma FX This trial was supported under an NCI Phase II grant (UO1 CA 69913) and supervised by CTEP, and the study drug was obtained through CTEP. This study was supported in part by a grant from the Lymphoma Research Foundation for Mantle Cell Lymphoma. NR 15 TC 33 Z9 33 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2009 VL 146 IS 6 BP 652 EP 655 DI 10.1111/j.1365-2141.2009.07775.x PG 4 WC Hematology SC Hematology GA 490WG UT WOS:000269538200007 PM 19624539 ER PT J AU Parascandola, J AF Parascandola, John TI Quarantining Women: Venereal Disease Rapid Treatment Centers in World War II America SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Editorial Material DE venereal disease; syphilis; quarantine; World War II; Public Health Service ID INTRAVENOUS DRIP METHOD; EARLY SYPHILIS; ARSENOTHERAPY AB Concern about the infection of servicemen and essential war workers with venereal disease led the U.S. Public Health Service, with the cooperation of state and local health officials, to set up a national program of venereal disease quarantine hospitals during World War II. Although some of the hospitals eventually accepted men, the initial purpose of these facilities was to detain and treat venereally affected prostitutes and "promiscuous women" who were considered a threat to the war effort. Using quarantine powers, officials forcibly detained venereally infected women and treated them for their disease. The hospitals were generally known as "rapid treatment centers" because of the methods employed to treat venereal disease. Health officials were especially concerned that prostitutes (and other women of "loose morals") would not comply with the traditional lengthy and arduous treatment for syphilis, which involved weekly injections of arsenical drugs for a year or more and unpleasant side effects. Therefore, the newly established quarantine hospitals used recently developed rapid treatment methods based on the administration of multiple injections or intravenous drips of arsenicals over a period of days. Although some objections were raised against these policies, which obviously discriminated against women, on the whole the rapid treatment centers were accepted as a necessary measure in the defense of national security. Some of the issues raised by these centers are still relevant to public health policy today. C1 [Parascandola, John] Univ Wisconsin, Hist Med Div, Natl Lib Med, Madison, WI 53706 USA. RP Parascandola, J (reprint author), 11503 Patapsco Dr, Rockville, MD 20852 USA. NR 78 TC 1 Z9 1 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD FAL PY 2009 VL 83 IS 3 BP 431 EP 459 PG 29 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 502FW UT WOS:000270442100001 PM 19801792 ER PT J AU Sappol, M AF Sappol, Michael TI The Odd Case of Charles Knowlton: Anatomical Performance, Medical Narrative, and Identity in Antebellum America SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Article DE Anatomy; narrative; bodysnatching; professional identity; Charles Knowlton; case history; freethought; dissection; medical pranks; grave robbery ID HISTORY; PHYSICIANS AB In early-nineteenth-century America, anatomical narrative was crucial to the acquisition and performance of medical identity. Dissecting the dead, robbing graves, making and exhibiting "anatomical preparations," and joking with bodies and body parts all served to affirm membership in the cult of medical knowledge. So did telling stories about such things. Through an examination of the autobiography of Charles Knowlton (1800-1850), a rural physician who practiced in northwestern Massachusetts, this article argues that the recitation and exchange of anatomical stories enabled medical practitioners to assert professional identity, healing competence, and filiations with theories and cliques. In both content and performance, the anatomical tale rehearsed the storyteller's structural relationship to patients, the public, colleagues and rivals, and, above all, made a claim to knowledge and mastery of the body. C1 NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Sappol, M (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM sappolm@mail.nih.gov NR 98 TC 3 Z9 3 U1 0 U2 2 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD FAL PY 2009 VL 83 IS 3 BP 460 EP 498 PG 39 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 502FW UT WOS:000270442100002 PM 19801793 ER PT J AU Pisle, ST Figg, WD AF Pisle, Stephen T. Figg, William D. TI Antiandrogens in the 21st century SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE prostate cancer; androgen deprivation therapy; antiandrogen C1 [Pisle, Stephen T.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 5AO1,MSC 1910, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 5 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP 1 PY 2009 VL 8 IS 17 BP 1614 EP 1614 PG 1 WC Oncology SC Oncology GA 514VQ UT WOS:000271424500009 ER PT J AU Howe, HL Lake, A Schymura, MJ Edwards, BK AF Howe, Holly L. Lake, Andrew Schymura, Maria J. Edwards, Brenda K. TI Indirect method to estimate specific Hispanic group cancer rates SO CANCER CAUSES & CONTROL LA English DT Article DE Neoplasms; Cancer; Cancer surveillance; United States Hispanic; United States Latinos; Cancer epidemiology ID UNITED-STATES; POPULATIONS AB Several states with large Hispanic populations have historically served as the source for US Hispanic cancer incidence rates, with aggregation of data across all states limited by different methodologies to identify Hispanic persons. Now with data available for more than 85% of the US Hispanic population, state rates suggest regional diversity in their Hispanic cancer profiles. We tested an approach of using a surrogate indicator of county residential homogeneity for Hispanic groups based on the 2000 US Census. The indicator used the counts of specific Hispanic residents compared to the total Hispanic population in the county to define counties with homogenous Hispanic populations. From these data, we aggregated counties into homogeneity categories for each Hispanic group and defined thresholds and rules for allocating Hispanic persons to a specific Hispanic group. We found that it was possible to use county demographic data in many counties to meaningfully attribute a specific Hispanic ethnicity to incident cancer cases based on homogeneity thresholds. Cancer rates for the US Hispanic population describe a profile of high rates of cancers of the liver, gallbladder, cervix (in female), stomach, and lower rates of the cancers of the lung, female breast, and prostate compared with the non-Hispanic white population. In general, rates among US Mexicans are lower than the US Hispanic rates, while rates for Puerto Ricans and Cubans are higher than the US Hispanic rates. Additional variations among the three Hispanic groups were also evident. The approach yielded reasonable and useful information to explore etiologic differences among the populations, as well as to develop relevant cancer control interventions. However, direct identification of specific Hispanic ethnicity in medical records and annual Census estimates of these populations would be preferable if they ever became available. C1 [Howe, Holly L.] N Amer Assoc Cent Canc Registries Inc, Springfield, IL USA. [Lake, Andrew] Informat Management Serv Inc, Silver Spring, MD USA. [Schymura, Maria J.] New York State Dept Hlth, Albany, NY USA. [Edwards, Brenda K.] NCI, Bethesda, MD 20892 USA. RP Howe, HL (reprint author), 550 Jackson Ave Apt 302, Cape Canaveral, FL 32920 USA. EM hlhowe@cfl.rr.com NR 20 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2009 VL 20 IS 7 BP 1215 EP 1226 DI 10.1007/s10552-009-9398-8 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 480ZF UT WOS:000268775300018 PM 19609690 ER PT J AU Ramanathan, RK Belani, CP Singh, DA Tanaka, M Lenz, HJ Yen, Y Kindler, HL Iqbal, S Longmate, J Mack, PC Lurje, G Gandour-Edwards, R Dancey, J Gandara, DR AF Ramanathan, Ramesh K. Belani, Chandra P. Singh, Deepti A. Tanaka, Michael Lenz, Heinz-Josef Yen, Yun Kindler, Hedy L. Iqbal, Syma Longmate, Jeff Mack, Philip C. Lurje, Georg Gandour-Edwards, Regina Dancey, Janet Gandara, David R. TI A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Lapatinib; Phase II study; Hepatocellular cancer; Biliary tree cancer ID CLINICAL-TRIALS; BREAST-CANCER; INTRON 1; CARCINOMA; ERLOTINIB; CHOLANGIOCARCINOMA; EXPRESSION; INHIBITOR; MUTATIONS; CELLS AB To evaluate the response to lapatinib, an inhibitor of epidermal growth factor receptors 1 and 2, in patients with advanced bilary tree cancer (BTC) and hepatocellular cancer (HCC). Lapatinib was dosed at 1,500 mg/day orally continuously. Fifty-seven patients were accrued (BTC 17, HCC 40). Therapy was well tolerated. The response in BTC was 0% and in HCC was 5%. The progression free survival (PFS) for BTC and HCC patients was 1.8 (95% CI: 1.7-5.2) months and 2.3 (95% CI: 1.7-5.6) months. The median survival for BTC and HCC patients was 5.2 (95% CI 3.3-a) months and 6.2 (95% CI: 5.1-a) months. EGFR genotyping indicated HCC patients with < 20 repeats have the lowest PFS. The occurrence of any skin rash significantly prolonged PFS and survival. Lapatinib was well-tolerated. There was evidence of activity in HCC, but therapy with lapatinib did not meet the predefined efficacy rate. C1 [Ramanathan, Ramesh K.] Scottsdale Clin Res Inst, Scottsdale, AZ 85258 USA. [Ramanathan, Ramesh K.; Belani, Chandra P.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Singh, Deepti A.; Kindler, Hedy L.] Univ Chicago, Chicago, IL 60637 USA. [Tanaka, Michael; Mack, Philip C.; Gandour-Edwards, Regina; Gandara, David R.] Univ Calif, Davis Canc Ctr, Sacramento, CA USA. [Lenz, Heinz-Josef; Iqbal, Syma; Lurje, Georg] Univ So Calif, Norris Canc Ctr, Los Angeles, CA USA. [Yen, Yun; Longmate, Jeff] City Hope Natl Canc Ctr, Duarte, CA USA. [Dancey, Janet] NCI, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20892 USA. RP Ramanathan, RK (reprint author), Scottsdale Clin Res Inst, 10510 N 92nd St,Suite 200, Scottsdale, AZ 85258 USA. EM rramanathan@tgen.org OI Belani, Chandra/0000-0001-5049-5329; Longmate, Jeffrey/0000-0002-0869-7928 FU NCI NIH HHS [N01-CM-57018-16, P30 CA47904]; NCRR NIH HHS [5M01 RR 00056] NR 30 TC 108 Z9 116 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2009 VL 64 IS 4 BP 777 EP 783 DI 10.1007/s00280-009-0927-7 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 476XI UT WOS:000268479700015 PM 19169683 ER PT J AU Pavlick, AC Wu, J Roberts, J Rosenthal, MA Hamilton, A Wadler, S Farrell, K Carr, M Fry, D Murgo, AJ Oratz, R Hochster, H Liebes, L Muggia, F AF Pavlick, Anna C. Wu, Jennifer Roberts, John Rosenthal, Mark A. Hamilton, Anne Wadler, Scott Farrell, Kathleen Carr, Michelle Fry, David Murgo, Anthony J. Oratz, Ruth Hochster, Howard Liebes, Leonard Muggia, Franco TI Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Bryostatin 1; Melanoma; Protein kinase C; Cisplatin ID CARCINOMA-CELLS; PKC-ETA; ONCOLOGY-GROUP; TRIAL; CIS-DIAMMINEDICHLOROPLATINUM(II); EXPRESSION; MELANOMA; CANCER; PROLIFERATION; RESISTANCE AB Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 mu g/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved. C1 [Pavlick, Anna C.; Wu, Jennifer; Rosenthal, Mark A.; Hamilton, Anne; Farrell, Kathleen; Carr, Michelle; Fry, David; Oratz, Ruth; Hochster, Howard; Liebes, Leonard; Muggia, Franco] NYU, Sch Med, Inst Canc, New York, NY 10003 USA. [Wadler, Scott] Montefiore Med Ctr, Bronx, NY 10467 USA. [Roberts, John] Virginia Commonwealth Univ, Med Coll Virginia, Massey Canc Ctr, Richmond, VA 23298 USA. [Murgo, Anthony J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Muggia, F (reprint author), NYU, Sch Med, Inst Canc, New York, NY 10003 USA. EM muggif01@med.nyu.edu OI Muggia, Franco/0000-0003-0703-9146 FU NCI NIH HHS [U01 CA076642, P30 CA016087, U01 CA76642, P30 CA16087]; NCRR NIH HHS [M01 RR00096, M01 RR000096] NR 41 TC 18 Z9 18 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2009 VL 64 IS 4 BP 803 EP 810 DI 10.1007/s00280-009-0931-y PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 476XI UT WOS:000268479700018 PM 19221754 ER PT J AU Roth, MJ Wei, WQ Baer, J Abnet, CC Wang, GQ Sternberg, LR Warner, AC Johnson, LL Lu, N Giffen, CA Dawsey, SM Qiao, YL Cherry, J AF Roth, Mark J. Wei, Wen-Qiang Baer, Jessica Abnet, Christian C. Wang, Guo-Qing Sternberg, Lawrence R. Warner, Andrew C. Johnson, Laura Lee Lu, Ning Giffen, Carol A. Dawsey, Sanford M. Qiao, You-Lin Cherry, James TI Aryl Hydrocarbon Receptor Expression Is Associated with a Family History of Upper Gastrointestinal Tract Cancer in a High-Risk Population Exposed to Aromatic Hydrocarbons SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN ESOPHAGEAL MUCOSA; TOBACCO-SMOKE; COLORECTAL-CANCER; CYTOCHROMES P450; SHANXI-PROVINCE; HUMAN LUNG; IN-VIVO; CHINA; LINXIAN AB Background: Polycyclic aromatic hydrocarbon (PAH) exposure is a risk factor for esophageal squamous cell carcinoma, and PAHs are ligands of the aryl hydrocarbon receptor (AhR). This study measured the expression of AhR and related genes in frozen esophageal cell samples from patients exposed to different levels of indoor air pollution, who did or did not have high-grade squamous dysplasia and who did or did not have a family history of upper gastrointestinal tract (UGI) cancer. Methods: 147 samples were evaluated, including 23 (16%) from patients with high-grade dysplasia and 48 (33%) from patients without dysplasia who heated their homes with coal, without a chimney (a "high" indoor air pollution group), and 27 (18%) from patients with high-grade dysplasia and 49 (33%) from patients without dysplasia who did not heat their homes at all (a "low" indoor air pollution group). Sixty-four (44%) had a family history of UGI cancer. RNA was extracted and quantitative PCR analysis was done. Results: AhR gene expression was detectable in 85 (58%) of the samples and was >9-fold higher in those with a family history of UGI cancer [median expression (interquartile range), -1,964 (-18,000, -610) versus -18,000 (-18,000, -1036); P = 0.02, Wilcoxon rank-sum test]. Heating status, dysplasia category, age, gender, and smoking were not associated with AhR expression (linear regression; all P values >= 0.1). Conclusion: AhR expression was higher in patients with a family history of UGI cancer. Such individuals may be more susceptible to the deleterious effects of PAH exposure, including PAH-induced cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2391-6) C1 [Roth, Mark J.; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Johnson, Laura Lee] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Wei, Wen-Qiang; Qiao, You-Lin] Chinese Acad Med Sci, Dept Canc Epidemiol, Beijing 100037, Peoples R China. [Wang, Guo-Qing] Chinese Acad Med Sci, Dept Endoscopy, Beijing 100037, Peoples R China. [Lu, Ning] Chinese Acad Med Sci, Dept Pathol, Inst Canc, Beijing 100037, Peoples R China. [Baer, Jessica; Cherry, James] Sci Applicat Int Corp Frederick Inc, Natl Canc Inst Frederick, Lab Mol Technol, Frederick, MD USA. [Sternberg, Lawrence R.; Warner, Andrew C.] Sci Applicat Int Corp Frederick Inc, Pathol & Histotechnol Lab, Frederick, MD USA. [Giffen, Carol A.] Informat Management Serv Inc, Silver Spring, MD USA. RP Roth, MJ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320,MSC 7232, Bethesda, MD 20892 USA. EM mr166i@nih.gov RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU National Cancer Institute/NIH [N01-CO-12400, N01-RC-91019]; NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX National Cancer Institute/NIH contracts N01-CO-12400 and N01-RC-91019 and Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 45 TC 9 Z9 9 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2009 VL 18 IS 9 BP 2391 EP 2396 DI 10.1158/1055-9965.EPI-08-1098 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 493KA UT WOS:000269734100008 PM 19690180 ER PT J AU Watters, JL Park, Y Hollenbeck, A Schatzkin, A Albanes, D AF Watters, Joanne L. Park, Yikyung Hollenbeck, Albert Schatzkin, Arthur Albanes, Demetrius TI Cigarette Smoking and Prostate Cancer in a Prospective US Cohort Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MIDDLE-AGED MEN; SEX-HORMONES; FOLLOW-UP; HEALTH-PROFESSIONALS; ALCOHOL-CONSUMPTION; DIETARY-INTAKE; GROWTH-FACTORS; RISK-FACTORS; ASSOCIATION; MORTALITY AB Smoking is an important risk factor for many cancers, yet the relationship between smoking and prostate cancer remains uncertain. We investigated whether smoking affected the risk of prostate cancers within a large prospective cohort study of dietary and environmental cancer risk factors among men ages 50 to 71 upon enrollment in 1995-1996 (n = 283,312). Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (95% CI) were adjusted for age, race, education, height, body mass index, physical activity, family history of prostate cancer, diabetes, self-reported health status, prostate-specific antigen testing, digital rectal exam, total energy, alpha-tocopherol, calcium, alpha-linolenic acid, selenium, red meat, fish, and tomato intake. There were 14,810 nonadvanced and 1,830 advanced incident prostate cancers identified through 2003, and 394 men died of their disease through 2005. Current smokers had a decreased risk of nonadvanced prostate cancer (HR, 0.82; 95% CI, 0.77-0.88), but an increased risk of fatal prostate cancer (HR, 1.69; 95% CI, 1.25-2.27). Former smoking was also associated with decreased risk of nonadvanced prostate cancers (HR, 0.89; 95% CI, 0.86-0.92), but not fatal prostate cancers (HR, 1.03; 95% CI, 0.83-1.27). There was no apparent association between smoking and advanced prostate cancer. A number of biologically plausible mechanisms could explain these results, including the direct effects of carcinogens in tobacco smoke and the resulting changes in sex hormone or growth factor profiles. These findings suggest that current and former smokers may be at decreased risk of being diagnosed with prostate cancer and current smokers are at an increased risk of dying from prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(9): 2427-35) C1 [Watters, Joanne L.; Park, Yikyung; Schatzkin, Arthur; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Watters, JL (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS,Suite 320, Bethesda, MD 20892 USA. EM wattersj@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS [Z99 CA999999] NR 39 TC 35 Z9 35 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2009 VL 18 IS 9 BP 2427 EP 2435 DI 10.1158/1055-9965.EPI-09-0252 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 493KA UT WOS:000269734100013 PM 19706848 ER PT J AU Kirchhoff, T Chen, ZQ Gold, B Pal, P Gaudet, MM Kosarin, K Levine, DA Gregersen, P Spencer, S Harlan, M Robson, M Klein, RJ Hudis, CA Norton, L Dean, M Offit, K AF Kirchhoff, Tomas Chen, Zhang-qun Gold, Bert Pal, Prodipto Gaudet, Mia M. Kosarin, Kristi Levine, Douglas A. Gregersen, Peter Spencer, Sara Harlan, Megan Robson, Mark Klein, Robert J. Hudis, Clifford A. Norton, Larry Dean, Michael Offit, Kenneth TI The 6q22.33 Locus and Breast Cancer Susceptibility SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; CONFER SUSCEPTIBILITY; COMMON VARIANTS; RISK; EXPRESSION; TWINS; POPULATION; INHIBITION; MUTATIONS; APOPTOSIS AB Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptorpositive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2468-75) C1 [Kirchhoff, Tomas; Pal, Prodipto; Kosarin, Kristi; Spencer, Sara; Harlan, Megan; Robson, Mark; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, New York, NY 10065 USA. [Gaudet, Mia M.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Klein, Robert J.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Hudis, Clifford A.; Norton, Larry] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Breast Med Serv, New York, NY 10065 USA. [Gold, Bert; Dean, Michael] NCI Frederick, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD USA. [Gregersen, Peter] N Shore Long Isl Jewish Res Inst, Ctr Genom & Human Genet, Manhasset, NY USA. [Chen, Zhang-qun] SAIC Frederick, Basic Sci Program, Human Genet Sect, Frederick, MD USA. RP Kirchhoff, T (reprint author), Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, 1275 York Ave, New York, NY 10065 USA. EM kirchhot@mskcc.org RI Dean, Michael/G-8172-2012; Klein, Robert/K-1888-2013; OI Dean, Michael/0000-0003-2234-0631; Klein, Robert/0000-0003-3539-5391; Norton, Larry/0000-0003-3701-9250; Kirchhoff, Tomas/0000-0002-9055-2364; Robson, Mark/0000-0002-3109-1692 FU Center for Cancer Research; National Cancer Institute; National Institute of Health; Breast Cancer Research Foundation [13740]; Susan Komen Foundation [RO1-BCTR0601361]; Lymphoma Foundation; Niehaus, Southworth, Weissenbach Cancer Research; [HHSN261200900001E] FX This project has been funded in whole or in part with federal funds from the Center for Cancer Research, National Cancer Institute, National Institute of Health, and Contract No. HHSN261200900001E. The content of this publication does not necessarily reflect the views of the Department of Health and Human Services nor does its mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This research was also supported by the Breast Cancer Research Foundation grant 13740 (K. Offit), the Susan Komen Foundation RO1-BCTR0601361 (K. Offit), the Lymphoma Foundation, and the Niehaus, Southworth, Weissenbach Cancer Research Fund. NR 29 TC 21 Z9 22 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 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2009 VL 18 IS 9 BP 2468 EP 2475 DI 10.1158/1055-9965.EPI-09-0151 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 493KA UT WOS:000269734100019 PM 19690183 ER PT J AU Xi, LF Edelstein, ZR Meyers, C Ho, J Cherne, SL Schiffman, M AF Xi, Long Fu Edelstein, Zoe R. Meyers, Craig Ho, Jesse Cherne, Stephen L. Schiffman, Mark TI Human Papillomavirus Types 16 and 18 DNA Load in Relation to Coexistence of Other Types, Particularly Those in the Same Species SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID VIRUS-LIKE PARTICLES; CERVICAL INTRAEPITHELIAL NEOPLASIA; CELLULAR IMMUNE-RESPONSES; ATYPICAL SQUAMOUS-CELLS; NONVACCINE HPV TYPES; CARCINOMA IN-SITU; AGED 16-26 YEARS; VIRAL LOAD; YOUNG-WOMEN; UNDETERMINED SIGNIFICANCE AB Background: Infection with multiple human papillomavirus (HPV) types is common. However, it is unknown whether viral DNA load is related to the coexistence of other types. Methods: Study subjects were 802 and 303 women who were positive for HPV16 and HPV18, respectively, at enrollment into the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study. HPV16 and HPV18 E7 copies per nanogram of cellular DNA in cervical swab samples were measured by real-time PCR in triplicate. Results: Concurrent coinfection was common in this population of women with minor cervical lesions; multiple HPV types were detected in 573 (71.4%) of 802 HPV16-positive women and 227 (74.9%) of 303 HPV18-positive women. The adjusted odds ratio associating co-infection with per I log unit increase in HPV16 DNA load was 0.78 (95% confidence interval, 0.68-0.89); it was 0.64 (95% confidence interval, 0.52-0.79) for a similar analysis of HPV18 DNA load. Women with, compared with without, coinfection of A9 species types possessed a significantly lower HPV16 DNA load (P < 0.001), whereas women with, compared with without, coinfection of A7 species types possessed a significantly lower HPV18 DNA load (P = 0.001). A trend of decrease in HPV16 DNA load with increasing number of the coexisting non-HPV16 A9 species types was statistically significant (P(trend) = 0.001) Conclusion: Coinfection with other types was associated with lower HPV16 and HPV18 DNA load. The extent of reduction was correlated to phylogenetic distance of the coexisting types to HPV16 and HPV18, respectively. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2507-12) C1 [Xi, Long Fu; Ho, Jesse; Cherne, Stephen L.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Xi, Long Fu; Edelstein, Zoe R.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Meyers, Craig] Penn State Coll Med, Dept Microbiol & Immunol, Hershey, PA USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Xi, LF (reprint author), Northgate Execut Ctr 1,Bldg B,155 NE 100th St,Sui, Seattle, WA 98125 USA. EM longfu@u.washington.edu FU Public Health Service [CA 84396] FX Public Health Service grant CA 84396 (L. F. Xi). NR 40 TC 10 Z9 10 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 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2009 VL 18 IS 9 BP 2507 EP 2512 DI 10.1158/1055-9965.EPI-09-0482 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 493KA UT WOS:000269734100024 PM 19690188 ER PT J AU Worschech, A Haddad, D Stroncek, DF Wang, E Marincola, FM Szalay, AA AF Worschech, Andrea Haddad, D. Stroncek, D. F. Wang, E. Marincola, Francesco M. Szalay, Aladar A. TI The immunologic aspects of poxvirus oncolytic therapy SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Vaccinia virus; Oncolytic therapy; Innate immunity; Tumor rejection ID NATURAL-KILLER-CELLS; VACCINIA-VIRUS; INTERFERON-GAMMA; IMMUNE-RESPONSE; INNATE IMMUNITY; T-CELLS; SPECIES-SPECIFICITY; ANTITUMOR IMMUNITY; CANCER-THERAPY; TUMOR-CELLS AB The concept of using replicating oncolytic viruses in cancer therapy dates to the beginning of the twentieth century. However, in the last few years, an increasing number of pre-clinical and clinical trials have been carried out with promising preliminarily results. Novel, indeed, is the suggestion that viral oncolytic therapy might not operate exclusively through an oncolysis-mediated process but additionally requires the "assistance" of the host's immune system. Originally, the host's immune response was believed to play a predominant obstructive role against viral replication, hence limiting the anti-tumor efficacy of viral vectors. Recent data, however, suggest that the immune response may also play a key role in promoting tumor destruction in association with the oncolytic process. In fact, immune effector pathways activated during oncolytic virus-induced tumor rejection seem to follow a similar pattern to those observed when the broader phenomenon of immune-mediated tissue-specific rejection occurs in other immune-related pathologies. We recently formulated the "Immunologic Constant of Rejection" hypothesis, emphasizing commonalties in transcriptional patterns observed when tissue-destruction occurs: whether with a favorable outcome, such as in tumor rejection and pathogen clearance; or a destructive one, such as in allograft rejection or autoimmunity. Here, we propose that a similar mechanism induces clearance of virally infected tumors and that such a mechanism is primarily dependent on innate immune functions. C1 [Worschech, Andrea; Haddad, D.; Szalay, Aladar A.] Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA. [Worschech, Andrea; Wang, E.; Marincola, Francesco M.] NIH, CHI, Ctr Clin, Bethesda, MD 20892 USA. [Worschech, Andrea; Wang, E.; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Bethesda, MD 20892 USA. [Worschech, Andrea; Haddad, D.; Szalay, Aladar A.] Univ Wurzburg, Inst Biochem, Virchow Ctr Expt Biomed, Wurzburg, Germany. [Haddad, D.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Stroncek, D. F.] NIH, Cell Therapy Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Szalay, AA (reprint author), Genelux Corp, San Diego Sci Ctr, 3030 Bunker Hill St,Suite 310, San Diego, CA 92109 USA. EM worschecha@mail.nih.gov; Fmarincola@mail.cc.nih.gov; aaszalay@genelux.com RI Worschech, Andrea/I-3919-2012; OI Worschech, Andrea/0000-0002-4303-8653; Haddad, Dana/0000-0002-8176-0102 FU Genelux Co. FX This work was supported by Genelux Co. NR 72 TC 24 Z9 24 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD SEP PY 2009 VL 58 IS 9 BP 1355 EP 1362 DI 10.1007/s00262-009-0686-7 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA 462XG UT WOS:000267391100001 PM 19266198 ER PT J AU Fojo, T AF Fojo, Tito TI Monitoring of Therapeutic Response to Cancer Treatment SO CANCER JOURNAL LA English DT Editorial Material C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD SEP-OCT PY 2009 VL 15 IS 5 BP 352 EP 353 PG 2 WC Oncology SC Oncology GA 508GQ UT WOS:000270918300002 PM 19826352 ER PT J AU Vidaurre, T Wilkerson, J Simon, R Bates, SE Fojo, T AF Vidaurre, Tatiana Wilkerson, Julia Simon, Richard Bates, Susan E. Fojo, Tito TI Stable Disease Is Not Preferentially Observed With Targeted Therapies and as Currently Defined Has Limited Value in Drug Development SO CANCER JOURNAL LA English DT Review DE stable disease; targeted therapies; cytotoxic therapies; cancer therapy; clinical trials; drug evaluation; drug assessment; phase II studies; RECIST; WHO criteria; complete response rate; partial response rate; overall response rate; progression free survival; time to progression; overall survival ID RENAL-CELL CARCINOMA; METASTATIC COLORECTAL-CANCER; CHRONIC LYMPHOCYTIC-LEUKEMIA; RECEPTOR TYROSINE KINASE; CLINICAL-TRIAL DESIGNS; PHASE-II TRIAL; ANTICANCER AGENTS; CYTOSTATIC AGENTS; SOLID TUMORS; PHARMACOKINETICS AB The assertion that efficacy of "targeted therapies" (TAR) cannot be assessed by traditional response measures has become conventional wisdom often guiding trial design and interpretation. Because stable disease (SD) has been increasingly reported as a measure of activity even for 11 cytotoxic therapies" (CTX), we sought to compare the occurrence of SD in phase 11 trials of cytotoxic-CTX and TAR. We catalogued response assessments in 143 phase 11 studies reported in 5 journals between October 2006 and March 2008. Eighty-five studies incorporated CTX and 58 administered TAR. Both groups had comparable distribution of histologies and similar progression free survival (PFS) (median 4.8/2.35 months) and OS (median 10.9/9.15 months). SD was defined in only 28.6% of studies (median 10 weeks). SD rates were nearly identical-mean/median 35.05/34.7% for CTX, and 32.3/31.05% for TAR-with similar distributions across histologies, suggesting SD may not reflect drug activity. There were no positive correlations between %SD and PFS or OS. The overall response rate (complete response + partial response) was higher with CTX therapies (mean/median,.18/25% versus 13.1/5.3%) and in both groups overall response rate demonstrated a strong correlation (P < 0.0001) with PFS and OS. As currently defined and measured SD is not a property of TAR but is as frequently found with CTX therapies and may not reflect antitumor activity. Responses are observed with "both classes" of therapy and should be sought as a measure of activity. Studies that use SD as an end point require an adequate control to distinguish antitumor activity from normal variability in time to progression. C1 [Vidaurre, Tatiana; Wilkerson, Julia; Bates, Susan E.; Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Simon, Richard] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, NIH, Bldg 10,RM 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 NR 26 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD SEP-OCT PY 2009 VL 15 IS 5 BP 366 EP 373 PG 8 WC Oncology SC Oncology GA 508GQ UT WOS:000270918300005 PM 19826355 ER PT J AU Wilkerson, J Fojo, T AF Wilkerson, Julia Fojo, Tito TI Progression-Free Survival Is Simply a Measure of a Drug's Effect While Administered and Is Not a Surrogate for Overall Survival SO CANCER JOURNAL LA English DT Review DE progressive-free survival; overall survival; clinical endpoints ID ADVANCED COLORECTAL-CANCER; ADVANCED BREAST-CANCER; PRIMARY END-POINT; PACLITAXEL PLUS BEVACIZUMAB; INDIVIDUAL PATIENT DATA; 18 RANDOMIZED-TRIALS; CELL LUNG-CANCER; PHASE-II TRIALS; CLINICAL-TRIALS; COLON-CANCER AB Since 1992, the Food and Drug Administration has allowed for accelerated approval of cancer drugs in cases where a statistically significant and clinically meaningful improvement in survival or side effect over alternative therapies is clearly demonstrated in controlled randomized trials. To this effect, endpoints other than overall survival (OS) are accepted as surrogate markets for survival. A lack of consensus exists regarding the validity of progression-free survival (PFS) as a true measure Of Outcome due to treatment. To quantitatively evaluate the correlation between the magnitude of the difference in PFS and that of OS in randomized trials conducted in patients with metastatic solid tumors, we performed electronic searches for trials that reported a statistically significant improvement in PFS, OS, or both for I treatment arm over another. We cataloged variables of interest such as the hazard ratio (HR) for PFS and HR for OS from 66 studies that met inclusion criteria and calculated the difference (delta) in response rate (RR), PFS, and OS. We performed linear regressions between the differences in OS and the differences in PFS as well as between both those values and RR. We also examined the correlations of HR for PFS and HR for OS. Regression analysis of both delta PFS/delta OS (R(2) = 0.49; P < 0.0001) and HR PFS/HR OS (R(2) = 0.62 P < 0.0001) showed strong statistical evidence that an increase in PFS is associated with an increase in OS of the same magnitude. Both PFS and OS showed strong association with RR. These results were reinforced when we looked at the 3 largest subgroups by cancer type. We found very little overlap in comparative analyses of genes annotated to terms of cell growth and death. We conclude that PFS is not a surrogate for OS; rather it is a straightforward measure of on-therapy benefit and is not predictive of tumor growth after the cessation of treatment. The magnitude of the improvement in PFS is the magnitude of the improvement in OS. PFS is simply a measure of a drug's effect on tumor growth while it is administered and is not a surrogate for OS. Although PFS should not replace OS in regulatory approval consideration should be given to studies that treat beyond current definitions of progressive disease as a strategy to augment OS. C1 [Wilkerson, Julia; Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 NR 60 TC 28 Z9 28 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD SEP-OCT PY 2009 VL 15 IS 5 BP 379 EP 385 PG 7 WC Oncology SC Oncology GA 508GQ UT WOS:000270918300007 PM 19826357 ER PT J AU Driscoll, JJ Rixe, O AF Driscoll, James J. Rixe, Oliver TI Overall Survival: Still the Gold Standard Why Overall Survival Remains the Definitive End Point in Cancer Clinical Trials SO CANCER JOURNAL LA English DT Review DE overall survival; end point; surrogate; biomarker; targeted therapy ID CELL LUNG-CANCER; RESPONSE EVALUATION CRITERIA; METASTATIC BREAST-CANCER; ACCELERATED APPROVAL; SOLID TUMORS; GEFITINIB; CHEMOTHERAPY; COMBINATION; DRUGS AB Overall survival (OS) is the gold standard primary end point to evaluate the outcome of any drug, biologic, intervention, or procedure that is assessed in oncologic clinical trials. OS is universally recognized as being unambiguous, unbiased, with a defined end point of paramount clinical relevance, and positive results provide confirmatory evidence that a given treatment extends the life of a patient. Clinical trialists relentlessly attempt to devise more easily measured, cost-effective, and readily available event-driven end points as predictive surrogates of a definitive outcome, such as CS, and reduce the time with which clinical trials deliver definitive results. For some treatment modalities used in a limited number of cancer types, certain event-driven surrogates, eg, progression-free survival or time-to-progression may predict OS benefit. Biologic, cell-based, and vaccine-generated treatments are rapidly expanding the oncologist's armamentarium to combat cancers and pose a dilemma in that response may not be reflected by progression-free survival, time-to-progression, or other surrogates? As targeted therapies march forward, will each new therapy require a unique biomarker validated for every disease indication? Moreover, adjuvant treatments have demonstrated efficacy and given the Current limited possibility of cure in the metastatic setting, should other end points, eg, quality-of-life, emerge as valid outcomes to demonstrate benefit. Clinical trials must continue to assess OS until biologically plausible measures are developed and emerge as valid early end point surrogates to replace the gold standard. C1 [Rixe, Oliver] Univ Cincinnati, Coll Med, Div Hematol & Oncol, Cincinnati, OH 45267 USA. [Driscoll, James J.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Rixe, O (reprint author), Univ Cincinnati, Coll Med, Div Hematol & Oncol, 231 Albert Sabin Way ML 0562, Cincinnati, OH 45267 USA. EM olivier.rixe@uc.edu NR 23 TC 17 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD SEP-OCT PY 2009 VL 15 IS 5 BP 401 EP 405 PG 5 WC Oncology SC Oncology GA 508GQ UT WOS:000270918300010 PM 19826360 ER PT J AU Stein, WD Huang, H Menefee, M Edgerly, M Kotz, H Dwyer, A Yang, J Bates, SE AF Stein, Wilfred D. Huang, Hui Menefee, Michael Edgerly, Maureen Kotz, Herb Dwyer, Andrew Yang, James Bates, Susan E. TI Other Paradigms: Growth Rate Constants and Tumor Burden Determined Using Computed Tomography Data Correlate Strongly With the Overall Survival of Patients With Renal Cell Carcinoma SO CANCER JOURNAL LA English DT Review DE RECIST; chemotherapy efficacy; cancer clinical trials; phase II studies; chemotherapy assessment; chemotherapy evaluation ID MICROTUBULE-STABILIZING AGENTS; HIGH-DOSE INTERLEUKIN-2; PHASE-III TRIAL; RADICAL PROSTATECTOMY; INTERFERON ALPHA-2A; DOUBLING TIME; UNITED-STATES; CANCER; EPOTHILONES; PACLITAXEL AB In solid tumors, where curative therapies still elude oncologists, novel paradigms are needed to assess the efficacy of new therapies and those already approved. We used radiologic measurements obtained in patients with metastatic renal cell carcinoma enrolled in a phase II study of the epothilone B analog, ixabepilone (Ixempra), to address this issue. Using a novel 2-phase mathematical equation, we used the radiologic measurements to estimate the concomitant rates of tumor regression and growth (regression and growth rate constants). Eighty-one patients were enrolled on the ixabepilone trial at the time of this analysis. Growth rate constants were determined using computed tomography measurements obtained exclusively while a patient was enrolled on study. The growth rate constants of renal cell carcinomas treated with ixabepilone were significantly reduced compared with those of tumors in patients who received placebo in a previous trial. Furthermore, a correlation with overall survival was found for both the growth rate constant and the initial tumor burden; and this correlation was even stronger when both the growth rate constant and the initial tumor burden were combined. The readily amenable mathematical model described herein has potential applications to many tumor types that can be assessed with imaging modalities. Because the growth rate constant seems to be a surrogate for survival, assessment could aid in the evaluation of relative efficacies of different therapies and perhaps in assessing the potential individual benefit of an experimental therapy. C1 [Stein, Wilfred D.; Huang, Hui; Edgerly, Maureen; Kotz, Herb; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stein, Wilfred D.] Hebrew Univ Jerusalem, Dept Biol Chem, Silberman Inst Life Sci, Jerusalem, Israel. [Menefee, Michael] Mayo Clin, Div Hematol & Oncol, Jacksonville, FL 32224 USA. [Dwyer, Andrew] Natl Inst Hlth, Dept Imaging Sci, Bethesda, MD USA. [Yang, James] Natl Inst Hlth, Surg Oncol Branch, Bethesda, MD USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, NIH, Bldg 10,RM 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov FU NCI NIH HHS [K12 CA090628, K12 CA090628-09] NR 39 TC 10 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD SEP-OCT PY 2009 VL 15 IS 5 BP 441 EP 447 PG 7 WC Oncology SC Oncology GA 508GQ UT WOS:000270918300016 PM 19826366 ER PT J AU Stern, MC Lin, J Figueroa, JD Kelsey, KT Kiltie, AE Yuan, JM Matullo, G Fletcher, T Benhamou, S Taylor, JA Placidi, D Zhang, ZF Steineck, G Rothman, N Kogevinas, M Silverman, D Malats, N Chanock, S Wu, XF Karagas, MR Andrew, AS Nelson, HH Bishop, DT Sak, SC Choudhury, A Barrett, JH Elliot, F Corral, R Joshi, AD Gago-Dominguez, M Cortessis, VK Xiang, YB Gao, YT Vineis, P Sacerdote, C Guarrera, S Polidoro, S Allione, A Gurzau, E Koppova, K Kumar, R Rudnai, P Porru, S Carta, A Campagna, M Arici, C Park, SSL Garcia-Closas, M AF Stern, Mariana C. Lin, Jie Figueroa, Jonine D. Kelsey, Karl T. Kiltie, Anne E. Yuan, Jian-Min Matullo, Giuseppe Fletcher, Tony Benhamou, Simone Taylor, Jack A. Placidi, Donatella Zhang, Zuo-Feng Steineck, Gunnar Rothman, Nathaniel Kogevinas, Manolis Silverman, Debra Malats, Nuria Chanock, Stephen Wu, Xifeng Karagas, Margaret R. Andrew, Angeline S. Nelson, Heather H. Bishop, D. Timothy Sak, Sei Chung Choudhury, Ananya Barrett, Jennifer H. Elliot, Faye Corral, Roman Joshi, Amit D. Gago-Dominguez, Manuela Cortessis, Victoria K. Xiang, Yong-Bing Gao, Yu-Tang Vineis, Paolo Sacerdote, Carlotta Guarrera, Simonetta Polidoro, Silvia Allione, Alessandra Gurzau, Eugen Koppova, Kvetoslava Kumar, Rajiv Rudnai, Peter Porru, Stefano Carta, Angela Campagna, Marcello Arici, Cecilia Park, Sung Shim Lani Garcia-Closas, Montserrat CA Int Consortium Bladder Canc TI Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer SO CANCER RESEARCH LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; XRCC1 POLYMORPHISMS; CHROMOSOMAL-ABERRATIONS; XPC POLYMORPHISMS; EXCISION-REPAIR; SUSCEPTIBILITY; DAMAGE; VARIANTS; GENOTYPE; NAT2 AB Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% Cl, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857-64] C1 [Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Gago-Dominguez, Manuela; Cortessis, Victoria K.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Zhang, Zuo-Feng; Park, Sung Shim Lani] Univ So Calif, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90089 USA. [Zhang, Zuo-Feng; Park, Sung Shim Lani] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Lin, Jie; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Figueroa, Jonine D.; Rothman, Nathaniel; Silverman, Debra; Chanock, Stephen; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kelsey, Karl T.] Brown Univ, Community Hlth Ctr Environm Hlth & Technol, Providence, RI 02912 USA. [Kiltie, Anne E.; Sak, Sei Chung; Choudhury, Ananya] Univ Leeds, Canc Res UK Clin Ctr, Sect Expt Oncol, Leeds, W Yorkshire, England. [Bishop, D. Timothy; Barrett, Jennifer H.; Elliot, Faye] Univ Leeds, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Leeds, W Yorkshire, England. [Yuan, Jian-Min] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Matullo, Giuseppe; Vineis, Paolo; Guarrera, Simonetta; Polidoro, Silvia; Allione, Alessandra] Univ Turin, Inst Sci Interchange Fdn, Turin, Italy. [Matullo, Giuseppe] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Sacerdote, Carlotta] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Sacerdote, Carlotta] Ctr Canc Epidemiol & Prevent CPO Piemonte, Turin, Italy. [Fletcher, Tony] London Sch Hyg & Trop Med, PEHRU Publ & Environm Hlth Res Unit, London WC1, England. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Benhamou, Simone] CEPH, Fdn Jean Dausset, INSERM, U794, Paris, France. [Benhamou, Simone] Inst Gustave Roussy, CNRS, FRE2939, Villejuif, France. [Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Placidi, Donatella; Porru, Stefano; Carta, Angela; Campagna, Marcello; Arici, Cecilia] Univ Brescia, Dept Expt & Appl Med, Sect Occupat Med & Ind Hyg, Brescia, Italy. [Steineck, Gunnar] Karolinska Inst, Clin Ctr Epidemiol, Stockholm, Sweden. [Steineck, Gunnar] Univ Gothenburg, Gothenburg, Sweden. [Kogevinas, Manolis] Ctr Res Environm Epidemiol, Barcelona, Spain. [Kogevinas, Manolis] Hosp Mar, IMIM, Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, Manolis] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Kogevinas, Manolis] Univ Crete, Sch Med, Iraklion, Greece. [Malats, Nuria] Ctr Nacl Invest Oncol, Madrid, Spain. [Karagas, Margaret R.; Andrew, Angeline S.; Nelson, Heather H.] Dartmouth Med Sch, Epidemiol & Biostat Sect, Lebanon, NH USA. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Gurzau, Eugen] Ctr Environm Hlth, Cluj Napoca, Romania. [Koppova, Kvetoslava] State Hlth Inst, Banska Bystrica, Slovakia. [Kumar, Rajiv] German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. RP Stern, MC (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. EM stern_m@ccnt.usc.edu RI Placidi, Donatella/A-6965-2011; Kelsey, Karl/I-1252-2014; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Benhamou, Simone/K-6554-2015; Matullo, Giuseppe/K-6383-2016; Campagna, Marcello/L-1011-2016; Kogevinas, Manolis/C-3918-2017; OI MATULLO, Giuseppe/0000-0003-0674-7757; Yuan, Jian-Min/0000-0002-4620-3108; Sacerdote, Carlotta/0000-0002-8008-5096; Bishop, Tim/0000-0002-8752-8785; Choudhury, Ananya/0000-0002-3561-6580; Steineck, Gunnar/0000-0002-0787-3969; Placidi, Donatella/0000-0003-1606-5397; Kumar, Rajiv/0000-0002-6093-0395; Kiltie, Anne/0000-0001-7208-2912; Allione, Alessandra/0000-0001-9599-309X; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Campagna, Marcello/0000-0002-5277-8477; Barrett, Jenny/0000-0002-1720-7724 FU 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 stir le Cancer, France; National Cancer Institute [R01 CA74880, 1P01CA86871, 1R01CA114665, N02-CP-11015]; Cancer Research UK; Yorkshire Cancer Research; NIH [K07 CA102327, R03 CA121382, R01CA57494, P42 ES007373, ES06718, CA09142]; Italian Association for Cancer Research; Ministry of Health, Oncology Integrated Project; University of California at Los Angeles Johnsson Comprehensive Cancer Center FX The FBCS was supported by the Ligue contre le Cancer du Val-de-Marne, the Fondation de France, the Groupement d'Entreprises Francaises dans la Lutte contre le Cancer, and the Association pour la Recherche stir le Cancer, France. The HBCS was supported by National Cancer Institute grant R01 CA74880 (X. Wu). The LBCS was funded by Cancer Research UK and Yorkshire Cancer Research. The NHBCS was supported by NIH grants K07 CA102327, R03 CA121382, R01CA57494, and P42 ES007373. The TBCS was supported by a grant to ECNIS, a network of excellence operating within the European Union 6th Framework Program, Priority 5: "Food Quality and Safety" (contract no. 513943), by a grant of the Italian Association for Cancer Research, of the Piedmont Region Progetti di Ricerca Sanitaria Finalizzata, and of the Ministry of Health, Oncology Integrated Project "Cancer Primary Prevention in Italy: a research-based approach: Italy. The LABCS and SHBCS were supported by the National Cancer Institute grants 1P01CA86871 and 1R01CA114665. This study was supported by the Intramural Research Program of the NIH, Division of Cancer Epidemiology and Genetics, National Cancer Institute contract N02-CP-11015 and FIS/Spain grants 00/0745, G03/174, G03/160, C03/09, and C03/10. The UCLABCS was supported in part by NIH, Department of Health and Human Services, grants ES06718 and CA09142, and the Seymour Family Gift for Innovative Investigator-Initiated Research in Bladder Cancer at the University of California at Los Angeles Johnsson Comprehensive Cancer Center. NR 49 TC 60 Z9 60 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2009 VL 69 IS 17 BP 6857 EP 6864 DI 10.1158/0008-5472.CAN-09-1091 PG 8 WC Oncology SC Oncology GA 491GH UT WOS:000269566000015 PM 19706757 ER PT J AU Kawabe, M Mandic, M Taylor, JL Vasquez, CA Wesa, AK Neckers, LM Storkus, WJ AF Kawabe, Mayumi Mandic, Maja Taylor, Jennifer L. Vasquez, Cecilia A. Wesa, Amy K. Neckers, Leonard M. Storkus, Walter J. TI Heat Shock Protein 90 Inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin Enhances EphA2(+) Tumor Cell Recognition by Specific CD8(+) T Cells SO CANCER RESEARCH LA English DT Article ID RECEPTOR TYROSINE KINASE; ER-ASSOCIATED DEGRADATION; ANTIGEN PRESENTATION; ENDOPLASMIC-RETICULUM; MALIGNANT-CELLS; EPH RECEPTORS; CANCER; CARCINOMA; IMMUNOTHERAPY; EXPRESSION AB EphA2, a member of the receptor tyrosine kinase family, is commonly expressed by a broad range of cancer types, where its level of (over)expression correlates with poor clinical outcome. Because tumor cell expressed EphA2 is a non-mutated "self" protein, specific CD8(+) T cells are subject to self-tolerance mechanisms and typically exhibit only moderate-to-low functional avidity, rendering them marginally competent to recognize EphA2(+) tumor cells in vitro or in vivo. We have recently reported that the ability of specific CD8(+) T cells to recognize EphA2(+) tumor cells can be augmented after the cancer cells are pretreated with EphA2 agonists that promote proteasomal degradation and up-regulated expression of EphA2/class I complexes on the tumor cell membrane. In the current study, we show that treatment of EphA2(+) tumor cells with the irreversible heat shock protein 90 inhibitor, 17dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), similarly enhances their recognition by EphA2-specific CD8(+) T-cell lines and clones in vitro via a mechanism that is dependent on proteasome and transporter-associated protein function as well as the retrotranslocation of EphA2 into the tumor cytoplasm. When 17-DMAG and agonist anti-EphA2 monoclonal antibodies are coapplied, T-cell recognition of tumor cells is further increased over that observed for either agent alone. These studies suggest that EphA2 represents a novel heat shock protein 90 client protein and that the treatment of cancer patients with 17-DMAG-based "pulse" therapy may improve the antitumor efficacy of CD8(+) T effector cells reactive against EphA2-derived epitopes. [Cancer Res 2009;69(17):6995-7003] C1 [Kawabe, Mayumi; Storkus, Walter J.] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15213 USA. [Mandic, Maja; Taylor, Jennifer L.; Vasquez, Cecilia A.; Wesa, Amy K.; Storkus, Walter J.] Univ Pittsburgh, Sch Med, Dept Dermatol, Pittsburgh, PA 15213 USA. [Storkus, Walter J.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Neckers, Leonard M.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Storkus, WJ (reprint author), Univ Pittsburgh, Sch Med, Dept Immunol, W1041-2 Biomed Sci Tower,200 Lothrop St, Pittsburgh, PA 15213 USA. EM storkuswj@upmc.edu OI Storkus, Walter/0000-0001-8961-4444 FU NIH [R01 CA114071, P50 CA121973] FX NIH grants R01 CA114071 and P50 CA121973 (W.J. Storkus).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; We thank Drs. Robert Binder, Jeff Brodsky, Merrill Egorin, Paul Robbins, Russell Salter, Alessandra Giodim, and Peter Cresswell for helpful discussions, careful review, and critical comments provided during the preparation of this article. NR 47 TC 19 Z9 20 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2009 VL 69 IS 17 BP 6995 EP 7003 DI 10.1158/0008-5472.CAN-08-4511 PG 9 WC Oncology SC Oncology GA 491GH UT WOS:000269566000031 PM 19690146 ER PT J AU Alper, O Stetler-Stevenson, WG Harris, LN Leitner, WW Ozdemirli, M Hartmann, D Raffeld, M Abu-Asab, M Byers, S Zhuang, Z Oldfield, EH Tong, Y Bergmann-Leitner, E Criss, WE Nagasaki, K Mol, SC Cramer, DW Karaveli, FS Goldbach-Mansky, R Leo, P Stromberg, K Weil, RJ AF Alper, Oezge Stetler-Stevenson, William G. Harris, Lyndsay N. Leitner, Wolfgang W. Ozdemirli, Metin Hartmann, Dan Raffeld, Mark Abu-Asab, Mones Byers, Stephen Zhuang, Zhengping Oldfield, Edward H. Tong, Yanhe Bergmann-Leitner, Elke Criss, Wayne E. Nagasaki, Koichi Mol, Samuel C. Cramer, Daniel W. Karaveli, F. Seyda Goldbach-Mansky, Raphaela Leo, Paul Stromberg, Kurt Weil, Robert J. TI Novel anti-filamin-A antibody detects a secreted variant of filamin-A in plasma from patients with breast carcinoma and high-grade astrocytoma SO CANCER SCIENCE LA English DT Article ID CATHEPSIN-B; SERUM HER-2/NEU; CANCER CELLS; EXPRESSION; BINDING; TRAFFICKING; ABP-280 AB Identification of tumor-derived proteins in the circulation may allow for early detection of cancer and evaluation of therapeutic responses. To identify circulating tumor-derived proteins, mice were immunized with concentrated culture medium conditioned by human breast cancer cells. Antibodies generated by hybridomas were screened against conditioned media from both normal epithelial cells and tumor cells. Antibody selectively reacting with tumor cell-conditioned media was further characterized. This led to the development of a monoclonal antibody (Alper-p280) that reacts with a newly identified 280-kDa secreted variant of human filamin-A. Circulating filamin-A was detected in patient plasma samples using Alper-p280 in an ELISA assay. Human plasma samples from 134 patients with brain, breast, or ovarian cancer, 15 patients with active arthritis, and 76 healthy controls were analyzed. Filamin-A protein levels in human cell lines and tissues were analyzed by western blotting, immunohistochemistry, and electron and confocal microscopy. Circulating filamin-A was detected in the plasma of 109 of 143 patients with breast cancer and primary brain tumors. Plasma levels of filamin-A showed 89.5% sensitivity (95% confidence interval [CI] = 0.67% to 0.99%) and 97.8% specificity (95% CI = 0.88% to 0.99%) for glioblastoma at a cut-off of 21.0 ng/mL. Plasma levels of filamin-A (> 36.0 ng/mL) had 96.7% sensitivity (95% CI = 0.80% to 0.99%) and 67.8% specificity (95% CI = 0.54% to 0.79%) for metastatic breast cancer. Filamin-A levels were increased in malignant breast or brain tissues, but not in normal control tissues. Filamin-A localized to lysosomes in MDA.MB.231 breast cancer cells, but not in normal human mammary epithelial cells, suggesting that filamin-A may undergo cancer-specific processing. Plasma filamin-A appears to be a specific and sensitive marker for patients with high-grade astrocytoma or metastatic breast cancer. Additional novel cancer biomarkers have been identified and are being developed alongside Alper-p280 for use in diagnosis of breast carcinoma and high-grade astrocytoma, and for use in the evaluation of therapeutic responses. (Cancer Sci 2009; 100: 1748-1756). C1 [Alper, Oezge] Alper Biotech LLC, Rockville, MD USA. [Stetler-Stevenson, William G.] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Harris, Lyndsay N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Leitner, Wolfgang W.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Ozdemirli, Metin; Hartmann, Dan] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Dept Pathol, Washington, DC 20007 USA. [Raffeld, Mark; Abu-Asab, Mones] NCI, Pathol Branch, Bethesda, MD 20892 USA. [Byers, Stephen] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Zhuang, Zhengping; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Tong, Yanhe] VaxGen Inc, San Francisco, CA USA. [Bergmann-Leitner, Elke] Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD USA. [Criss, Wayne E.] Hacettepe Univ, Dept Biochem, Ankara, Turkey. [Nagasaki, Koichi] Natl Genome Res Ctr, Tokyo, Japan. [Mol, Samuel C.; Cramer, Daniel W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Karaveli, F. Seyda] Akdeniz Univ, Sch Med, Dept Pathol, TR-07058 Antalya, Turkey. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Leo, Paul] NIH, Human Genome Res Ctr, Bethesda, MD 20892 USA. [Stromberg, Kurt] US FDA, Div Therapeut Prot, Bethesda, MD 20014 USA. [Weil, Robert J.] Cleveland Clin Fdn, Neurol Inst, Dept Neurosurg, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44195 USA. RP Alper, O (reprint author), Alper Biotech LLC, Rockville, MD USA. EM oalper@alperbiotech.com RI Bergmann-Leitner, Elke/B-3548-2011; Leitner, Wolfgang/F-5741-2011; Stetler-Stevenson, William/H-6956-2012; Leo, Paul/B-3470-2011; KARAVELI, FATMA SEYDA/C-6335-2016; OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Leitner, Wolfgang/0000-0003-3125-5922; Stetler-Stevenson, William/0000-0002-5500-5808; Leo, Paul/0000-0001-8325-4134; Abu-Asab, Mones/0000-0002-4047-1232 FU National Institute Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA FX This research was supported in part by the Intramural Research Program of the National Institute Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. The authors thank Dianne Hirsch, PhD, for critical reading and editing of the manuscript. The authors thank Ken Yamaguchi, MD, for scientific discussions and support during the early stages of project development. NR 27 TC 25 Z9 27 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD SEP PY 2009 VL 100 IS 9 BP 1748 EP 1756 DI 10.1111/j.1349-7006.2009.01244.x PG 9 WC Oncology SC Oncology GA 482XL UT WOS:000268923800028 PM 19594548 ER PT J AU Lee, JY Park, AK Lee, KM Park, SK Han, S Han, W Noh, DY Yoo, KY Kim, H Chanock, SJ Rothman, N Kang, D AF Lee, Ji-Young Park, Ae Kyung Lee, Kyoung-Mu Park, Sue K. Han, Sohee Han, Wonshik Noh, Dong-Young Yoo, Keun-Young Kim, Ho Chanock, Stephen J. Rothman, Nathaniel Kang, Daehee TI Candidate gene approach evaluates association between innate immunity genes and breast cancer risk in Korean women SO CARCINOGENESIS LA English DT Article ID ALPHA-CHAIN GENE; SERUM IGE LEVELS; CAUCASIAN WOMEN; POLYMORPHISMS; RECEPTOR; INFLAMMATION; INVOLVEMENT; STATISTICS; VARIANTS AB Objectives: This study was conducted to investigate the role of common variation in innate immunity-related genes as susceptibility factors to breast cancer risk in Korean women. Methods: Total 1536 single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed by Illumina GoldenGate assay in 209 cases and the same numbers of controls. Both SNP and gene-based tests were used to evaluate the association with breast cancer risk. The robustness of results was further evaluated with permutation method, false discovery rate and haplotype analyses. Results: Both SNP and gene-based analyses showed promising associations with breast cancer risk for 17 genes: OR10J3, FCER1A, NCF4, CNTNAP1, CTNNB1, KLKB1, ITGB2, ALOX12B, KLK2, IRAK3, KLK4, STAT6, NCF2, CCL1, C1QR1, MBP and NOS1. The most significant association with breast cancer risk was observed for the OR10J3 SNP (rs2494251, P-value = 1.2 x 10(-4)) and FCER1A SNP (rs7548864, P-value = 7.7 x 10(-4)). Gene-based permutation and false discovery rate P-values for OR10J3 SNP (rs2494251) with breast cancer risk were also significant (P = 4 x 10(-5) and 0.008, respectively). Haplotype analyses supported these findings that OR10J3 and FCER1A were most significantly associated with risk for breast cancer (P = 2 x 10(-4) and 0.004, respectively). Conclusion: This study suggests that common genetic variants in the OR10J3 and FCER1A be strongly associated with breast cancer risk among Korean women. C1 [Lee, Ji-Young; Lee, Kyoung-Mu; Park, Sue K.; Han, Sohee; Yoo, Keun-Young; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Park, Ae Kyung; Lee, Kyoung-Mu; Kim, Ho] Seoul Natl Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Seoul 110460, South Korea. [Lee, Kyoung-Mu; Chanock, Stephen J.; Rothman, Nathaniel] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Park, Sue K.; Han, Wonshik; Noh, Dong-Young; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Coll Med, Seoul 110799, South Korea. [Han, Wonshik; Noh, Dong-Young] Seoul Natl Univ, Dept Surg, Coll Med, Seoul 110799, South Korea. [Chanock, Stephen J.] Natl Canc Inst, Dept Hlth & Human Serv, Core Genotyping Facil, Adv Technol Ctr, Bethesda, MD USA. [Kang, Daehee] Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul 151742, South Korea. [Kang, Daehee] Seoul Natl Univ, Coll Med, Seoul 151742, South Korea. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Dept Prevent Med, 103 Daehak Ro, Seoul 110799, South Korea. EM dhkang@snu.ac.kr RI Noh, Dong-Young/G-5531-2011; Kang, Dae Hee/E-8631-2012; Yoo, Keun-Young/J-5548-2012; Park, Sue Kyung/J-2757-2012; Han, Wonshik/B-3699-2008 FU Ministry for Health, Welfare and family affair [AO30001]; Ministry of Education, Science Technology; Korea Science and Engineering Foundation through Seoul National University [R312008-000-10103-0] FX Korea Health 21 R& D Project, Ministry for Health, Welfare and family affair (AO30001); World Class University project of Ministry of Education, Science & Technology and the Korea Science and Engineering Foundation through Seoul National University (R312008-000-10103-0). NR 28 TC 32 Z9 32 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2009 VL 30 IS 9 BP 1528 EP 1531 DI 10.1093/carcin/bgp084 PG 4 WC Oncology SC Oncology GA 491VG UT WOS:000269608200007 PM 19372141 ER PT J AU Cleveland, AG Oikarinen, SI Bynote, KK Marttinen, M Rafter, JJ Gustafsson, JA Roy, SK Pitot, HC Korach, KS Lubahn, DB Mutanen, M Gould, KA AF Cleveland, Alicia G. Oikarinen, Seija I. Bynote, Kimberly K. Marttinen, Maija Rafter, Joseph J. Gustafsson, Jan-Ake Roy, Shyamal K. Pitot, Henry C. Korach, Kenneth S. Lubahn, Dennis B. Mutanen, Marja Gould, Karen A. TI Disruption of estrogen receptor signaling enhances intestinal neoplasia in Apc(Min/+) mice SO CARCINOGENESIS LA English DT Article ID COLON-CANCER; COLORECTAL-CANCER; MIN MICE; ER-BETA; REPRODUCTIVE PHENOTYPES; POSTMENOPAUSAL WOMEN; TUMOR-FORMATION; CPG ISLAND; MOUSE; EXPRESSION AB Estrogen receptors (ERs) [ER alpha (Esr1) and ER beta (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ER alpha and ER beta is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ER alpha knockout and Apc(Min) mouse strains, we demonstrate that ER alpha deficiency is associated with a significant increase in intestinal tumor multiplicity, size and burden in Apc(Min/+) mice. Within the normal intestinal epithelium of Apc(Min/+) mice, ER alpha deficiency is associated with an accumulation of nuclear beta-catenin, an indicator of activation of the Wnt-beta-catenin-signaling pathway, which is known to play a critical role in intestinal cancers. Consistent with the hypothesis that ER alpha deficiency is associated with activation of Wnt-beta-catenin signaling, ER alpha deficiency in the intestinal epithelium of Apc(Min/+) mice also correlated with increased expression of Wnt-beta-catenin target genes. Through crosses between an ER beta knockout and Apc(Min) mouse strains, we observed some evidence that ER beta deficiency is associated with an increased incidence of colon tumors in Apc(Min/+) mice. This effect of ER beta deficiency does not involve modulation of Wnt-beta-catenin signaling. Our studies suggest that ER alpha and ER beta signaling modulate colorectal carcinogenesis, and ER alpha does so, at least in part, by regulating the activity of the Wnt-beta-catenin pathway. C1 [Cleveland, Alicia G.; Bynote, Kimberly K.; Gould, Karen A.] Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. [Oikarinen, Seija I.; Marttinen, Maija; Mutanen, Marja] Univ Helsinki, Dept Appl Chem & Microbiol Nutr, FIN-00014 Helsinki, Finland. [Rafter, Joseph J.; Gustafsson, Jan-Ake] Karolinska Inst, Novum, Dept Biosci & Nutr, S-14186 Huddinge, Sweden. [Rafter, Joseph J.; Gustafsson, Jan-Ake] Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 USA. [Roy, Shyamal K.] Univ Nebraska, Med Ctr, Dept Cellular & Integrat Physiol, Omaha, NE 68198 USA. [Pitot, Henry C.] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. [Korach, Kenneth S.] NIEHS, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. [Lubahn, Dennis B.] Univ Missouri, Dept Biochem, Columbia, MO USA. [Lubahn, Dennis B.] Univ Missouri, Dept Child Hlth, Columbia, MO 65201 USA. [Lubahn, Dennis B.] Univ Missouri, Dept Anim Sci, Columbia, MO 65201 USA. [Lubahn, Dennis B.] Univ Missouri, MU Ctr Phytonutrient & Phytochem Studies, Columbia, MO 65201 USA. RP Gould, KA (reprint author), Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, 600 S 42nd St, Omaha, NE 68198 USA. EM kagould@unmc.edu RI Rafter, Joseph/L-6049-2014; OI Oikarinen, Seija/0000-0002-6189-4672 FU Nebraska Department of Health and Human Services; National Institutes of Health [K01-CA113413] FX Nebraska Department of Health and Human Services; National Institutes of Health (K01-CA113413 to K. A. G.). NR 44 TC 22 Z9 23 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2009 VL 30 IS 9 BP 1581 EP 1590 DI 10.1093/carcin/bgp132 PG 10 WC Oncology SC Oncology GA 491VG UT WOS:000269608200014 PM 19520794 ER PT J AU Hoshi, S Hoshi, N Okamoto, M Paiz, J Kusakabe, T Ward, JM Kimura, S AF Hoshi, Sayuri Hoshi, Nobuo Okamoto, Minoru Paiz, Jorge Kusakabe, Takashi Ward, Jerrold M. Kimura, Shioko TI Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice SO CARCINOGENESIS LA English DT Article ID THYROTROPIN RECEPTOR GENE; TRANSCRIPTION FACTOR-I; ESTROGENIC COMPOUNDS; CARCINOMA LINES; TRANSGENIC MICE; WISTAR RATS; N-BIS(2-HYDROXYPROPYL)NITROSAMINE; TUMORS; EXPRESSION; PROMOTER AB NKX2-1 is a homeodomain transcription factor that is critical for genesis of the thyroid and transcription of the thyroid-specific genes. Nkx2-1-thyroid-conditional hypomorphic mice were previously developed in which Nkx2-1 gene expression is lost in 50% of the thyroid cells. Using this mouse line as compared with wild-type and Nkx2-1 heterozygous mice, a thyroid carcinogenesis study was carried out using the genotoxic carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN), followed by sulfadimethoxine (SDM) or the non-genotoxic carcinogen amitrole (3-amino-1,2,4-triazole). A significantly higher incidence of adenomas was obtained in Nkx2-1-thyroid-conditional hypomorphic mice as compared with the other two groups of mice only when they were treated with DHPN + SDM, but not amitrole. A bromodeoxyuridine incorporation study revealed that thyroids of the Nkx2-1-thyroid-conditional hypomorphic mice had > 2-fold higher constitutive cell proliferation rate than the other two groups of mice, suggesting that this may be at least partially responsible for the increased incidence of adenoma in this mouse line after genotoxic carcinogen exposure. Thus, NKX2-1 may function to control the proliferation of thyroid follicular cells following damage by a genotoxic carcinogen. C1 [Hoshi, Sayuri; Hoshi, Nobuo; Okamoto, Minoru; Paiz, Jorge; Kusakabe, Takashi; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Ward, Jerrold M.] Global VetPathol, Montgomery Village, MD 20886 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3118,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov FU National Cancer Institute, Center for Cancer Research [Z01 BC 005522] FX Intramural Research Program of the National Cancer Institute, Center for Cancer Research ( Project no. Z01 BC 005522). NR 39 TC 6 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2009 VL 30 IS 9 BP 1614 EP 1619 DI 10.1093/carcin/bgp167 PG 6 WC Oncology SC Oncology GA 491VG UT WOS:000269608200018 PM 19581346 ER PT J AU Chun, KS Lao, HC Trempus, CS Okada, M Langenbach, R AF Chun, Kyung-Soo Lao, Huei-Chen Trempus, Carol S. Okada, Manabu Langenbach, Robert TI The prostaglandin receptor EP2 activates multiple signaling pathways and beta-arrestin1 complex formation during mouse skin papilloma development SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR RECEPTOR; PROTEIN-COUPLED RECEPTORS; PROSTANOID RECEPTORS; MOLECULAR-BIOLOGY; TUMOR-DEVELOPMENT; ONCOGENIC RAS; CANCER-CELLS; HA-RAS; CARCINOGENESIS; E-2 AB Prostaglandin E(2) (PGE(2)) is elevated in many tumor types, but PGE(2)'s contributions to tumor growth are largely unknown. To investigate PGE(2)'s roles, the contributions of one of its receptors, EP2, were studied using the mouse skin initiation/promotion model. Initial studies indicated that protein kinase A (PKA), epidermal growth factor receptor (EGFR) and several effectors-cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB), H-Ras, Src, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2-were activated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and that PKA and EGFR inhibition (H89 and AG1478, respectively) decreased papilloma formation. EP2's contributions to the activation of these pathways and papilloma development were determined by inhibiting endogenous TPA-induced PGE(2) production with indomethacin (Indo) and concomitantly treating with the EP2 agonist, CAY10399 (CAY). CAY treatment restored papilloma formation in TPA/Indo-treated mice and increased cyclic adenosine 3',5'-monophosphate and PKA activation as measured by p-CREB formation. CAY treatment also increased EGFR and Src activation and their inhibition by AG1478 and PP2 indicated that Src was upstream of EGFR. CAY also increased H-Ras, ERK1/2 and AKT activation, and AG1478 decreased their activation indicating EGFR being upstream. Supporting EP2's contribution, EP2-/- mice exhibited 65% fewer papillomas and reduced Src, EGFR, H-Ras, AKT and ERK1/2 activation. G protein-coupled receptor (GPCR) activation of EGFR has been reported to involve Src's activation via a GPCR-beta-arrestin-Src complex. Indeed, immunoprecipitation of beta-arrestin1 or p-Src indicated the presence of an EP2-beta-arrestin1-p-Src complex in papillomas. The data indicated that EP2 contributed to tumor formation via activation of PKA and EGFR and that EP2 formed a complex with beta-arrestin1 and Src that contributed to signaling and/or EP2 desensitization. C1 [Chun, Kyung-Soo; Lao, Huei-Chen; Trempus, Carol S.; Okada, Manabu; Langenbach, Robert] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Langenbach, R (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM langenb1@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX National Institute of Environmental Health Sciences, National Institutes of Health, Intramural program. NR 46 TC 41 Z9 41 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2009 VL 30 IS 9 BP 1620 EP 1627 DI 10.1093/carcin/bgp168 PG 8 WC Oncology SC Oncology GA 491VG UT WOS:000269608200019 PM 19587094 ER PT J AU Zhang, XD Zhu, J Loh, YP Berghman, LR AF Zhang, Xiaodong Zhu, James Loh, Y. Peng Berghman, Luc R. TI Carboxypeptidase E, an essential element of the regulated secretory pathway, is expressed and partially co-localized with chromogranin A in chicken thymus SO CELL AND TISSUE RESEARCH LA English DT Article DE Carboxypeptidase E; Thymus; Chromogranin A; Neuroendocrine; Chicken ID POMC-DERIVED PEPTIDES; GRANULE BIOGENESIS; STROMAL CELLS; TARGETED ABLATION; SORTING RECEPTOR; CYTOKINES; IDENTIFICATION; THYMOCYTES; SITE AB Although the functions of hormones and neuropeptides in the thymus have been extensively studied, we still do not know whether these intra-thymic humoral elements are released in a stimulated manner via the regulated secretory pathway or in a constitutive manner. Carboxypeptidase E (CpE) and chromogranin A (CgA) are functional and structural hallmarks of the regulated secretory pathway in (neuro)endocrine cells. Whereas we have previously shown a CgA-positive neuroendocrine population in the chicken thymus, the current study assesses the expression of CpE in the thymus, both at the mRNA and the protein level. Our immunohistochemical studies provide evidence for the co-existence of CgA and CpE in identical neuroendocrine cells in the thymus. CpE and CgA dual-positive cells have primarily been found in the transition zone between the cortex and medulla of the thymus, an area known to contain numerous arterioles and to be innervated by the autonomic nervous system. Our findings suggest that the diffuse neuroendocrine system serves as a relay for nervous stimuli delivered by the sympathetic and/or parasympathetic nervous system. Thus, these newly defined neuroendocrine cells might play an important role in the immuno-neuro-endocrine cross-talk in the thymus, potentially enabling thymopoiesis to be fine-tuned via the regulated secretory pathway by a variety of physical and environmental factors. C1 [Zhang, Xiaodong; Zhu, James; Berghman, Luc R.] Texas A&M Univ, Dept Poultry Sci, College Stn, TX 77843 USA. [Loh, Y. Peng] NICHHD, Cellular Neurobiol Sect, Bethesda, MD 20892 USA. [Berghman, Luc R.] Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX 77843 USA. RP Berghman, LR (reprint author), Texas A&M Univ, Dept Poultry Sci, College Stn, TX 77843 USA. EM berghman@poultry.tamu.edu FU Intramural NIH HHS [Z99 HD999999, ZIA HD000056-37] NR 31 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X EI 1432-0878 J9 CELL TISSUE RES JI Cell Tissue Res. PD SEP PY 2009 VL 337 IS 3 BP 371 EP 379 DI 10.1007/s00441-009-0830-x PG 9 WC Cell Biology SC Cell Biology GA 484OH UT WOS:000269055200003 PM 19603184 ER PT J AU Hanse, EA Nelsen, CJ Goggin, MM Anttila, CK Mullany, LK Berthet, C Kaldis, P Crary, GS Kuriyama, R Albrecht, JH AF Hanse, Eric A. Nelsen, Christopher J. Goggin, Melissa M. Anttila, Chelsea K. Mullany, Lisa K. Berthet, Cyril Kaldis, Philipp Crary, Gretchen S. Kuriyama, Ryoko Albrecht, Jeffrey H. TI Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo SO CELL CYCLE LA English DT Article DE apoptosis; cdk2; centrosomes; cyclin D1; liver regeneration; seliciclib ID S-PHASE ENTRY; DEPENDENT KINASE; HEPATOCELLULAR-CARCINOMA; MYELOMA CELLS; CANCER-CELLS; APOPTOSIS; LIVER; INHIBITION; MICE; OVEREXPRESSION AB Cdk2 was once believed to play an essential role in cell cycle progression, but cdk2(-/-) mice have minimal phenotypic abnormalities. In this study, we examined the role of cdk2 in hepatocyte proliferation, centrosome duplication and survival. Cdk2(-/-) hepatocytes underwent mitosis and had normal centrosome content after mitogen stimulation. Unlike wild-type cells, cdk2(-/-) liver cells failed to undergo centrosome overduplication in response to ectopic cyclin D1 expression. After mitogen stimulation in culture or partial hepatectomy in vivo, cdk2(-/-) hepatocytes demonstrated diminished proliferation. Cyclin D1 is a key mediator of cell cycle progression in hepatocytes, and transient expression of this protein is sufficient to promote robust proliferation of these cells in vivo. In cdk2(-/-) mice and animals treated with the cdk2 inhibitor seliciclib, cyclin D1 failed to induce hepatocyte cell cycle progression. Surprisingly, cdk2 ablation or inhibition led to massive hepatocyte and animal death following cyclin D1 transfection. In a transgenic model of chronic hepatic cyclin D1 expression, seliciclib induced hepatocyte injury and animal death, suggesting that cdk2 is required for survival of cyclin D1-expressing cells even in the absence of substantial proliferation. In conclusion, our studies demonstrate that cdk2 plays a role in liver regeneration. Furthermore, it is essential for centrosome overduplication, proliferation and survival of hepatocytes that aberrantly express cyclin D1 in vivo. These studies suggest that cdk2 may warrant further investigation as a target for therapy of liver tumors with constitutive cyclin D1 expression. C1 [Hanse, Eric A.; Albrecht, Jeffrey H.] Hennepin Cty Med Ctr, Div Gastroenterol, Minneapolis, MN 55415 USA. [Crary, Gretchen S.] Hennepin Cty Med Ctr, Dept Pathol, Minneapolis, MN 55415 USA. [Hanse, Eric A.; Nelsen, Christopher J.; Goggin, Melissa M.; Anttila, Chelsea K.; Mullany, Lisa K.; Albrecht, Jeffrey H.] Minneapolis Med Res Fdn Inc, Minneapolis, MN USA. [Berthet, Cyril; Kaldis, Philipp] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Kuriyama, Ryoko] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA. RP Albrecht, JH (reprint author), Hennepin Cty Med Ctr, Div Gastroenterol, 701 Pk Ave, Minneapolis, MN 55415 USA. EM albre010@umn.edu RI Kaldis, Philipp/G-2714-2010 OI Kaldis, Philipp/0000-0002-7247-7591 FU NIH [DK54921] FX This work was supported by NIH Grant DK54921 (J.H.A.). NR 49 TC 21 Z9 21 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2009 VL 8 IS 17 BP 2802 EP 2809 PG 8 WC Cell Biology SC Cell Biology GA 494FK UT WOS:000269795800028 PM 19652536 ER PT J AU Ng, KW Mauck, RL Wang, CCB Kelly, TAN Ho, MMY Chen, FYH Ateshian, GA Hung, CT AF Ng, Kenneth W. Mauck, Robert L. Wang, Christopher C. -B. Kelly, Terri-Ann N. Ho, Mandy M. -Y. Chen, Faye Hui Ateshian, Gerard A. Hung, Clark T. TI Duty Cycle of Deformational Loading Influences the Growth of Engineered Articular Cartilage SO CELLULAR AND MOLECULAR BIOENGINEERING LA English DT Article DE Functional tissue engineering; Cartilage oligomeric matrix protein; Cartilage; Agarose; Bioreactor; Dynamic modulus; Mechanical properties; Collagen; Chondrocyte ID OLIGOMERIC MATRIX PROTEIN; SEEDED AGAROSE GELS; HUMAN HIP-JOINT; DYNAMIC COMPRESSION; EXTRACELLULAR-MATRIX; CANINE KNEE; UNCONFINED COMPRESSION; INDENTATION STIFFNESS; BIOSYNTHETIC RESPONSE; MECHANICAL-PROPERTIES AB This study examines how variations in the duty cycle (the duration of applied loading) of deformational loading can influence the mechanical properties of tissue engineered cartilage constructs over one month in bioreactor culture. Dynamic loading was carried out with three different duty cycles: 1 h on/1 h off for a total of 3 h loading/day, 3 h continuous loading, or 6 h of continuous loading per day, with all loading performed 5 days/week. All loaded groups showed significant increases in Young's modulus after one month (vs. free swelling controls), but only loading for a continuous 3 and 6 h showed significant increases in dynamic modulus by this time point. Histological analysis showed that dynamic loading can increase cartilage oligomeric matrix protein (COMP) and collagen types II and IX, as well as prevent the formation of a fibrous capsule around the construct. Type II and IX collagen deposition increased with increased with duration of applied loading. These results point to the efficacy of dynamic deformational loading in the mechanical preconditioning of engineered articular cartilage constructs. Furthermore, these results highlight the ability to dictate mechanical properties with variations in mechanical input parameters, and the possible importance of other cartilage matrix molecules, such as COMP, in establishing the functional material properties of engineered constructs. C1 [Ng, Kenneth W.; Wang, Christopher C. -B.; Kelly, Terri-Ann N.; Ho, Mandy M. -Y.; Ateshian, Gerard A.; Hung, Clark T.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Mauck, Robert L.] Univ Penn, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Chen, Faye Hui] NIAMS, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD USA. RP Hung, CT (reprint author), Columbia Univ, Dept Biomed Engn, 351 Engn Terrace,MC8904,1210 Amsterdam Ave, New York, NY 10027 USA. EM cth6@columbia.edu FU National Institutes of Health [R01 AR46532, AR46568, R03 AR053668]; Whitaker Foundation FX This study was supported by Grants from the National Institutes of Health (R01 AR46532, AR46568; R03 AR053668) and a pre-doctoral fellowship from the Whitaker Foundation. Special thanks to Ashby Thomas, Qiqi Cheng, and Nicole Gabriel for their technical assistance throughout this study. NR 62 TC 11 Z9 11 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1865-5025 J9 CELL MOL BIOENG JI Cell. Mol. Bioeng. PD SEP PY 2009 VL 2 IS 3 BP 386 EP 394 DI 10.1007/s12195-009-0070-x PG 9 WC Cell & Tissue Engineering; Biophysics; Cell Biology SC Cell Biology; Biophysics GA 498UF UT WOS:000270168900012 PM 20703332 ER PT J AU Benicky, J Sanchez-Lemus, E Pavel, J Saavedra, JM AF Benicky, Julius Sanchez-Lemus, Enrique Pavel, Jaroslav Saavedra, Juan M. TI Anti-Inflammatory Effects of Angiotensin Receptor Blockers in the Brain and the Periphery SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Renin-angiotensin system; LPS; Brain inflammation; Microglia; AT1 receptor antagonist ID SPONTANEOUSLY HYPERTENSIVE-RATS; PITUITARY-ADRENAL AXIS; INNATE IMMUNE-RESPONSE; IN-SITU HYBRIDIZATION; CEREBRAL-BLOOD-FLOW; FACTOR-KAPPA-B; MESSENGER-RNA; VASCULAR INFLAMMATION; ISOLATION STRESS; PARAVENTRICULAR NUCLEUS AB In addition to regulating blood pressure, Angiotensin II (Ang II) exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT(1) receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Ang II receptor blockers (ARBs) decreases hypertension-related vascular inflammation in peripheral organs. In rodent models of genetic hypertension, ARBs reverse the inflammation in the cerebral microcirculation. We hypothesized that ARBs could be effective in inflammatory conditions beyond hypertension. Our more recent studies, summarized here, indicate that this is indeed the case. We used the model of systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). LPS produces a robust initial inflammatory reaction, the innate immune response, in peripheral organs and in the brain. Pretreatment with the ARB candesartan significantly diminishes the response to LPS, including reduction of pro-inflammatory cytokine release to the general circulation and decreased production and release of the pro-inflammatory adrenal hormone aldosterone. In addition, the ARB very significantly decreased the LPS-induced gene expression of pro-inflammatory cytokines and microglia activation in the brain. Our results demonstrate that AT(1) receptor activity is essential for the unrestricted development of full-scale innate immune response in the periphery and in the brain. ARBs, due to their immune response-limiting properties, may be considered as therapeutically useful in a number of inflammatory diseases of the peripheral organs and the brain. C1 [Benicky, Julius; Sanchez-Lemus, Enrique; Pavel, Jaroslav; Saavedra, Juan M.] NIMH, US Dept HHS, Pharmacol Sect, Div Intramural Res Programs,NIH, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, US Dept HHS, Pharmacol Sect, Div Intramural Res Programs,NIH, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA FX This research was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA. NR 75 TC 41 Z9 42 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD SEP PY 2009 VL 29 IS 6-7 BP 781 EP 792 DI 10.1007/s10571-009-9368-4 PG 12 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 476YI UT WOS:000268482300002 PM 19259805 ER PT J AU Peters, NC Sacks, DL AF Peters, Nathan C. Sacks, David L. TI The impact of vector-mediated neutrophil recruitment on cutaneous leishmaniasis SO CELLULAR MICROBIOLOGY LA English DT Review ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; T-CELL RESPONSES; DENDRITIC CELLS; MAJOR INFECTION; INFLAMMATORY PROCESS; APOPTOTIC CELLS; IN-VIVO; MICE; MACROPHAGES; GRANULOCYTES AB P>The dynamic process of pathogen transmission by the bite of an insect vector combines several biological processes that have undergone extensive co-evolution. Whereas the host response to an insect bite is only occasionally confronted with the parasitic pathogens that competent vectors might transmit, the transmitted parasites will always be confronted with the acute, wound-healing response that is initiated by the bite itself. Invariably, this response involves neutrophils. In the case of Leishmania, infection is initiated in the skin following the bite of an infected sand fly, suggesting that Leishmania must possess some means to survive their early encounter with recruited neutrophils at the bite site. Here, we review the literature regarding the impact of neutrophils on the outcome of infection with Leishmania, with special attention to the role of the sand fly bite. C1 [Peters, Nathan C.; Sacks, David L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Peters, NC (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr, Bethesda, MD 20892 USA. EM NPeters@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000494-25] NR 55 TC 48 Z9 48 U1 1 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD SEP PY 2009 VL 11 IS 9 BP 1290 EP 1296 DI 10.1111/j.1462-5822.2009.01348.x PG 7 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 481EP UT WOS:000268790500002 PM 19545276 ER PT J AU Hahn, B Ross, TJ Wolkenberg, FA Shakleya, DM Huestis, MA Stein, EA AF Hahn, Britta Ross, Thomas J. Wolkenberg, Frank A. Shakleya, Diaa M. Huestis, Marilyn A. Stein, Elliot A. TI Performance Effects of Nicotine during Selective Attention, Divided Attention, and Simple Stimulus Detection: An fMRI Study SO CEREBRAL CORTEX LA English DT Article DE deactivation; default; fMRI; reaction time; skin patch; smokers ID CEREBRAL BLOOD OXYGENATION; WORKING-MEMORY TASK; CIGARETTE-SMOKING; COGNITIVE PERFORMANCE; VISUOSPATIAL ATTENTION; TRANSDERMAL NICOTINE; BRAIN ACTIVATION; VISUAL-ATTENTION; PARIETAL CORTEX; SMOKERS AB Attention-enhancing effects of nicotine appear to depend on the nature of the attentional function. Underlying neuroanatomical mechanisms, too, may vary depending on the function modulated. This functional magnetic resonance imaging study recorded blood oxygen level-dependent (BOLD) activity in minimally deprived smokers during tasks of simple stimulus detection, selective attention, or divided attention after single-blind application of a transdermal nicotine (21 mg) or placebo patch. Smokers' performance in the placebo condition was unimpaired as compared with matched nonsmokers. Nicotine reduced reaction time (RT) in the stimulus detection and selective attention but not divided attention condition. Across all task conditions, nicotine reduced activation in frontal, temporal, thalamic, and visual regions and enhanced deactivation in so-called "default" regions. Thalamic effects correlated with RT reduction selectively during stimulus detection. An interaction with task condition was observed in middle and superior frontal gyri, where nicotine reduced activation only during stimulus detection. A visuomotor control experiment provided evidence against nonspecific effects of nicotine. In conclusion, although prefrontal activity partly displayed differential modulation by nicotine, most BOLD effects were identical across tasks, despite differential performance effects, suggesting that common neuronal mechanisms can selectively benefit different attentional functions. Overall, the effects of nicotine may be explained by increased functional efficiency and downregulated task-independent "default" functions. C1 [Hahn, Britta; Ross, Thomas J.; Wolkenberg, Frank A.; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, IRP,Biomed Res Ctr, Baltimore, MD 21224 USA. [Shakleya, Diaa M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Chem & Drug Metab Sect, NIH, IRP,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Hahn, B (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM bhahn@mprc.umaryland.edu RI Ross, Thomas/B-7469-2008; Hahn, Britta/G-4593-2012 OI Ross, Thomas/0000-0002-7745-3572; FU National Institutes of Health; National Institute on Drug Abuse FX Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse. NR 73 TC 51 Z9 51 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2009 VL 19 IS 9 BP 1990 EP 2000 DI 10.1093/cercor/bhn226 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 481JT UT WOS:000268806900005 PM 19073624 ER PT J AU Munoz, M Mishkin, M Saunders, RC AF Munoz, Monica Mishkin, Mortimer Saunders, Richard C. TI Resection of the Medial Temporal Lobe Disconnects the Rostral Superior Temporal Gyrus from Some of its Projection Targets in the Frontal Lobe and Thalamus SO CEREBRAL CORTEX LA English DT Article DE auditory cortex; auditory memory; disconnection; frontal cortex; Macaca mulatta ID COMPARATIVE CYTOARCHITECTONIC ANALYSIS; CORTICOCORTICAL CONNECTION PATTERNS; RHESUS-MONKEY; PREFRONTAL CORTEX; MACAQUE MONKEYS; PERIRHINAL CORTEX; AUDITORY-CORTEX; INTRINSIC CONNECTIONS; VISUAL RECOGNITION; ENTORHINAL CORTEX AB Auditory memory in the monkey does not appear to extend beyond the limits of working memory. It is therefore surprising that this ability is impaired by medial temporal lobe (MTL) resections, because such lesions spare working memory in other sensory modalities. To determine whether MTL ablations might have caused the auditory deficit through inadvertent transection of superior temporal gyrus (STG) projections to its downstream targets, and, if so, which targets might have been compromised, we injected anterograde tracer (biotinylated dextran amine) in the STG of both the normal and MTL-lesioned hemispheres of split-brain monkeys. Interhemispheric comparison of label failed to show any effect of the MTL ablation on efferents from caudal STG, which projects to the inferior prefrontal convexity. However, the ablation did consistently interrupt the normally dense projections from rostral STG to both the ventral medial prefrontal cortex and medial thalamic nuclei. The findings support the possibility that the auditory working memory deficit after MTL ablation is due to transection of downstream auditory projections, and indicate that the candidate structures for mediating auditory working memory are the ventral medial prefrontal cortical areas, the medial thalamus, or both. C1 [Munoz, Monica; Mishkin, Mortimer; Saunders, Richard C.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Munoz, M (reprint author), Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. EM monica.munoz@ich.ucl.ac.uk RI Munoz, Monica/C-9189-2009; Munoz-Lopez, Monica/F-3154-2016; OI Munoz Lopez, Monica/0000-0002-5530-2394 FU National Institute of Mental Health FX Funding for this article and for the Open Access publication charges for this article was provided by Intramural Research Program of the National Institute of Mental Health. NR 55 TC 12 Z9 12 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2009 VL 19 IS 9 BP 2114 EP 2130 DI 10.1093/cercor/bhn236 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 481JT UT WOS:000268806900014 PM 19150921 ER PT J AU Papoutsi, M de Zwart, JA Jansma, JM Pickering, MJ Bednar, JA Horwitz, B AF Papoutsi, Marina de Zwart, Jacco A. Jansma, J. Martijn Pickering, Martin J. Bednar, James A. Horwitz, Barry TI From Phonemes to Articulatory Codes: An fMRI Study of the Role of Broca's Area in Speech Production SO CEREBRAL CORTEX LA English DT Article DE articulation; fMRI; left inferior frontal gyrus; pars opercularis; phonological processing ID EVENT-RELATED FMRI; INFERIOR PREFRONTAL CORTEX; PHONOTACTIC PROBABILITY; FUNCTIONAL-ANATOMY; WORD PRODUCTION; WORKING-MEMORY; FRONTAL-CORTEX; SPOKEN WORDS; PERCEPTION; FREQUENCY AB We used event-related functional magnetic resonance imaging to investigate the neuroanatomical substrates of phonetic encoding and the generation of articulatory codes from phonological representations. Our focus was on the role of the left inferior frontal gyrus (LIFG) and in particular whether the LIFG plays a role in sublexical phonological processing such as syllabification or whether it is directly involved in phonetic encoding and the generation of articulatory codes. To answer this question, we contrasted the brain activation patterns elicited by pseudowords with high- or low-sublexical frequency components, which we expected would reveal areas related to the generation of articulatory codes but not areas related to phonological encoding. We found significant activation of a premotor network consisting of the dorsal precentral gyrus, the inferior frontal gyrus bilaterally, and the supplementary motor area for low- versus high-sublexical frequency pseudowords. Based on our hypothesis, we concluded that these areas and in particular the LIFG are involved in phonetic and not phonological encoding. We further discuss our findings with respect to the mechanisms of phonetic encoding and provide evidence in support of a functional segregation of the posterior part of Broca's area, the pars opercularis. C1 [Papoutsi, Marina; Bednar, James A.] Univ Edinburgh, Inst Adapt & Neural Computat, Edinburgh EH8 9YL, Midlothian, Scotland. [Papoutsi, Marina; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging Modeling Sect, Voice Speech & Language Branch, NIH, Bethesda, MD USA. [de Zwart, Jacco A.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Jansma, J. Martijn] NIMH, Neuroimaging Sect, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Pickering, Martin J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland. RP Papoutsi, M (reprint author), Univ Cambridge, Ctr Speech Language & Brain, Downing St, Cambridge CB2 3EB, England. EM marina@csl.psychol.cam.ac.uk FU Neuroinformatics Doctoral Training Centre studentship; UK Engineering and Physical Sciences Research Council; Greek Bakalas Bros Foundation; National Institute on Deafness and Other Communication Disorders of the US National Institutes of Health; National Institute of Neurological Disorders and Stroke of the US National Institutes of Health FX Neuroinformatics Doctoral Training Centre studentship; UK Engineering and Physical Sciences Research Council; Greek Bakalas Bros Foundation to MP; Intramural Research Program of the National Institute on Deafness and Other Communication Disorders of the US National Institutes of Health; Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the US National Institutes of Health to JAdZ and JMJ. NR 58 TC 64 Z9 64 U1 4 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2009 VL 19 IS 9 BP 2156 EP 2165 DI 10.1093/cercor/bhn239 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 481JT UT WOS:000268806900017 PM 19181696 ER PT J AU Clore, GM Iwahara, J AF Clore, G. Marius Iwahara, Junji TI Theory, Practice, and Applications of Paramagnetic Relaxation Enhancement for the Characterization of Transient Low-Population States of Biological Macromolecules and Their Complexes SO CHEMICAL REVIEWS LA English DT Review ID NUCLEAR-MAGNETIC-RESONANCE; RESIDUAL DIPOLAR COUPLINGS; PROTEIN-PROTEIN ASSOCIATION; LONG-RANGE STRUCTURE; SITE-DIRECTED SPIN; CYTOCHROME-C PEROXIDASE; MOLECULAR-STRUCTURE DETERMINATION; 3-DIMENSIONAL SOLUTION STRUCTURE; HETERONUCLEAR NMR-SPECTROSCOPY; MALTODEXTRIN-BINDING-PROTEIN C1 [Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Iwahara, Junji] Univ Texas Med Branch, Dept Biochem & Mol Biol, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov; j.iwahara@utmb.edu RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Intramural NIH HHS [Z01 DK029023-17, Z01 DK029039-01, Z01 DK029042-01, Z01 DK029043-01] NR 241 TC 256 Z9 262 U1 12 U2 113 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 J9 CHEM REV JI Chem. Rev. PD SEP PY 2009 VL 109 IS 9 BP 4108 EP 4139 DI 10.1021/cr900033p PG 32 WC Chemistry, Multidisciplinary SC Chemistry GA 493XU UT WOS:000269773600007 PM 19522502 ER PT J AU Bartoshuk, LM Catalanotto, FA Duffy, VB Grushka, M Mayo, VD Skarulis, MC Snyder, DJ AF Bartoshuk, Linda M. Catalanotto, Frank A. Duffy, Valerie B. Grushka, Miriam Mayo, Vicki D. Skarulis, Monica C. Snyder, Derek J. TI Taste Damage Associated with Otitis Media SO CHEMICAL SENSES LA English DT Meeting Abstract CT 31st Annual Meeting of the Association-for-Chemoreception-Sciences CY APR 22-23, 2009 CL Sarasota, FL SP Assoc Chemorecept Sci C1 [Bartoshuk, Linda M.; Catalanotto, Frank A.; Grushka, Miriam; Mayo, Vicki D.; Snyder, Derek J.] Univ Florida, Ctr Smell & Taste, Gainesville, FL USA. [Duffy, Valerie B.] Univ Connecticut, Storrs, CT USA. [Skarulis, Monica C.] NIH, Bethesda, MD 20892 USA. [Snyder, Derek J.] Yale Univ, New Haven, CT USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X J9 CHEM SENSES JI Chem. Senses PD SEP PY 2009 VL 34 IS 7 BP A119 EP A120 PG 2 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA 486LE UT WOS:000269196800382 ER PT J AU Elson, AET Dotson, CD Egan, JM Munger, SD AF Elson, Amanda E. T. Dotson, Cedrick D. Egan, Josephine M. Munger, Steven D. TI Modulation of Sweet Taste Sensitivity by Glucagon Signaling in Taste Buds SO CHEMICAL SENSES LA English DT Meeting Abstract CT 31st Annual Meeting of the Association-for-Chemoreception-Sciences CY APR 22-23, 2009 CL Sarasota, FL SP Assoc Chemorecept Sci C1 [Elson, Amanda E. T.; Dotson, Cedrick D.; Munger, Steven D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X J9 CHEM SENSES JI Chem. Senses PD SEP PY 2009 VL 34 IS 7 BP A39 EP A40 PG 2 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA 486LE UT WOS:000269196800129 ER PT J AU Roullet, FI Wohr, M Yang, M Crawley, JN AF Roullet, Florence I. Woehr, Markus Yang, Mu Crawley, Jacqueline N. TI Scent Marking and Countermarking Behaviors as a Measure of Olfactory Communication in the BTBR T plus tf/J Inbred Strain, a Mouse Model of Autism SO CHEMICAL SENSES LA English DT Meeting Abstract CT 31st Annual Meeting of the Association-for-Chemoreception-Sciences CY APR 22-23, 2009 CL Sarasota, FL SP Assoc Chemorecept Sci C1 [Roullet, Florence I.; Woehr, Markus; Yang, Mu; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X J9 CHEM SENSES JI Chem. Senses PD SEP PY 2009 VL 34 IS 7 BP A23 EP A23 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA 486LE UT WOS:000269196800078 ER PT J AU Taveira-DaSilva, AM Burstein, D Hathaway, OM Fontana, JR Gochuico, BR Avila, NA Moss, J AF Taveira-DaSilva, Angelo M. Burstein, Dora Hathaway, Olanda M. Fontana, Joseph R. Gochuico, Bernardette R. Avila, Nilo A. Moss, Joel TI Pneumothorax After Air Travel in Lymphangioleiomyomatosis, Idiopathic Pulmonary Fibrosis, and Sarcoidosis SO CHEST LA English DT Article ID MANIFESTATIONS; DISEASE AB Background: The prevalence of pneumothorax associated with travel in patients with interstitial lung diseases is unknown. In patients with lymphangioleiomyomatosis (LAM), in whom pneumothorax is common, patients are often concerned about the occurrence of a life-threatening event during air travel. The aim of this study was to determine the prevalence of pneumothorax associated with air travel in patients with LAM, idiopathic pulmonary fibrosis (IPF), and sarcoidosis. Methods: Records and imaging studies of 449 patients traveling to the National Institutes of Health were reviewed. Results: A total of 449 patients traveled 1,232 times; 299 by airplane (816 trips) and 150 by land (416 trips). Sixteen of 281 LAM patients arrived at their destination with a pneumothorax. In 5 patients, the diagnosis was made by chest roentgenogram, and in 11 patients by CT scans only. Of the 16 patients, 14 traveled by airplane and 2 by land. Seven of the 16 patients, 1. of whom traveled by train, had a new pneumothorax; 9 patients had chronic pneumothoraces. A new pneumothorax was more likely in patients with large cysts and more severe disease. The frequency of a new pneumothorax for LAM patients who traveled by airplane was 2.9% (1.1 per 100 flights) and by ground transportation, 1.3% (0.5 per 100 trips). No IPF (n = 76) or sarcoidosis (n = 92) patients presented with a pneumothorax. Conclusions: In interstitial lung diseases with a high prevalence of spontaneous pneumothorax, there is a relatively low risk of pneumothorax following air travel. In LAM, the presence of a pneumothorax associated with air travel may be related to the high incidence of pneumothorax and not to travel itself. (CHEST 2009; 136:665-670) C1 [Taveira-DaSilva, Angelo M.; Burstein, Dora; Hathaway, Olanda M.; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Fontana, Joseph R.] NHLBI, Pulm Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Gochuico, Bernardette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Avila, Nilo A.] NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Taveira-DaSilva, AM (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,Room 6D05,MSC 1590, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute; National Human Genome Research Institute, National Institutes of Health FX Funding/Support: This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute, National Institutes of Health. NR 20 TC 18 Z9 18 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD SEP PY 2009 VL 136 IS 3 BP 665 EP 670 DI 10.1378/chest.08-3034 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 493JT UT WOS:000269733400006 PM 19318672 ER PT J AU Storch, EA Khanna, M Merlo, LJ Loew, BA Franklin, M Reid, JM Goodman, WK Murphy, TK AF Storch, Eric A. Khanna, Muniya Merlo, Lisa J. Loew, Benjamin A. Franklin, Martin Reid, Jeannette M. Goodman, Wayne K. Murphy, Tanya K. TI Children's Florida Obsessive Compulsive Inventory: Psychometric Properties and Feasibility of a Self-Report Measure of Obsessive-Compulsive Symptoms in Youth SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Obsessive-Compulsive disorder; Children; Assessment; Treatment; Validity; Reliability ID TEST-RETEST RELIABILITY; MULTIDIMENSIONAL ANXIETY SCALE; BEHAVIOR CHECKLIST; FUNCTIONAL IMPAIRMENT; DISORDER; ADOLESCENTS; VALIDITY; VALIDATION; THERAPY; VERSION AB This report describes the development and psychometric properties of the Children's Florida Obsessive Compulsive Inventory (C-FOCI). Designed specifically as a brief measure for assessing obsessive-compulsive symptoms, the C-FOCI was created for use in both clinical and community settings. Study 1 included 82 children and adolescents diagnosed with primary Obsessive-Compulsive Disorder, and their parents. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was administered to assess symptom severity. Thereafter, parents completed the Child Obsessive-Compulsive Impact Scale-Parent Version and Child Behavior Checklist, and youth completed the C-FOCI, Child Obsessive-Compulsive Impact Scale-Child Version, Multidimensional Anxiety Scale for Children, and Children's Depression Inventory-Short Form. A subgroup of 21 individuals was retested with the C-FOCI after completing 14 sessions of intensive cognitive-behavioral therapy. Construct validity of the C-FOCI was supported vis-A -vis evidence of treatment sensitivity, and moderate relations with clinician-rated symptom severity, the CY-BOCS Symptom Checklist, child- and parent-rated functional impairment, child-rated anxiety, and parent-rated internalizing symptoms. Discriminant validity was evidenced by weak relationships with parent-reports of externalizing symptoms. For Study 2, 191 non-clinical adolescents completed the C-FOCI to assess the feasibility of internet administration. Overall, internal consistency was acceptable for the C-FOCI Symptom Checklist and Severity Scale, and respondents were able to complete the measure with little difficulty. Taken together, the findings of Studies 1 and 2 provide initial support for the reliability and validity of the C-FOCI for the assessment of pediatric obsessive-compulsive symptoms. C1 [Storch, Eric A.; Reid, Jeannette M.; Murphy, Tanya K.] Univ S Florida, Dept Pediat, St Petersburg, FL 33701 USA. [Storch, Eric A.; Murphy, Tanya K.] Univ S Florida, Dept Psychiat, St Petersburg, FL 33701 USA. [Khanna, Muniya; Loew, Benjamin A.; Franklin, Martin] Univ Penn, Ctr Treatment & Study Anxiety, Philadelphia, PA 19104 USA. [Merlo, Lisa J.] Univ Florida, Dept Psychiat, Gainesville, FL 32611 USA. [Goodman, Wayne K.] NIH, Bethesda, MD 20892 USA. RP Storch, EA (reprint author), Univ S Florida, Dept Pediat, 800 6th St S,4th Floor, St Petersburg, FL 33701 USA. EM estorch@health.usf.edu RI Storch, Eric/I-4935-2012 FU NIMH NIH HHS [L40 MH081950-02] NR 57 TC 26 Z9 27 U1 5 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD SEP PY 2009 VL 40 IS 3 BP 467 EP 483 DI 10.1007/s10578-009-0138-9 PG 17 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 451UG UT WOS:000266495700010 PM 19326209 ER PT J AU Martinez, HG Prajapati, SI Estrada, CA Jimenez, F Quinones, MP Wu, I Bahadur, A Sanderson, A Johnson, CR Shim, M Keller, C Ahuja, SS AF Martinez, Hernan G. Prajapati, Suresh I. Estrada, Carlos A. Jimenez, Fabio Quinones, Marlon P. Wu, Isabel Bahadur, Ali Sanderson, Allen Johnson, Christopher R. Shim, Minsub Keller, Charles Ahuja, Seema S. TI Microscopic Computed Tomography-Based Virtual Histology for Visualization and Morphometry of Atherosclerosis in Diabetic Apolipoprotein E Mutant Mice SO CIRCULATION LA English DT Editorial Material ID LESIONS C1 [Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, Dept Med, San Antonio, TX 78229 USA. [Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA. [Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Prajapati, Suresh I.; Wu, Isabel; Bahadur, Ali; Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Sanderson, Allen; Johnson, Christopher R.] Univ Utah, Sci Comp & Imaging Inst, Salt Lake City, UT USA. [Shim, Minsub] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Ahuja, Seema S.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Keller, C (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, Dept Med, 7703 Floyd Curl Dr,MC7870, San Antonio, TX 78229 USA. EM ahuja@uthscsa.edu OI Keller, Charles/0000-0003-2505-7487 FU NCRR NIH HHS [P41 RR012553, 5P41RR012553]; NIAMS NIH HHS [R01 AR 052755, R01 AR052755, R01 AR052755-01A2] NR 4 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 1 PY 2009 VL 120 IS 9 BP 821 EP U216 DI 10.1161/CIRCULATIONAHA.108.829531 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 489SZ UT WOS:000269444300015 PM 19720948 ER PT J AU Hsu, DT Pearson, GD AF Hsu, Daphne T. Pearson, Gail D. TI Heart Failure in Children Part II: Diagnosis, Treatment, and Future Directions SO CIRCULATION-HEART FAILURE LA English DT Article ID CRITICAL AORTIC-STENOSIS; MEDICINE PRACTICE GUIDELINES; RIGHT-VENTRICULAR FUNCTION; OF-CLINICAL-BIOCHEMISTRY; DILATED CARDIOMYOPATHY; NATRIURETIC PEPTIDE; NATURAL-HISTORY; RESYNCHRONIZATION THERAPY; BALLOON VALVULOPLASTY; CIRCULATORY SUPPORT C1 [Pearson, Gail D.] NHLBI, Heart Dev & Struct Dis Branch, NIH, Bethesda, MD 20892 USA. [Hsu, Daphne T.] Childrens Hosp Montefiore, Div Pediat Cardiol, Bronx, NY USA. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. RP Pearson, GD (reprint author), NHLBI, Heart Dev & Struct Dis Branch, NIH, 6701 Rockledge Dr,Room 8104, Bethesda, MD 20892 USA. EM pearsong@nhlbi.nih.gov OI Hsu, Daphne/0000-0002-2654-0430 FU NHLBI NIH HHS [HL 068290, HL 053392] NR 81 TC 16 Z9 17 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD SEP PY 2009 VL 2 IS 5 BP 490 EP 498 DI 10.1161/CIRCHEARTFAILURE.109.856229 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 494PY UT WOS:000269827500015 PM 19808380 ER PT J AU Wang, J Visness, CM Calatroni, A Gergen, PJ Mitchell, HE Sampson, HA AF Wang, J. Visness, C. M. Calatroni, A. Gergen, P. J. Mitchell, H. E. Sampson, H. A. TI Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE Alternaria; asthma; cockroach; dust mite; sensitization ID SKIN-TEST REACTIVITY; INDOOR ALLERGENS; EXPOSURE; IGE; CHILDHOOD; RISK; SENSITIVITY; SEVERITY; ASSOCIATION; ANTIBODIES AB P>Background Asthma causes significant morbidity in children, and studies have demonstrated that environmental allergies contribute to increased asthma morbidity. Objective We investigated the differences between allergen skin tests and specific IgE (SIgE) and the role of IgG in regards to allergen exposure levels, and asthma morbidity in inner-city children. Methods Five hundred and six serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for SIgE to cockroach (Blattella germanica), dust mite (Dermatophagoides farinae), and Alternaria as well as specific IgG (SIgG) and IgG(4) to cockroach (B. germanica) and total IgE levels. Associations between sensitization to these allergens, exposures, and asthma morbidity were determined. Results Sensitization to environmental allergens and total IgE correlated with increased health care and medication use, but not with symptoms of wheeze. Sensitization with exposure to cockroach was associated with increased asthma morbidity, whereas dust mite sensitization was correlated with asthma morbidity independent of exposure. There was also a strong correlation between SIgE levels and skin test results, but the tests did not always agree. The relationship between SIgE and asthma morbidity is linear with no obvious cutoff value. Increased Bla g 1 in the home was a good predictor for sensitization; however, this relationship was not demonstrated for Der f 1. Cockroach SIgG correlated with increased health care use, however, there was no modifying effect of SIgG or SIgG(4) on the association between cockroach SIgE and asthma morbidity. Conclusions SIgE levels and skin prick test results to environmental allergens can serve as markers of severe asthma for inner-city children. Asthma morbidity increased in a linear manner with SIgE levels. IgG was not an important predictor or modifier of asthma morbidity. C1 [Wang, J.] Mt Sinai Hosp, Mt Sinai Sch Med, Div Allergy & Immunol, Dept Pediat, New York, NY 10029 USA. [Visness, C. M.; Calatroni, A.; Mitchell, H. E.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Gergen, P. J.] NIAID, NIH, Bethesda, MD 20892 USA. RP Wang, J (reprint author), Mt Sinai Hosp, Mt Sinai Sch Med, Div Allergy & Immunol, Dept Pediat, Box 1198,1Gustave L Levy Pl, New York, NY 10029 USA. EM julie.wang@mssm.edu FU National Institutes of Allergy and Infectious Disease (National Institutes of Health, Bethesda, MD, USA) [UOI A1-30751, A1-30752, A1-30756, A1-30772, A1-30773-01, A1-30777, A1-30779, A1-30780, N01-A1-15105]; National Center for Research Resources (NCRR) [M01-RR-00071]; component of the National Institutes of Health (NIH) FX Funding source: The National Cooperative Inner-City Asthma Study was supported by grants UOI A1-30751, A1-30752, A1-30756, A1-30772, A1-30773-01, A1-30777, A1-30779, A1-30780, and N01-A1-15105 from the National Institutes of Allergy and Infectious Disease (National Institutes of Health, Bethesda, MD, USA). The project described was supported in part by Grant number M01-RR-00071 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. NR 25 TC 43 Z9 45 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD SEP PY 2009 VL 39 IS 9 BP 1381 EP 1389 DI 10.1111/j.1365-2222.2009.03225.x PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 480TF UT WOS:000268759000015 PM 19489919 ER PT J AU Levin, MJ Oxman, MN Johnson, GR Zhang, JH Hayward, AR Weinberg, A AF Levin, Myron J. Oxman, Michael N. Johnson, Gary R. Zhang, Jane H. Hayward, Anthony R. Weinberg, Adriana TI Immune Response to a Refrigerator-Stable Zoster Vaccine SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Letter ID HERPES-ZOSTER C1 [Levin, Myron J.; Weinberg, Adriana] Univ Colorado Denver, Dept Pediat, Aurora, CO 80045 USA. [Weinberg, Adriana] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Weinberg, Adriana] Univ Colorado Denver, Dept Pathol, Aurora, CO 80045 USA. [Oxman, Michael N.] San Diego Healthcare Syst, Dept Vet Affairs, San Diego, CA USA. [Johnson, Gary R.; Zhang, Jane H.] Coordinating Ctr, Cooperat Studies Program, Dept Vet Affairs, West Haven, CT USA. [Hayward, Anthony R.] NIAID, NIH, Bethesda, MD 20892 USA. RP Levin, MJ (reprint author), Univ Colorado Denver, Dept Pediat, Bldg 401,1784 Racine St, Aurora, CO 80045 USA. EM myron.levin@ucdenver.edu NR 4 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD SEP PY 2009 VL 16 IS 9 BP 1381 EP 1381 DI 10.1128/CVI.00338-08 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 491LL UT WOS:000269580200021 PM 19734522 ER PT J AU Cheever, MA Allison, JP Ferris, AS Finn, OJ Hastings, BM Hecht, TT Mellman, I Prindiville, SA Viner, JL Weiner, LM Matrisian, LM AF Cheever, Martin A. Allison, James P. Ferris, Andrea S. Finn, Olivera J. Hastings, Benjamin M. Hecht, Toby T. Mellman, Ira Prindiville, Sheila A. Viner, Jaye L. Weiner, Louis M. Matrisian, Lynn M. TI The Prioritization of Cancer Antigens: A National Cancer Institute Pilot Project for the Acceleration of Translational Research SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; PHASE-I TRIAL; KEYHOLE LIMPET HEMOCYANIN; TUMOR-ASSOCIATED ANTIGEN; CYTOTOXIC T-LYMPHOCYTES; PROSTATE-CANCER; DNA VACCINE; IMMUNE-RESPONSES; MELANOMA PATIENTS; TESTIS ANTIGEN AB The purpose of the National Cancer Institute pilot project to prioritize cancer antigens was to develop a well-vetted, priority-ranked list of cancer vaccine target antigens based on predefined and preweighted objective criteria. An additional aim was for the National Cancer Institute to test a new approach for prioritizing translational research opportunities based on an analytic hierarchy process for dealing with complex decisions. Antigen prioritization involved developing a list of "ideal" cancer antigen criteria/characteristics, assigning relative weights to those criteria using pairwise comparisons, selecting 75 representative antigens for comparison and ranking, assembling information on the predefined criteria for the selected antigens, and ranking the antigens based on the predefined, preweighted criteria. Using the pairwise approach, the result of criteria weighting, in descending order, was as follows: (a) therapeutic function, (b) immunogenicity, (c) role of the antigen in oncogenicity, (d) specificity, (e) expression level and percent of antigen-positive cells, (f) stem cell expression, (g) number of patients with antigen-positive cancers, (h) number of antigenic epitopes, and (1) cellular location of antigen expression. None of the 75 antigens had all of the characteristics of the ideal cancer antigen. However, 46 were immunogenic in clinical trials and 20 of them had suggestive clinical efficacy in the "therapeutic function" category. These findings reflect the current status of the cancer vaccine field, highlight the possibility that additional organized efforts and funding would accelerate the development of therapeutically effective cancer vaccines, and accentuate the need for prioritization. (Clin Cancer Res 2009;15(17):5323-37) C1 [Cheever, Martin A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Allison, James P.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Ferris, Andrea S.; Hastings, Benjamin M.] Decis Lens Inc, Arlington, VA USA. [Finn, Olivera J.] Univ Pittsburgh, Pittsburgh, PA USA. [Hecht, Toby T.] NCI, Translat Res Program, NIH, Bethesda, MD 20892 USA. [Prindiville, Sheila A.; Viner, Jaye L.; Matrisian, Lynn M.] NCI, Coordinating Ctr Clin Trials, NIH, Bethesda, MD 20892 USA. [Mellman, Ira] Genentech Inc, San Francisco, CA 94080 USA. [Weiner, Louis M.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Cheever, MA (reprint author), Seattle Canc Care Alliance, 825 Eastlake Ave E,G4-810, Seattle, WA 98109 USA. EM mcheever@seattlecca.org FU NIH, National Cancer Institute [UL1 FIR 025014-01, P30 CA 15704-35] FX NIH, National Cancer Institute (M.A. Cheever); UL1 FIR 025014-01 (principal investigator: M. Disis); and P30 CA 15704-35 (principal investigator: L. Hartwell). NR 79 TC 472 Z9 485 U1 2 U2 26 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2009 VL 15 IS 17 BP 5323 EP 5337 DI 10.1158/1078-0432.CCR-09-0737 PG 15 WC Oncology SC Oncology GA 491GF UT WOS:000269565800007 PM 19723653 ER PT J AU Comstock, CES Augello, MA Benito, RP Karch, J Tran, TH Utama, FE Tindall, EA Wang, Y Burd, CJ Groh, EM Hoang, HN Giles, GG Severi, G Hayes, VM Henderson, BE Le Marchand, L Kolonel, LN Haiman, CA Baffa, R Gomella, LG Knudsen, ES Rui, H Henshall, SM Sutherland, RL Knudsen, KE AF Comstock, Clay E. S. Augello, Michael A. Benito, Ruth Pe Karch, Jason Tran, Thai H. Utama, Fransiscus E. Tindall, Elizabeth A. Wang, Ying Burd, Craig J. Groh, Eric M. Hoang, Hoa N. Giles, Graham G. Severi, Gianluca Hayes, Vanessa M. Henderson, Brian E. Le Marchand, Loic Kolonel, Laurence N. Haiman, Christopher A. Baffa, Raffaele Gomella, Leonard G. Knudsen, Erik S. Rui, Hallgeir Henshall, Susan M. Sutherland, Robert L. Knudsen, Karen E. TI Cyclin D1 Splice Variants: Polymorphism, Risk, and Isoform-Specific Regulation in Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID MANTLE CELL LYMPHOMA; ANDROGEN-RECEPTOR; BREAST-CANCER; LUNG-CANCER; PROTEIN EXPRESSION; GENE POLYMORPHISM; A870G POLYMORPHISM; COLORECTAL-CANCER; DEPENDENT KINASES; AA GENOTYPE AB Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, pro-tumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. Results: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed non-correlated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. Conclusions: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism. (Clin Cancer Res 2009;15(17):5338-49) C1 [Knudsen, Karen E.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA. [Baffa, Raffaele; Gomella, Leonard G.; Knudsen, Karen E.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Urol, Philadelphia, PA 19107 USA. [Benito, Ruth Pe; Tindall, Elizabeth A.; Hayes, Vanessa M.; Henshall, Susan M.; Sutherland, Robert L.] St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Sydney, NSW 2010, Australia. [Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Tindall, Elizabeth A.; Hayes, Vanessa M.] Univ New S Wales, Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Hoang, Hoa N.; Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Melbourne, Vic, Australia. [Karch, Jason; Wang, Ying; Groh, Eric M.] Univ Cincinnati, Dept Cell & Canc Biol, Cincinnati, OH USA. [Burd, Craig J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Knudsen, KE (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, 233 S 10th St,BLSB 1008A, Philadelphia, PA 19107 USA. EM Karen.Knudsen@kimmelcancercenter.org OI Comstock, Clay/0000-0001-5867-1489; Burd, Craig/0000-0002-6899-6751; Giles, Graham/0000-0003-4946-9099 FU American Chemical Society [IRG114958]; NIH [CA099996]; National Health and Medical Research Council [276408]; Cancer Institute New South Wales; Australian Cancer Research Foundation; FIT Hall Trust; National Health and Medical Research Council, Australia [209057, 251533, 450104]; VicHealth; The Cancer Council Victoria; The Whitten Foundation; Tattersall's; National Cancer Institute [CA63464, CA54281]; Department of Health and Human Services [N01-PC-35139, N01-PC-35137] FX American Chemical Society grant IRG114958 (C.E.S. Comstock), NIH grant CA099996 (K.E. Knudsen), National Health and Medical Research Council grant 276408 (R.L. Sutherland), Cancer Institute New South Wales, Australian Cancer Research Foundation, and FIT Hall Trust. The Risk Factors for Prostate Cancer Study was supported by the National Health and Medical Research Council, Australia (209057, 251533, and 450104); VicHealth; The Cancer Council Victoria; The Whitten Foundation; and Tattersall's. The Multiethnic Cohort Study was supported by the National Cancer Institute grants CA63464 and CA54281 and Department of Health and Human Services contracts N01-PC-35139 and N01-PC-35137). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 72 TC 42 Z9 43 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2009 VL 15 IS 17 BP 5338 EP 5349 DI 10.1158/1078-0432.CCR-08-2865 PG 12 WC Oncology SC Oncology GA 491GF UT WOS:000269565800008 PM 19706803 ER PT J AU Choi, WWL Weisenburger, DD Greiner, TC Piris, MA Banham, AH Delabie, J Braziel, RM Geng, HM Iqbal, J Lenz, G Vose, JM Hans, CP Fu, K Smith, LM Li, M Liu, ZF Gascoyne, RD Rosenwald, A Ott, G Rimsza, LM Campo, E Jaffe, ES Jaye, DL Staudt, LM Chan, WC AF Choi, William W. L. Weisenburger, Dennis D. Greiner, Timothy C. Piris, Miguel A. Banham, Alison H. Delabie, Jan Braziel, Rita M. Geng, Huimin Iqbal, Javeed Lenz, Georg Vose, Julie M. Hans, Christine P. Fu, Kai Smith, Lynette M. Li, Min Liu, Zhongfeng Gascoyne, Randy D. Rosenwald, Andreas Ott, German Rimsza, Lisa M. Campo, Elias Jaffe, Elaine S. Jaye, David L. Staudt, Louis M. Chan, Wing C. TI A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy SO CLINICAL CANCER RESEARCH LA English DT Article ID GERMINAL CENTER PHENOTYPE; TISSUE MICROARRAY; TRANSCRIPTION FACTOR; RISK STRATIFICATION; PREDICTS SURVIVAL; PROGNOSTIC IMPACT; BCL-2 EXPRESSION; HODGKIN LYMPHOMA; GENE; FOXP1 AB Purpose: Hans and coworkers previously developed an immunohistochemical algorithm with similar to 80% concordance with the gene expression profiling (GEP) classification of diffuse large B-cell lymphoma (DLBCL) into the germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes. Since then, new antibodies specific to germinal center B-cells have been developed, which might improve the performance of an immunostain algorithm. Experimental Design: We studied 84 cases of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP)-treated DLBCL (47 GCB, 37 ABC) with GCET1, CD10, BCL6, MUM1, FOXP1, BCL2, MTA3, and cyclin D2 immunostains, and compared different combinations of the immunostaining results with the GEP classification. A perturbation analysis was also applied to eliminate the possible effects of interobserver or intraobserver variations. A separate set of 63 DLBCL cases treated with rituximab plus CHOP (37 GCB, 26 ABC) was used to validate the new algorithm. Results: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance. Perturbation analysis indicated that the algorithm was robust within the range of observer variance. The new algorithm predicted 3-year overall survival of the validation set [GCB (87%) versus ABC (44%); P < 0.001], simulating the predictive power of the GEP classification. For a group of seven primary mediastinal large B-cell lymphoma, the new algorithm is a better prognostic classifier (all "GCB") than the Hans' algorithm (two GCB, five non-GCB). Conclusion: Our new algorithm is significantly more accurate than the Hans' algorithm and will facilitate risk stratification of DLBCL patients and future DLBCL research using archival materials. (Clin Cancer Res 2009;15(17):5494-502) C1 [Choi, William W. L.; Weisenburger, Dennis D.; Greiner, Timothy C.; Geng, Huimin; Iqbal, Javeed; Hans, Christine P.; Fu, Kai; Li, Min; Liu, Zhongfeng; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Vose, Julie M.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Smith, Lynette M.] Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE USA. [Piris, Miguel A.] Spanish Natl Canc Ctr, Mol Pathol Program, Lymphoma Grp, Madrid, Spain. [Banham, Alison H.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. [Delabie, Jan] Univ Oslo, Rikshosp, Radiumhosp Med Ctr, Dept Pathol, N-0027 Oslo, Norway. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Lenz, Georg; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Rosenwald, Andreas; Ott, German] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Inst Clin Pharmacol, Stuttgart, Germany. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Campo, Elias] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer, Hematopathol Sect,Lab Pathol, Barcelona, Spain. [Jaye, David L.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. RP Chan, WC (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 983135 Nebraska Med Ctr, Omaha, NE USA. EM jchan@unmc.edu RI Piris, Miguel/B-7067-2008; Lenz, Georg/I-6844-2012; Banham, Alison/B-2966-2009; OI Piris, Miguel/0000-0001-5839-3634; Banham, Alison/0000-0002-3197-273X; Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793 FU National Cancer Institute [U01CAl14778, CA36727]; Leukaemia Research Fund of the United Kingdom FX National Cancer Institute Grants U01CAl14778 (W.C. Chan) and CA36727 (W.C. Chan, K. Fu, T.C. Greiner, J.M. Vose, and D.D. Weisenburger), and the Leukaemia Research Fund of the United Kingdom (A.H. Banham). NR 45 TC 307 Z9 330 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2009 VL 15 IS 17 BP 5494 EP 5502 DI 10.1158/1078-0432.CCR-09-0113 PG 9 WC Oncology SC Oncology GA 491GF UT WOS:000269565800025 PM 19706817 ER PT J AU Wei, JS Johansson, P Chen, QR Song, YK Durinck, S Wen, XY Cheuk, ATC Smith, MA Houghton, P Morton, C Khan, J AF Wei, Jun S. Johansson, Peter Chen, Qing-Rong Song, Young K. Durinck, Steffen Wen, Xinyu Cheuk, Adam T. C. Smith, Malcolm A. Houghton, Peter Morton, Christopher Khan, Javed TI microRNA Profiling Identifies Cancer-Specific and Prognostic Signatures in Pediatric Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ARTIFICIAL NEURAL-NETWORKS; GENE-EXPRESSION; MICROARRAY ANALYSIS; CELL-PROLIFERATION; NEUROBLASTOMA; DIFFERENTIATION; AMPLIFICATION; TARGET; CLASSIFICATION AB Purpose: microRNAs have been shown to be involved indifferent human cancers. We therefore have performed expression profiles on a panel of pediatric tumors to identify cancer-specific microRNAs. We also investigated if microRNAs are coregulated with their host gene. Experimental Design: We performed parallel microRNAs and mRNA expression profiling on 57 tumor xenografts and cell lines representing 10 different pediatric solid tumors using microarrays. For those microRNAs that map to their host mRNA, we calculated correlations between them. Results: We found that the majority of cancer types clustered together based on their global microRNA expression profiles by unsupervised hierarchical clustering. Fourteen microRNAs were significantly differentially expressed between rhabdomyosarcoma and neuroblastoma, and 8 of them were validated in independent patient tumor samples. Exploration of the expression of microRNAs in relationship with their host genes showed that the expression for 43 of 68 (63%) microRNAs located inside known coding genes was significantly correlated with that of their host genes. Among these 43 microRNAs, 5 of 7 microRNAs in the OncomiR-1 cluster correlated significantly with their host gene MIRHG1 (P < 0.01). In addition, high expression of MIRHG1 was significantly associated with high stage and MYCN amplification in neuroblastoma tumors, and the expression level of MIRHG1 could predict the outcome of neuroblastoma patients independently from the current neuroblastoma risk-stratification in two independent patient cohorts. Conclusion: Pediatric cancers express cancer-specific microRNAs. The high expression of the OncomiR-1 host gene MIRHG1 correlates with poor outcome for patients with neuroblastoma, indicating important oncogenic functions of this microRNA cluster in neuroblastoma biology. (Clin Cancer Res 2009;15(17):5560-8) C1 [Wei, Jun S.; Johansson, Peter; Chen, Qing-Rong; Song, Young K.; Durinck, Steffen; Wen, Xinyu; Cheuk, Adam T. C.; Khan, Javed] Natl Canc Inst, Oncogenom Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD 20877 USA. [Chen, Qing-Rong; Wen, Xinyu] NCI, Adv Biomed Comp Ctr, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Houghton, Peter; Morton, Christopher] St Jude Childrens Hosp, Memphis, TN 38105 USA. RP Wei, JS (reprint author), Natl Canc Inst, Oncogenom Sect, Pediat Oncol Branch, Adv Technol Ctr, 8717 Grovemont Circle,Room 225D, Gaithersburg, MD 20877 USA. EM weij@mail.nih.gov; khanjav@mail.nih.gov RI Houghton, Peter/E-3265-2011; Khan, Javed/P-9157-2014; Johansson, Peter/K-1053-2014 OI Khan, Javed/0000-0002-5858-0488; Johansson, Peter/0000-0001-7015-5452 FU NIH, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 33 Z9 34 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2009 VL 15 IS 17 BP 5560 EP 5568 DI 10.1158/1078-0432.CCR-08-3287 PG 9 WC Oncology SC Oncology GA 491GF UT WOS:000269565800033 PM 19706822 ER PT J AU Narva, AS AF Narva, Andrew S. TI Assessment of Kidney Function for Drug Dosing SO CLINICAL CHEMISTRY LA English DT Editorial Material ID ESTIMATED GFR C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Narva, AS (reprint author), NIDDK, NIH, 2 Democracy Plaza,Room 645,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov NR 4 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD SEP PY 2009 VL 55 IS 9 BP 1609 EP 1611 DI 10.1373/clinchem.2009.127944 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 492DY UT WOS:000269636000003 PM 19589844 ER PT J AU Keil, MF Merke, DP Gandhi, R Wiggs, EA Obunse, K Stratakis, CA AF Keil, Margaret F. Merke, Deborah P. Gandhi, Roma Wiggs, Edythe A. Obunse, Kathy Stratakis, Constantine A. TI Quality of life in children and adolescents 1-year after cure of Cushing syndrome: a prospective study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID CONSENSUS STATEMENT; DIAGNOSTIC-TESTS; DISEASE; HEALTH; HYPERCORTISOLISM; REVERSIBILITY; OVERWEIGHT; REMISSION; CORTISOL; REMOVAL AB Objective Cushing syndrome (CS) in children is associated with symptoms that may impair health related quality of life (HRQL). There are no prospective reports of HRQL in children with CS. Methods Prospective study of 40 children (mean age 13 +/- 3 center dot 2 years) with CS evaluated prior to and 1-year post-treatment. The Child Health Questionnaire (CHQ) was used to assess HRQL; Wechsler Intelligence Scale for Children (WASI) was used to assess cognitive function, and patient-reported symptoms were assessed with a CS symptom checklist. Results Active CS was associated with low physical and psychosocial summary scores compared to US population data (P < 0 center dot 001). Despite improvement from pre- to 1-year postcure, residual impairment remained in physical summary and function, and role-physical, global health and emotional impact (parent) scores. Incomplete recovery of adrenal function at 1-year post-treatment was associated with impaired scores. WASI IQ scores declined and a correlation was noted between age at first evaluation and IQ score changes. Most self-reported CS symptoms showed improvement, but forgetfulness, unclear thinking and decreased attention span did not improve after cure of CS. Conclusion CS in children and adolescents is associated with impaired HRQL, with residual impairment 1 year after cure. Our results also suggest that younger children are more likely to experience negative changes in cognitive function. HRQL is an important outcome measure in children and adolescents with CS and identification of factors that contribute to HRQL may help to diminish the physical and psychological burden of disease in this population of patients. C1 [Keil, Margaret F.; Gandhi, Roma; Stratakis, Constantine A.] NICHHD, Off Chief, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Keil, Margaret F.; Merke, Deborah P.; Stratakis, Constantine A.] NICHHD, Paediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. [Merke, Deborah P.; Stratakis, Constantine A.] NICHHD, Program Reprod Biol & Med, Bethesda, MD 20892 USA. [Merke, Deborah P.; Obunse, Kathy] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Wiggs, Edythe A.] NINDS, NIH, Bethesda, MD 20892 USA. RP Keil, MF (reprint author), Bldg 10,CRC,Room I-3330 E Labs,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov FU National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH) [Z01-HD-000642-04] FX We thank the patients and their families who participated in our research studies and donated their time for this investigation. This work was supported by the Eunice Kennedy Shriver, National Institute of Child Health and Human Development (NICHD), intramural National Institutes of Health (NIH) project Z01-HD-000642-04 to Dr C. Stratakis, and, in part, by the NIH Clinical Center. We would like to dedicate this report to one of the coauthors, Mrs Kathy Obunse who passed away suddenly as this investigation was being completed; Kathy was an experienced endocrine nurse of the NIH Clinical Center; she loved working with children with CS and was absolutely dedicated to her patients and their families. NR 37 TC 20 Z9 20 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2009 VL 71 IS 3 BP 326 EP 333 DI 10.1111/j.1365-2265.2008.03515.x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 482XN UT WOS:000268924000003 PM 19170709 ER PT J AU Waryah, AM Rehman, A Ahmed, ZM Bashir, ZH Khan, SY Zafar, AU Riazuddin, S Friedman, TB Riazuddin, S AF Waryah, A. M. Rehman, A. Ahmed, Z. M. Bashir, Z-H Khan, S. Y. Zafar, A. U. Riazuddin, S. Friedman, T. B. Riazuddin, S. TI DFNB74, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 12q14.2-q15 SO CLINICAL GENETICS LA English DT Article DE deafness; DFNB74; Pakistan; chromosome 12q14; 2-q15; ahl4 ID INNER-EAR; TRANSCRIPTION FACTOR; DEAFNESS; GENE; MUTATIONS; MAPS; MOUSE; DNA AB Autosomal recessive nonsyndromic hearing impairment (ARNSHI) segregating in three unrelated, large consanguineous Pakistani families (PKDF528, PKDF859 and PKDF326) is linked to markers on chromosome 12q14.2-q15. This novel locus is designated DFNB74. Maximum two-point limit of detection (LOD) scores of 5.6, 5.7 and 2.6 were estimated for markers D12S313,D12S83 and D12S75 at theta = 0 for recessive deafness segregating in these three families. Haplotype analyses identified a critical linkage interval of 5.35 cM (5.36 Mb) defined by D12S329 at 74.58 cM and D12S313 at 79.93 cM. DFNB74 is the second ARNSHI locus mapped to chromosome 12, but the physical intervals do not overlap with one another. A locus contributing to the early onset, rapidly progressing hearing loss of A/J mice (ahl4, age-related hearing loss 4) was reported to map to chromosome 10 in a region of conserved synteny to DFNB74, suggesting that ahl4 and DFNB74 may be due to mutations of the same gene in these two species. C1 [Waryah, A. M.; Rehman, A.; Bashir, Z-H; Khan, S. Y.; Zafar, A. U.; Riazuddin, S.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Ahmed, Z. M.; Riazuddin, S.; Friedman, T. B.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD USA. RP Riazuddin, S (reprint author), Univ Punjab, Natl Ctr Excellence Mol Biol, 87 W Canal Bank Rd, Lahore 53700, Pakistan. EM riaz@lhr.comsats.net.pk FU Higher Education Commission, Islamabad, Pakistan; EMRO/WHO-COMSTECH [RABGH 06 -07_24]; Ministry of Science and Technology (MoST), Islamabad; National Institute on Deafness and Other Communication Disorders [1 Z01 DC000039-12] FX The authors are grateful to the families who made this research possible. We thank the readers of this manuscript including Ken Johnson, Karen Friderici, Julie Schultz, and Byung Yoon Choi. We also thank Barbara Ploplis and Erich Boger for their technical assistance. This study was supported by the Higher Education Commission, Islamabad, Pakistan; EMRO/WHO-COMSTECH (RABGH 06 -07_24) and Ministry of Science and Technology (MoST), Islamabad. Part of this study was carried out in the USA and was supported by intramural funds from the National Institute on Deafness and Other Communication Disorders (1 Z01 DC000039-12) to TBF. NR 33 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD SEP PY 2009 VL 76 IS 3 BP 270 EP 275 DI 10.1111/j.1399-0004.2009.01209.x PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 498WG UT WOS:000270175600007 PM 19650862 ER PT J AU Sacktor, N Nakasujja, N Skolasky, RL Rezapour, M Robertson, K Musisi, S Katabira, E Ronald, A Clifford, DB Laeyendecker, O Quinn, TC AF Sacktor, Ned Nakasujja, Noeline Skolasky, Richard L. Rezapour, Mona Robertson, Kevin Musisi, Seggane Katabira, Elly Ronald, Allan Clifford, David B. Laeyendecker, Oliver Quinn, Thomas C. TI HIV Subtype D Is Associated with Dementia, Compared with Subtype A, in Immunosuppressed Individuals at Risk of Cognitive Impairment in Kampala, Uganda SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VIRUS TYPE-1 SUBTYPES; DISEASE PROGRESSION; GENETIC SUBTYPES; INFECTION; ENV; VARIANTS; THERAPY; TROPISM; COHORT; RATES AB Background. In the United States, clade B is the predominant human immunodeficiency virus (HIV) subtype, whereas in sub-Saharan Africa, clades A, C, and D are the predominant subtypes. HIV subtype may have an impact on HIV disease progression. The effect of HIV subtype on the risk of dementia has, to our knowledge, not been examined. The objective of this study was to examine the relationship between HIV subtype and the severity of HIV-associated cognitive impairment among individuals initiating antiretroviral therapy in Uganda. Methods. Sixty antiretroviral-naive HIV-infected individuals with advanced immunosuppression who were at risk of HIV-associated cognitive impairment underwent neurological, neuropsychological, and functional assessments, and gag and gp41 regions were subtyped. Subtype assignments were generated by sequence analysis using a portion of the gag and gp41 regions. Results. Thirty-three HIV-infected individuals were infected with subtype A, 2 with subtype C, 9 with subtype D, and 16 with A/D recombinants. Eight (89%) of 9 HIV-infected individuals with subtype D had dementia, compared with 7 (24%) of 33 HIV-infected individuals with subtype A (P = .004). Conclusions. These results suggest that, in untreated HIV-infected individuals with advanced immunosuppression who are at risk of developing HIV-associated cognitive impairment, HIV dementia may be more common among patients infected with subtype D virus than among those infected with subtype A virus. These findings provide the first evidence, to our knowledge, to demonstrate that HIV subtypes may have a pathogenetic factor with respect to their capacity to cause cognitive impairment. Additional studies are needed to confirm this observation and to define the mechanism by which subtype D leads to an increased risk of neuropathogenesis. C1 [Sacktor, Ned] Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. [Skolasky, Richard L.] Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD 21224 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21224 USA. [Rezapour, Mona; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Robertson, Kevin] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. [Clifford, David B.] Washington Univ, Dept Neurol, St Louis, MO USA. [Nakasujja, Noeline; Musisi, Seggane] Makerere Univ, Dept Psychiat, Kampala, Uganda. [Katabira, Elly] Makerere Univ, Dept Med, Kampala, Uganda. [Ronald, Allan] Univ Manitoba, Dept Med, Winnipeg, MB, Canada. RP Sacktor, N (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave,B 123, Baltimore, MD 21224 USA. EM sacktor@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Ronald, Allan/0000-0002-5746-3490; Laeyendecker, Oliver/0000-0002-6429-4760; Skolasky, Richard/0000-0002-2598-4427 FU National Institute of Neurological Disorders and Stroke [NS 32228]; National Institute of Mental Health [MH71150]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX The Neurologic AIDS Research Consortium, which receives support from National Institute of Neurological Disorders and Stroke (NS 32228), National Institute of Mental Health (MH71150); and the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 36 TC 63 Z9 63 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2009 VL 49 IS 5 BP 780 EP 786 DI 10.1086/605284 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 479MA UT WOS:000268662300019 PM 19622045 ER PT J AU Graham, BS Ledgerwood, JE Nabel, GJ AF Graham, B. S. Ledgerwood, J. E. Nabel, G. J. TI Vaccine Development in the Twenty-First Century: Changing Paradigms for Elusive Viruses SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Graham, B. S.; Ledgerwood, J. E.; Nabel, G. J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU Intramural NIH HHS [ZIA AI005047-07] NR 0 TC 8 Z9 8 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2009 VL 86 IS 3 BP 234 EP 236 DI 10.1038/clpt.2009.128 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 491AL UT WOS:000269549100007 PM 19707212 ER PT J AU Powers, JH Fleming, TR AF Powers, J. H. Fleming, T. R. TI Design, Conduct, and Analysis of Clinical Trials in Disease due to Methicillin-Resistant Staphylococcus aureus SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID NOSOCOMIAL PNEUMONIA; DOUBLE-BLIND; MULTICENTER; VANCOMYCIN AB Given the changing epidemiology of disease due to Staphylococcus aureus (SA), including the emergence of drug-resistant organisms such as methicillin-resistant SA, investigators may wish to evaluate the effects of antimicrobials in disease due to SA as well as in disease due to other organisms in the same trial. Here we discuss issues that investigators should address in trial design, conduct, and analysis to evaluate overall effects or effects within subgroups according to causative organisms. C1 [Powers, J. H.] NIAID, Collaborat Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Fleming, T. R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Powers, JH (reprint author), NIAID, Collaborat Clin Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM powersjohn@mail.nih.gov FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [R37 AI 29168] NR 10 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2009 VL 86 IS 3 BP 244 EP 247 DI 10.1038/clpt.2009.132 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 491AL UT WOS:000269549100011 PM 19707216 ER PT J AU Kampmann, C Linhart, A Devereux, RB Schiffmann, R AF Kampmann, Christoph Linhart, Ales Devereux, Richard B. Schiffmann, Raphael TI Effect of Agalsidase Alfa Replacement Therapy on Fabry Disease-Related Hypertrophic Cardiomyopathy: A 12-to 36-Month, Retrospective, Blinded Echocardiographic Pooled Analysis SO CLINICAL THERAPEUTICS LA English DT Article DE Fabry disease; agalsidase alfa; cardiomyopathy; heart disease ID LEFT-VENTRICULAR HYPERTROPHY; M-MODE ECHOCARDIOGRAPHY; CLINICAL-MANIFESTATIONS; CARDIAC MANIFESTATIONS; NATURAL-HISTORY; OUTCOME SURVEY; BETA THERAPY; IMPACT; TRIAL; GALACTOSIDASE AB Background: Fabry disease is an X-linked disease caused by a deficiency in the activity of the lysosomal enzyme a-galactosidase A. Affected individuals typically develop left ventricular hypertrophy (LVH) among other pathologies. Objective: The purpose of the present study was to investigate the effect of >= 12 months of enzyme replacement therapy (ERT) with agalsidase alfa on LV mass (LVM) in men and women with Fabry disease. Methods: This was a retrospective, blinded, pooled analysis of data from several studies assessing the effect of ERT with agalsidase alfa on LVM in patients with Fabry disease with baseline LVH. Men and women aged 48 years with a confirmed diagnosis of Fabry disease who had received >= 36 months of ERT with agalsidase alfa were eligible, provided they had a baseline echocardiogram and a follow-up echocardiogram at 12 and/or 36 months. Data from 4 studies were included in the present analysis. LVM was normalized to height (in meters) to the 2.7 power (LVM/h LVM/m(2.7)). Results: In total, 45 adult patients (34 men and 11 women) with a confirmed diagnosis of Fabry disease and serial echocardiograms obtained at baseline and after 12 and/or 36 months of treatment were included. The mean (SD) age of this cohort was 39.8 (10.4) years (range, 18.9-67.2 years), and the mean weight was 72.5 (13.4) kg (range, 46.7-102.9 kg). Forty-two patients were white, 2 were Hispanic, and 1 was classified as other. At baseline, 14 patients had LVH (mean LVM/h = 55.4 [5.71 g/m(2.7)). After 12 months of ERT with agalsidase alfa, LVM/h decreased significantly by 9.2 (7.9) g/m(2.7) in 9 patients (P = 0.008), and after 36 months, LVM/h decreased significantly by 5.1. (7.5) g/m(2.7) in 10 patients (P = 0.037). In patients without baseline LVH (n = 3 1), a significant increase in LVM/h was observed after .2 months of treatment (3.6 [5.7] g/m(2.7); P = 0.002). After 36 months of treatment, however, there was no significant change from baseline in 10 patients (2.1 [7.9] g/m(2.7); P = NS). Conclusion: Treatment with agalsidase alfa for 12 or 36 months was associated with reduced LVM in these patients with Fabry disease with baseline LVH, and it appeared to stabilize LVM in these patients without baseline LVH. (Clin Ther. 2009;31:1966-1976) (C) 2009 Excerpta Medica Inc. C1 [Kampmann, Christoph] Univ Childrens Hosp, Div Cardiol, Mainz, Germany. [Kampmann, Christoph] Univ Childrens Hosp, Div Lysosomal Storage Dis, Mainz, Germany. [Linhart, Ales] Charles Univ Prague, Sch Med 1, Prague, Czech Republic. [Devereux, Richard B.] Cornell Univ, Div Cardiol, Weill Cornell Med Coll, New York, NY 10021 USA. [Schiffmann, Raphael] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. RP Kampmann, C (reprint author), Univ Kinderklin, Langenbeckstr 1, D-55131 Mainz, Germany. EM kampmann@uni-mainz.de FU National Institute of Neurological Disorders and Stroke FX This study was funded in part by the Intramural Program of the National Institute of Neurological Disorders and Stroke, and by Shire HGT The statistical analysis was designed by Shire HGT and the final statistical analyses were conducted by the biostatistics department of Shire HGT. Editorial assistance was provided by Edward Weselcouch, PhD, of PharmaWrite, Princeton, New Jersey, and was paid for by Shire HGT. The authors equally participated in the writing of the manuscript and are fully responsible for its content. NR 46 TC 22 Z9 24 U1 0 U2 2 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 J9 CLIN THER JI Clin. Ther. PD SEP PY 2009 VL 31 IS 9 BP 1966 EP 1976 DI 10.1016/j.clinthera.2009.09.008 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 509UE UT WOS:000271043100007 PM 19843486 ER PT J AU Kost, GJ Hale, KN Brock, TK Louie, RF Gentile, NL Kitano, TK Tran, NK AF Kost, Gerald J. Hale, Kristin N. Brock, T. Keith Louie, Richard F. Gentile, Nicole L. Kitano, Tyler K. Tran, Nam K. TI Point-of-Care Testing for Disasters: Needs Assessment Strategic Planning, and Future Design SO CLINICS IN LABORATORY MEDICINE LA English DT Article DE Biohazard containment; Hurricane Katrina; Modular test design; Newdemics; Sampling method; Small-world network (SWN); Tsunami ID DROUGHT-INDUCED AMPLIFICATION; NATURAL DISASTERS; RAPID DETECTION; INFECTIONS; INFLUENZA; VIRUS; WORLD; DIAGNOSIS; TSUNAMI; PERFORMANCE AB Objective evidence-based national surveys serve as a first step in identifying suitable point-of-care device designs, effective test clusters, and environmental operating conditions. Preliminary survey results show the need for point-of-care testing (POCT) devices using test clusters that specifically detect pathogens found in disaster scenarios. Hurricane Katrina, the tsunami in southeast Asia, and the current influenza pandemic (H1N1, "swine flu") vividly illustrate lack of national and global preparedness. Gap analysis of current POCT devices versus survey results reveals how POCT needs can be fulfilled. Future thinking will help avoid the worst consequences of disasters on the horizon, such as extensively drug-resistant tuberculosis and pandemic influenzas. A global effort must be made to improve POC technologies to rapidly diagnose and treat patients to improve triaging, on-site decision making, and, ultimately, economic and medical outcomes. C1 [Kost, Gerald J.; Hale, Kristin N.; Brock, T. Keith; Louie, Richard F.; Gentile, Nicole L.; Kitano, Tyler K.; Tran, Nam K.] Univ Calif Davis, Dept Pathol & Lab Med, UC Davis LLNL Point Care Technol Ctr NIBIB NIH, Sch Med,POCT CTR, Davis, CA 95616 USA. RP Kost, GJ (reprint author), Univ Calif Davis, Dept Pathol & Lab Med, UC Davis LLNL Point Care Technol Ctr NIBIB NIH, Sch Med,POCT CTR, 3455 Tupper Hall, Davis, CA 95616 USA. EM gjkost@ucdavis.edu FU School of Medicine, University of California, Davis; NIBIB [NIH U54 E8007959] FX This study was supported by the Point-of-Care Testing Center for Teaching and Research (POCT*CTRSM), School of Medicine, University of California, Davis, and by a NIBIB Point-of-Care Technologies Center grant (Dr Kost, PI, NIH U54 E8007959). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Biomedical Imaging and Bioengineering or the National Institutes of Health. NR 43 TC 7 Z9 7 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD SEP PY 2009 VL 29 IS 3 BP 583 EP + DI 10.1016/j.cll.2009.07.014 PG 24 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 516QY UT WOS:000271558700015 PM 19840690 ER PT J AU Stunkard, AJ Allison, KC Geliebter, A Lundgren, JD Gluck, ME O'Reardon, JP AF Stunkard, Albert J. Allison, Kelly C. Geliebter, Allan Lundgren, Jennifer D. Gluck, Marci E. O'Reardon, John P. TI Development of criteria for a diagnosis: lessons from the night eating syndrome SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID OBESE OUTPATIENTS; FOOD-INTAKE; SLEEP; DISORDER; PREVALENCE; TOPIRAMATE; SERTRALINE; POPULATION; FEATURES; THERAPY AB Criteria for inclusion of diagnoses of Axis I disorders in the forthcoming Diagnostic and Statistical Manual (DSM-V) of the American Psychiatric Association arc being considered. The 5 criteria that were proposed by Blashfield et al as necessary for inclusion in DSM-IV are reviewed and are met by the night eating syndrome (NES). Seventy-seven publications in refereed journals in the last decade indicate growing recognition of NES. Two core diagnostic criteria have been established: evening hyperphagia (consumption of at least 25% of daily food intake after the evening meal) and/or the presence of nocturnal awakenings with ingestions. These criteria have been validated in studies that used self-reports, structured interviews, and symptom scales. Night eating syndrome can be distinguished from binge eating disorder and sleep-related eating disorder. Four additional features attest to the usefulness of the diagnosis of NES: (1) its prevalence, (2) its association with obesity, (3) its extensive comorbidity, and (4) its biological aspects. In conclusion, research on NES supports the validity of the diagnosis and its inclusion in DSM-V. (C) 2009 Elsevier Inc. All rights reserved. C1 [Stunkard, Albert J.] Univ Penn, Sch Med, Ctr Weight & Eating Disorders, Dept Psychiat, Philadelphia, PA 19104 USA. [Geliebter, Allan] Columbia Univ, St Lukes Roosevelt Hosp Ctr, New York Obes Res Ctr, New York, NY USA. [Lundgren, Jennifer D.] Univ Missouri, Dept Psychol, Kansas City, MO 64110 USA. [Gluck, Marci E.] NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Bethesda, MD USA. RP Stunkard, AJ (reprint author), Univ Penn, Sch Med, Ctr Weight & Eating Disorders, Dept Psychiat, Philadelphia, PA 19104 USA. EM stunkard@mail.med.upenn.edu FU NIDDK NIH HHS [R01 DK074046-01A1, R01 DK074046-03, R01 DK074046-05, R01 DK074046-01A1S1, R01 DK074046-02S2, R01 DK074046, R01 DK074046-04, R01 DK074046-02S1, R01 DK074046-02] NR 71 TC 16 Z9 16 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD SEP-OCT PY 2009 VL 50 IS 5 BP 391 EP 399 DI 10.1016/j.comppsych.2008.09.013 PG 9 WC Psychiatry SC Psychiatry GA 487DP UT WOS:000269251100001 PM 19683608 ER PT J AU Shih, JH Lu, SE AF Shih, Joanna H. Lu, Shou-En TI Semiparametric estimation of a nested random effects model for the analysis of multi-level clustered failure time data SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article ID FRAILTY MODEL; LIKELIHOOD-ESTIMATION; ASYMPTOTIC THEORY; VITAMIN-A; NEPAL AB Multi-level clustered failure time data arise when the clustering of data occurs at more than one level. It is of interest to estimate the relative risks of covariates and clustering effect of failure times at each level. We consider a nested random effect proportional hazards model, where a subcluster-specific frailty operates multiplicatively on the conditional hazard model, and its distribution function depends on a cluster-specific random frailty. Under this model, we propose a Monte-Carlo EM-based semiparametric estimation procedure to estimate regression coefficients, nonparametric baseline cumulative hazard and the association parameters. In addition, we derive a covariance matrix of the parameter estimates. We illustrate the proposed method using clustered survival data collected from a vitamin A supplementation trial in Nepal, where it is of scientific interest to assess the clustering effect of mortality within households and within villages. We use simulations to study the performance of the proposed estimation procedure. Published by Elsevier B.V. C1 [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN, Bethesda, MD 20892 USA. [Lu, Shou-En] Univ Med & Dent New Jersey, Dept Biostat, Piscataway, NJ 08854 USA. RP Shih, JH (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN, Room 8132, Bethesda, MD 20892 USA. EM jshih@mail.nih.gov FU Office of Health and Nutrition, US Agency for Interactional Development (USAID), Washington DC [HRN A-00-97-00015-00]; Center for Human Nutrition, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore MD FX The authors thank Drs. Keith West Jr. and Joanne Katz for providing the Vitamin A intervention trial data that were collected under Cooperative Agreement No. HRN A-00-97-00015-00 between the Office of Health and Nutrition, US Agency for Interactional Development (USAID), Washington DC and the Center for Human Nutrition, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, with additional financial assistance of the Bill and Melinda Gates Foundation, Seattle, WA, and the Sight and Life Institute, Baltimore, MD. The authors also thank Dr. Katz for reviewing the manuscript and valuable comments. NR 18 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD SEP 1 PY 2009 VL 53 IS 11 BP 3864 EP 3871 DI 10.1016/j.csda.2009.04.014 PG 8 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 464LE UT WOS:000267505600013 ER PT J AU Sutin, AR AF Sutin, Angelina R. TI Visual perspective and genetics: A commentary on Lemogne and colleagues SO CONSCIOUSNESS AND COGNITION LA English DT Article DE Visual perspective; Genetics; Neuroticism; Depression; Autobiographical memory; 5-HTT ID AUTOBIOGRAPHICAL MEMORY; POLYMORPHISM; ASSOCIATION; NEUROTICISM; DEPRESSION; ANXIETY; SELF; PERSONALITY; TRAITS; ME AB Lemogne and colleagues offer an interesting extension to their previous work on visual perspective and depression: Individuals at-risk for depression (defined as higher scores on Harm Avoidance), without a history of mood disorders, report retrieval of positive memories from the 3rd person perspective. Their findings suggest that the retrieval of positive experiences from the 3rd person perspective may be a risk-factor for depression, not just a lingering consequence of it. Their study, however, also reports a genetic association in a severely underpowered sample. Rather than focusing on gene x environment interactions, which large, well-powered studies on related phenotypes have failed to detect, a greater understanding of the phenomenology of visual perspective may be a more fruitful avenue for future research. Published by Elsevier Inc. C1 NIA, Lab Personal & Cognit, NIH, DHHS, Baltimore, MD 21224 USA. RP Sutin, AR (reprint author), NIA, Lab Personal & Cognit, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@nia.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 21 TC 4 Z9 4 U1 3 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8100 J9 CONSCIOUS COGN JI Conscious. Cogn. PD SEP PY 2009 VL 18 IS 3 BP 831 EP 833 DI 10.1016/j.concog.2009.05.002 PG 3 WC Psychology, Experimental SC Psychology GA 501IV UT WOS:000270376100030 PM 19546011 ER PT J AU Della Sala, S Grafman, J AF Della Sala, Sergio Grafman, Jordan TI Five-year impact factor SO CORTEX LA English DT Editorial Material C1 [Della Sala, Sergio] Univ Edinburgh, Edinburgh EH 89JZ, Midlothian, Scotland. [Grafman, Jordan] NINDS, Cognit Neurosci Sect, Bethesda, MD 20892 USA. RP Della Sala, S (reprint author), Univ Edinburgh, 7 George Sq, Edinburgh EH 89JZ, Midlothian, Scotland. EM sergio@ed.ac.uk OI Grafman, Jordan H./0000-0001-8645-4457 NR 2 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD SEP PY 2009 VL 45 IS 8 BP 911 EP 911 DI 10.1016/j.cortex.2009.04.002 PG 1 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 473LD UT WOS:000268206700001 ER PT J AU Cressoni, M Zanella, A Epp, M Corti, I Patroniti, N Kolobow, T Pesenti, A AF Cressoni, Massimo Zanella, Alberto Epp, Myra Corti, Ivan Patroniti, Nicolo Kolobow, Theodor Pesenti, Antonio TI Decreasing pulmonary ventilation through bicarbonate ultrafiltration: An experimental study SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory failure; mechanical ventilation; ventilator-induced lung injury; acid base; extracorporeal CO(2) removal; hemofiltration; ultrafiltration; kidney failure; bicarbonate ID RESPIRATORY-DISTRESS-SYNDROME; CARBON-DIOXIDE REMOVAL; EXTRACORPOREAL CO2 REMOVAL; MECHANICAL VENTILATION; AIRWAY PRESSURE; FAILURE; LUNG; TRIAL; CYTOKINES; DIALYSIS AB Objective. To demonstrate the technical feasibility Of CO(2) removal with a commercial hemofilter and a replacement solution containing sodium hydroxide to replace bicarbonate. Design: Prospective animal experiment in sheep. Subjects. Seven mixed-breed female sheep. Interventions: Blood ultrafiltrate containing half of the metabolic production of CO(2) was removed with a commercial hemofilter and a replacement solution containing sodium hydroxide was given as replacement. Minute ventilation was lowered to less than half of its baseline value. Ultrafiltration was stopped at 18 hrs, and Paco(2) was allowed to increase for about 1 hr; at this time, the sheep were electively killed. Measurements and Main Results. Every 6 hrs, blood was sampled from the carotid artery, the pulmonary artery, and from the extracorporeal perfusion circuit (before the hemofilter, immediately after the hemofilter, and after mixing with the replacement solution). To maintain normocapnia, minute ventilation was reduced from 3.8 +/- 0.1 L/min to 1.9 +/- 0.7 L/min; Paco(2) remained near constant during the study. The average blood pH, after mixing with the replacement solution, was 7.64 +/- 0.12. One hour after the ultrafiltration had stopped, Paco(2) had increased from 36.7 +/- 4.2 torr (4.9 +/- 0.6 kPa) to 59.6 +/- 9 torr (7.9 +/- 1.2 kPa) (p < .01) and blood pH had decreased from 7.317 +/- 0.041 to 7.151 +/- 0.051 (p < .01). Conclusion: CO(2) removal with bicarbonate ultrafiltration may be an effective treatment for patients with respiratory failure. (Crit Care Med 2009; 37:2612-2618) C1 [Cressoni, Massimo; Zanella, Alberto; Epp, Myra; Corti, Ivan; Kolobow, Theodor] NHLBI, NIH, Sect Pulm & Cardiac Assist Devices, Pulm & Crit Care Med Branch, Bethesda, MD 20892 USA. [Cressoni, Massimo] Osped Maggiore, Policlin Mangiagalli Regina Elena, Fdn IRCCS, Ist Anestesiol & Rianimaz, Milan, Italy. Univ Milan, Milan, Italy. [Zanella, Alberto; Patroniti, Nicolo; Pesenti, Antonio] Univ Milano Bicocca, Dept Expt Med, Monza, Italy. RP Cressoni, M (reprint author), NHLBI, NIH, Sect Pulm & Cardiac Assist Devices, Pulm & Crit Care Med Branch, Bldg 10, Bethesda, MD 20892 USA. EM mcressoni@hotmail.com RI Pesenti, Antonio/H-7483-2012; Cressoni, Massimo/B-7315-2017; Patroniti, Nicolo/K-6347-2016; OI Patroniti, Nicolo/0000-0003-3600-193X; Cressoni, Massimo/0000-0002-0089-2905; zanella, Alberto/0000-0002-2967-2527 NR 31 TC 16 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD SEP PY 2009 VL 37 IS 9 BP 2612 EP 2618 DI 10.1097/CCM.0b013e3181a5668a PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 486JI UT WOS:000269191900017 PM 19602976 ER PT J AU Chaturvedi, A Pierce, SK AF Chaturvedi, Akanksha Pierce, Susan K. TI Autophagy in immune cell regulation and dysregulation SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review ID TOLL-LIKE RECEPTORS; DENDRITIC CELLS; SELF-DIGESTION; GENE ATG5; T-CELLS; STARVATION; DISEASE; ANTIGEN; MICE; RECOGNITION AB Autophagy is an ancient pathway required for cell and tissue homeostasis and differentiation. Initially thought to be a process leading to cell death, autophagy is currently viewed as a beneficial catabolic process that promotes cell survival under starvation conditions by sequestering components of the cytoplasm, including misfolded proteins, protein aggregates, and damaged organelles, and targeting them for lysosome-mediated degradation. In this way, autophagy plays a role in maintaining a balance between degradation and recycling of cellular material. The importance of autophagy is underscored by the fact that malfunctioning of this pathway results in neurodegeneration, cancer, susceptibility to microbial infection, and premature aging. Autophagy occurs in almost all cell types, including immune cells. Recent advances in the field suggest that autophagy plays a central role in regulating the immune system at multiple levels. In this review, we focus on recent developments in the area of autophagy-mediated modulation of immune responses. C1 [Chaturvedi, Akanksha] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Chaturvedi, A (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Room 213,MSC 8180, Rockville, MD 20852 USA. EM achaturvedi@niaid.nih.gov NR 42 TC 8 Z9 9 U1 0 U2 0 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD SEP PY 2009 VL 9 IS 5 BP 341 EP 346 DI 10.1007/s11882-009-0050-1 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 482FX UT WOS:000268871200004 PM 19671376 ER PT J AU Gubitz, AK Gwinn, K AF Gubitz, A. K. Gwinn, K. TI Mining the Genome for Susceptibility to Complex Neurological Disorders SO CURRENT MOLECULAR MEDICINE LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; SINGLE-NUCLEOTIDE POLYMORPHISMS; RESTLESS LEGS SYNDROME; PROGRESSIVE SUPRANUCLEAR PALSY; ONSET ALZHEIMERS-DISEASE; WIDE ASSOCIATION; PARKINSON-DISEASE; MULTIPLE-SCLEROSIS; INTERLEUKIN-7 RECEPTOR; GENETIC ASSOCIATION AB Genome-wide association studies (GWAS) have become increasingly widely used to determine regions of the genome which may contain loci influencing the risk of neurological disorders. While linkage studies have identified genes that cause a number of Mendelian disorders, linkage analysis is less well suited for the more common complex disorders. This has led to the widespread use of GWAS for that purpose. Here we present and discuss several of the major extant GWAS in neurological disorders, their limitations, and implications of findings to date. C1 [Gwinn, K.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Gubitz, A. K.] NINDS, NIH, Bethesda, MD 20892 USA. RP Gwinn, K (reprint author), Baylor Coll Med, Dept Mol & Human Genet, T-903 BCM 225,1 Baylor Plaza, Houston, TX 77030 USA. EM gwinn@bcm.edu NR 91 TC 2 Z9 2 U1 2 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD SEP PY 2009 VL 9 IS 7 BP 801 EP 813 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 514FY UT WOS:000271380900002 PM 19860660 ER PT J AU Montefiori, DC Mascola, JR AF Montefiori, David C. Mascola, John R. TI Neutralizing antibodies against HIV-1: can we elicit them with vaccines and how much do we need? SO CURRENT OPINION IN HIV AND AIDS LA English DT Editorial Material DE B-cells; HIV-1 vaccine; neutralizing antibodies ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; PASSIVE TRANSFER; CHIMERIC VIRUS; ENV CLONES; PROTECTION; INFECTION; MACAQUES; EPITOPE; GLYCOPROTEIN AB Purpose of review This review describes some of the major obstacles that have impeded progress in the development of an effective neutralizing antibody-based HIV-1 vaccine and explains why it may be possible to overcome these obstacles. A renewed interest in the B-cell response in HIV-1-infected individuals is emphasized. Recent findings New assay technologies and access to large numbers of clinical specimens have permitted a detailed assessment of the neutralizing antibody response in HIV-1-infected individuals. Recent studies have demonstrated that B cells can be stimulated to generate high titers of broadly cross-reactive neutralizing antibodies against multiple genetic subtypes of the virus. Preliminary evidence suggests that some of these antibodies are directed against epitopes in the CD4 binding site on monomeric gp120, whereas many others are directed against epitopes that remain to be identified. Summary The rationale for pursuing an effective neutralizing antibody-based HIV-1 vaccine is strengthened by the recent demonstration of potent neutralizing antibody responses in a subset of HIV-1-infected individuals. Information on how this response develops and what epitopes are targeted could provide the insights that are needed to design improved vaccine strategies. C1 [Montefiori, David C.] Duke Univ, Med Ctr, Lab AIDS Vaccine Res & Dev, Dept Surg, Durham, NC 27710 USA. [Mascola, John R.] NIAID, Vaccine Res Ctr, US NIH, Bethesda, MD 20892 USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Lab AIDS Vaccine Res & Dev, Dept Surg, Box 2926, Durham, NC 27710 USA. EM monte@duke.edu FU NIAID NIH HHS [N01 AI030034, R13 AI053895-01] NR 54 TC 37 Z9 37 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2009 VL 4 IS 5 BP 347 EP 351 DI 10.1097/COH.0b013e32832f4a4d PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V19PC UT WOS:000208083300001 PM 20048696 ER PT J AU Keele, BF Derdeyn, CA AF Keele, Brandon F. Derdeyn, Cynthia A. TI Genetic and antigenic features of the transmitted virus SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE acute infection; HIV; simian immunodeficiency virus; transmitted virus; viral evolution AB Purpose of review Methodological and analytical advances in obtaining genetic information during acute HIV infection have provided an unprecedented view into viral transmission and early immune evasion. The findings suggest that a better understanding of the restricted viral diversity that follows mucosal transmission could lead to novel strategies for vaccine, microbicide or other therapeutic interventions. Recent findings During sexual transmission of HIV-1, viral diversity is reduced presumably due to obstacles an infectious virion must overcome to establish infection within a new host. Recently, single-genome amplification followed by direct sequencing from samples obtained during acute infection has been utilized to quantify the actual number of infecting variants. Overall, the vast majority (over 75%) of new infections were initiated by a single genetic variant. Transmission of multiple variants from a single donor (between two and five) was also observed and is associated with factors that compromise the genital mucosa. These analyses included over 200 patients representing subtypes A, B, C, D and have been reproduced in nonhuman primate model systems. Summary During acute infection, there is limited viral diversity in most patients, which provides a window of opportunity for vaccines or therapies to inhibit or prevent infection. Identifying the common genetic and antigenic properties of newly transmitted viruses will be necessary to advance vaccine design. C1 [Keele, Brandon F.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Derdeyn, Cynthia A.] Emory Univ, Dept Pathol & Lab Med, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. RP Keele, BF (reprint author), NCI, SAIC Frederick, Room 408,Bldg 535, Frederick, MD 21702 USA. EM keelebf@mail.nih.gov FU NIH [AI-58706, AI-51231]; Bill and Melinda Gates Foundation; IAVI; NIH Center for HIV/AIDS Vaccine Immunology; American Foundation for AIDS research [106997-3]; National Cancer Institute, National Institutes of Health [HHSN266200400088C] FX C.A.D.'s work cited in this review was supported by funding from NIH (AI-58706 and AI-51231), The Bill and Melinda Gates Foundation, and IAVI. B. F. K. was supported by the NIH Center for HIV/AIDS Vaccine Immunology, the American Foundation for AIDS research (106997-3) and the National Cancer Institute, National Institutes of Health under contract HHSN266200400088C. We sincerely thank the investigators, participants, and staff of the Zambia Emory HIV Research Project in Lusaka, Zambia and Project San Francisco in Kigali, Rwanda; and our collaborators for access to prepublished data. 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 United States Government. NR 31 TC 39 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2009 VL 4 IS 5 BP 352 EP 357 DI 10.1097/COH.0b013e32832d9fef PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V19PC UT WOS:000208083300002 PM 20048697 ER PT J AU Forsell, MNE Schief, WR Wyatt, RT AF Forsell, Mattias N. E. Schief, William R. Wyatt, Richard T. TI Immunogenicity of HIV-1 envelope glycoprotein oligomers SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE antibody responses; HIV-1 envelope glycoproteins; oligomer; vaccine ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING ANTIBODY-RESPONSES; HAMSTER OVARY CELLS; MONOCLONAL-ANTIBODIES; MONOMERIC GP120; SHIV CHALLENGE; TRIMERIC FORM; SUBTYPE-B; TYPE-1; GP140 AB Purpose of review We summarize and discuss recent developments regarding the immunogenicity of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) oligomers, focusing, for the most part, on trimeric, recombinant protein immunogens. Recent findings The three-dimensional cryo-electron tomography images of the HIV-1 Env trimeric spike, coupled with previous data demonstrating the impact on envelope glycoprotein (gp120)-transmembrane glycoprotein (gp41) cleavage of the architecture of the Env trimers, provide exciting information that may lead to new avenues for novel immunogen design. Through new processes to map region-specific anti-Env antibodies present in immune serum, it is now possible to define antibody specificities against conformationally sensitive surfaces of Env. A number of strategies designed to counteract the immunodominance of the HIV-1 Env variable regions were attempted, and a recent study demonstrates that immunization with Env trimers provides sterilizing protection against mucosal challenge with virus. Importantly, protection against the challenge virus was associated with in-vitro HIV-1 neutralization titers. Summary Several studies within the past 18 months provide exciting structural information and the development of tools that have the potential to improve Env trimer design and the analysis of trimer immunogenicity studies. The ability to predict protection against a challenge virus through an in-vitro neutralization screen may be very helpful for evaluation of immunogens to move forward into clinical trials. C1 [Wyatt, Richard T.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. RP Wyatt, RT (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bill and Melinda Gates Foundation; Neutralizing Antibody Consortium of IAVI FX We would like to thank Brenda Hartman and Morteza Loghmani for assistance with the figures. Leo Kong and Peter Kwong for predicting the occurrence of particular glycoforms on core gp120, consistent with published data on gp120 glycosylation patterns. Andrew Ban for glycan modeling, Sriram Subramaniam for providing the 3D electron microscope representation of the HIV-1 Bal virion and to Gunilla Karlsson Hedestam for helpful discussions. This study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health intramural research program to RTW and the Collaboration for Aids Vaccine Discovery of Bill and Melinda Gates Foundation, and Neutralizing Antibody Consortium of IAVI to WS and RTW. NR 55 TC 57 Z9 58 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2009 VL 4 IS 5 BP 380 EP 387 DI 10.1097/COH.0b013e32832edc19 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V19PC UT WOS:000208083300006 PM 20048701 ER PT J AU Doria-Rose, NA Connors, M AF Doria-Rose, Nicole A. Connors, Mark TI Antibody-secreting B cells in HIV infection SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE antibodies; B cell; enzyme-linked immunosorbent spot; Envelope; HIV AB Purpose of review Several recent advances are permitting a detailed examination of the HIV-specific B-cell response. In this review, we summarize these advances and their implications for understanding the response to HIV during chronic infection or in vaccine. Recent findings In HIV-infected patients, aberrant B-cell phenotypes have been associated with diminished humoral responses to other pathogens. HIV-specific B cells are overrepresented in some of these abnormal subsets. Over the past 2 years, flow cytometry-based techniques have been developed to stain HIV-specific B cells. These techniques are permitting a re-examination of frequency, phenotype, and function of HIV-specific B cells. They are also permitting the isolation of HIV-specific B cells in high purity. Immunoglobulin G from sorted HIV-specific B cells is oligoclonal, uses a limited repertoire of immunoglobulin genes, and targets multiple epitopes on Env. Summary It is likely that the defects found in total B cells in HIV-infected patients also play a role in the poorly effective HIV-specific antibody response. A subset of HIV-infected patients produced broadly neutralizing antibodies. Understanding this antibody response, and the B cells that underlie it, may be critical in efforts to elicit neutralizing antibodies against HIV. C1 [Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Connors, M (reprint author), NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11B-07, Bethesda, MD 20892 USA. EM mconnors@nih.gov FU Intramural NIH HHS [ZIA AI001090-01] NR 38 TC 9 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2009 VL 4 IS 5 BP 426 EP 430 DI 10.1097/COH.0b013e32832d9fac PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V19PC UT WOS:000208083300012 PM 20048707 ER PT J AU Bouchelouche, K Capala, J Oehr, P AF Bouchelouche, Kirsten Capala, Jacek Oehr, Peter TI Positron emission tomography/computed tomography and radioimmunotherapy of prostate cancer SO CURRENT OPINION IN ONCOLOGY LA English DT Editorial Material DE choline; fluoride; HER2 receptor; positron emission tomography; prostate cancer; prostate-specific membrane antigen; radioimmunotherapy ID MONOCLONAL-ANTIBODY J591; MEMBRANE ANTIGEN PSMA; EXTRACELLULAR DOMAIN; AFFIBODY MOLECULE; BONE METASTASES; PHASE-II; UROLOGICAL MALIGNANCIES; BIOCHEMICAL RECURRENCE; RADICAL PROSTATECTOMY; RADIONUCLIDE THERAPY AB Purpose of review Traditional morphologically based imaging modalities are now being complemented by positron emission tomography (PET)/computed tomography (CT) in prostate cancer. Metastatic prostate cancer is an attractive target for radioimmunotherapy (RIT) as no effective therapies are available. This review highlights the most important achievements within the last year in PET/CT and RIT of prostate cancer. Recent findings Conflicting results exist on the use of choline for detection of malignant disease in the prostate gland. The role of PET/CT in N-staging remains to be elucidated further. However, (18)F-choline and (11)C-choline PET/CT have been demonstrated to be useful for detection of recurrence. (18)F-choline and (18)F-fluoride PET/CT are useful for detection of bone metastases. Prostate tumor antigens may be used as targets for RIT. Prostate-specific membrane antigen is currently under focus of a number of diagnostic and therapeutic strategies. J591, a monoclonal antibody, which targets the extracellular domain of prostate-specific membrane antigen, shows promising results. HER2 receptors may also have a potential as target for PET/CT imaging and RIT of advanced prostate cancer. Summary PET/CT in prostate cancer has proven to play a significant role, in particular for detection of prostate cancer recurrence and bone metastases. RIT of metastatic prostate cancer warrants further investigations. C1 [Bouchelouche, Kirsten] Univ Copenhagen, Koege Hosp, Canc & Mol Imaging Unit, Res Div Clin Biochem, DK-4600 Koege, Denmark. [Capala, Jacek] NCI, Mol Targeting Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Oehr, Peter] Univ Bonn, Dept Nucl Med, D-5300 Bonn, Germany. RP Bouchelouche, K (reprint author), Univ Copenhagen, Koege Hosp, Canc & Mol Imaging Unit, Res Div Clin Biochem, DK-4600 Koege, Denmark. EM bouchelouche@mail.tele.dk FU Intramural NIH HHS [ZIA BC010727-04] NR 54 TC 18 Z9 20 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2009 VL 21 IS 5 BP 469 EP 474 DI 10.1097/CCO.0b013e32832d56e4 PG 6 WC Oncology SC Oncology GA 486CF UT WOS:000269172400013 PM 19535981 ER PT J AU Reynolds, HY AF Reynolds, Herbert Y. TI Present status of bronchoalveolar lavage in interstitial lung disease SO CURRENT OPINION IN PULMONARY MEDICINE LA English DT Article DE bronchoalveolar lavage; connective tissue diseases; hypersensitivity pneumonitis; idiopathic pulmonary fibrosis; interstitial lung disease; polymorphonuclear neutrophils; pulmonary alveolar proteinosis; pulmonary Langerhans cell histiocytosis; scleroderma ID ACTIVATED-RECEPTOR-GAMMA; IDIOPATHIC PULMONARY-FIBROSIS; HYPERSENSITIVITY PNEUMONITIS; ALVEOLAR MACROPHAGES; BRONCHIAL LAVAGE; SARCOIDOSIS; SCLERODERMA; FLUID; CYCLOPHOSPHAMIDE; PARAMETERS AB Purpose of review Sampling the detachable cells and acellular lining secretions of the human respiratory tract by bronchoalveolar lavage (BAL) is a means of obtaining relevant components from the airways and alveolar areas for research use and clinical analysis in normals (controls) and patients with a wide spectrum of interstitial lung diseases (ILDs). This review attempts to discuss recent findings from BAL studies that provide insight into pathogenic mechanisms of ILDs and/or assist in diagnosing disease activity. Recent findings BAL analysis and usefulness are reviewed for the major forms of ILDs. In addition, some perspective about this sampling method is given and the context for BAL is provided for the respective disease, either for diagnosis or research use. Summary Whereas BAL findings continue to impact on understanding disease pathogenesis and this may be its major use now, BAL fluid components, cells in particular, are not correlated well with activity of disease nor for monitoring disease progress or response to treatment. For a few rarer ILDs, BAL fluid characteristics may strongly support a diagnosis. C1 NHLBI, Lung Biol & Dis Branch, Div Lung Dis, Bethesda, MD 20892 USA. RP Reynolds, HY (reprint author), NHLBI, Lung Biol & Dis Branch, Div Lung Dis, 6701 Rockledge Dr,Suite 10042,2 Rockledge Ctr,MSC, Bethesda, MD 20892 USA. EM reynoldh@nhlbi.nih.gov NR 62 TC 10 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-5287 J9 CURR OPIN PULM MED JI Curr. Opin. Pulm. Med. PD SEP PY 2009 VL 15 IS 5 BP 479 EP 485 DI 10.1097/MCP.0b013e32832d03ef PG 7 WC Respiratory System SC Respiratory System GA 483QM UT WOS:000268982600013 PM 19636227 ER PT J AU Nikolov, NP Illei, GG AF Nikolov, Nikolay P. Illei, Gabor G. TI Pathogenesis of Sjogren's syndrome SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE autonomic nervous system; exocrinopathy; innate immunity; sex steroids ID CHOLINERGIC ANTIINFLAMMATORY PATHWAY; CELL ACTIVATING FACTOR; I INTERFERON ACTIVITY; SALIVARY-GLANDS; AUTOIMMUNE EXOCRINOPATHY; SUBMANDIBULAR-GLAND; EXPRESSION; MICE; DEHYDROEPIANDROSTERONE; RECEPTOR AB Purpose of review To summarize recent developments in our understanding of the pathogenesis of Sjogren's syndrome with a focus on the relationship between inflammation and exocrine dysfunction. Recent findings Animal models demonstrated the complex interactions between immunologic and nonimmunologic mechanisms in Sjogren's syndrome. Activation of the innate immune system can lead to exocrine dysfunction before or without significant inflammation, whereas in other models, salivary gland function is preserved despite intense inflammatory infiltrates. Primary or inflammation-related abnormalities in water channels contribute to the exocrinopathy. Activation of the innate immunity in patients is demonstrated by the upregulation of type-1 interferon-regulated genes (interferon signature) in peripheral blood and salivary glands and abnormal expression of B cell-activating factor and its receptors. Nonimmune mechanisms that may contribute to exocrine dysfunction include local and systemic androgen deficiency and autonomic nervous system dysfunction. Autoantibodies against the muscarinic acetylcholine receptors would provide a link between autoimmunity and exocrine dysfunction, but the data on the presence, frequency and physiologic affect of these antibodies remain controversial. Summary Recent discoveries from studies in patients with Sjogren's syndrome and animal models suggest a complex interplay between genetic factors, environmental and stochastic events that involve innate and adaptive immunity, hormonal mechanisms and the autonomic nervous system. Some of these findings suggest that exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation in the pathogenesis of Sjogren's syndrome. C1 [Nikolov, Nikolay P.; Illei, Gabor G.] NIDCR, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Illei, GG (reprint author), NIDCR, Sjogrens Clin, MPTB, NIH, Bldg 10,Room 1N-110, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov FU National Institute of Dental and Craniofacial Research and National Institutes of Health FX This work was supported by the intramural research program of the National Institute of Dental and Craniofacial Research and National Institutes of Health. NR 39 TC 62 Z9 71 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD SEP PY 2009 VL 21 IS 5 BP 465 EP 470 DI 10.1097/BOR.0b013e32832eba21 PG 6 WC Rheumatology SC Rheumatology GA 487PC UT WOS:000269286000004 PM 19568172 ER PT J AU Thomas, CJ Auld, DS Huang, RL Huang, WW Jadhav, A Johnson, RL Leister, W Maloney, DJ Marugan, JJ Michael, S Simeonov, A Southall, N Xia, MH Zheng, W Inglese, J Austin, CP AF Thomas, Craig J. Auld, Douglas S. Huang, Ruili Huang, Wenwei Jadhav, Ajit Johnson, Ronald L. Leister, William Maloney, David J. Marugan, Juan J. Michael, Sam Simeonov, Anton Southall, Noel Xia, Menghang Zheng, Wei Inglese, James Austin, Christopher P. TI The Pilot Phase of the NIH Chemical Genomics Center SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review ID HIGH-THROUGHPUT SCREEN; SCHISTOSOMA-MANSONI; FUROXAN DERIVATIVES; GAUCHER-DISEASE; MECHANISM; RECEPTOR; INHIBITION; LIBRARIES; ASSAYS; IDENTIFICATION AB The NIH Chemical Genomics Center (NCGC) was the inaugural center of the Molecular Libraries and Screening Center Network (MLSCN). Along with the nine other research centers of the MLSCN, the NCGC was established with a primary goal of bringing industrial technology and experience to empower the scientific community with small molecule compounds for use in their research. We intend this review to serve as 1) an introduction to the NCGC standard operating procedures, 2) an overview of several of the lessons learned during the pilot phase and 3) a review of several of the innovative discoveries reported during the pilot phase of the MLSCN. C1 [Thomas, Craig J.; Auld, Douglas S.; Huang, Ruili; Huang, Wenwei; Jadhav, Ajit; Johnson, Ronald L.; Leister, William; Maloney, David J.; Marugan, Juan J.; Michael, Sam; Simeonov, Anton; Southall, Noel; Xia, Menghang; Zheng, Wei; Inglese, James; Austin, Christopher P.] NHGRI, NIH, Chem Genom Ctr, Rockville, MD 20850 USA. RP Thomas, CJ (reprint author), NHGRI, NIH, Chem Genom Ctr, 9800 Med Ctr Dr,Bldg B,Room 3005,MSC 3370, Bethesda, MD 20892 USA. EM craigt@nhgri.nih.gov; austinc@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU National Institutes of Health Roadmap for Medical Research; National Human Genome Research Institute, National Institutes of Health FX The authors would foremost like to acknowledge the talent, dedication and hard work of the entire staff of the NIH Chemical Genomics Center. We thank Ms. Allison Peck for critical reading of this manuscript. Special thanks to Adam Yasgar and Paul Shin. We further thank the Sidransky, Shoichet, Gershengorn, Nirenberg and Williams's laboratories for their exceptional expertise and efforts. The research reviewed here was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 48 TC 9 Z9 10 U1 0 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD SEP PY 2009 VL 9 IS 13 BP 1181 EP 1193 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 514HF UT WOS:000271384300004 PM 19807664 ER PT J AU Egwuagu, CE AF Egwuagu, Charles E. TI STAT3 in CD4(+) T helper cell differentiation and inflammatory diseases SO CYTOKINE LA English DT Review DE STAT3; T cell lineage commitment; CNS inflammatory diseases; Th17 and Treg development; Cytokine signaling pathways ID CYTOKINE SIGNALING SOCS; TRANSCRIPTIONAL REGULATION; FOXP3 EXPRESSION; BOWEL-DISEASE; UNPHOSPHORYLATED STAT3; IMMUNE-RESPONSE; IN-VIVO; ACTIVATION; GROWTH; MICE AB Jak/STAT pathways influence cell-fate decisions made by differentiating naive T cells, regulate the intensity and duration of inflammatory responses and are implicated in pathogenic mechanisms of a number of chronic inflammatory diseases. Among the STATs, the STAT3 protein has emerged as an important determinant of whether the naive T cell differentiates into regulatory (Treg) or an inflammatory (Th17) T cell lineage. STAT3 also has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and transcription of inflammatory genes. Dysregulation of STAT3 pathway has therefore been implicated in the development of chronic inflammatory diseases, as well as, a number of malignant and neurodegenerative diseases. This review focuses on recent findings regarding the role of STAT3 in immunity, with particular emphasis on T cell lineage specification and disease etiology. New insights from animal models of uveitis, multiple sclerosis and inflammatory bowel diseases are discussed as exemplars of critical roles that STAT3 pathways play in inflammatory diseases and on how inhibiting STAT3 can be exploited to mitigate pathogenic autoimmunity. Published by Elsevier Ltd. C1 NEI, NIH, Immunol Lab, Mol Immunol Sect, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, NIH, Immunol Lab, Mol Immunol Sect, Bldg 10,Room 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Eye Institute (NEI); National Institutes of Health (NIH) FX Author thanks Drs. Cheng-Rong Yu, Nady Golestaneh and Yunsang Lee of the Molecular Immunology Section, National Eye Institute, National Institutes of Health for critical reading the paper. Author also acknowledges support by the Intramural Research Programs of the National Eye Institute (NEI) and the National Institutes of Health (NIH). NR 96 TC 75 Z9 89 U1 1 U2 14 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2009 VL 47 IS 3 BP 149 EP 156 DI 10.1016/j.cyto.2009.07.003 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 494BN UT WOS:000269784300001 PM 19648026 ER PT J AU Marsh, RA Villanueva, J Zhang, KJ Snow, AL Su, HC Madden, L Mody, R Kitchen, B Marmer, D Jordan, MB Risma, KA Filipovich, AH Bleesing, JJ AF Marsh, Rebecca A. Villanueva, Joyce Zhang, Kejian Snow, Andrew L. Su, Helen C. Madden, Lisa Mody, Rajen Kitchen, Brenda Marmer, Dan Jordan, Michael B. Risma, Kimberly A. Filipovich, Alexandra H. Bleesing, Jack J. TI A Rapid Flow Cytometric Screening Test for X-Linked Lymphoproliferative Disease due to XIAP Deficiency SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE X-linked lymphoproliferative disease; XLP; X-linked inhibitor of apoptosis; XIAP; hemophagocytic lymphohistiocytosis; HLH; flow cytometry; BIRC4 ID CYTOTOXIC LYMPHOCYTES; FAMILY-MEMBERS AB Background: Deficiency of X-linked inhibitor of apoptosis (XIAP), caused by BIRC4 gene mutations, is the second known cause of X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency that often presents with life-threatening hemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis of the known genetic causes of HLH, including XIAP deficiency, facilitates the initiation of life-saving treatment and preparation for allogeneic hematopoietic cell transplantation (HCT). Until now, a rapid screening test for XIAP deficiency has not been available. Methods: To develop a flow cytometric screening test for XIAP deficiency, we first used lymphoblastic cell lines generated from controls and patients with BIRC4 mutations to identify two commercially available antibodies specific for native intracellular XIAP. Next, we used these antibodies to study control whole blood leukocyte XIAP expression. We then studied XIAP expression in leukocytes from patients with XLP due to BIRC4 mutations, maternal carriers, and patients following HCT. Results: XIAP was expressed by the majority of all whole blood nucleated cells in normal controls. In contrast, XIAP was absent or decreased in all lymphocyte subsets, monocytes and granulocytes from four unrelated patents with XLP due to BIRC4 mutations. Bimodal distribution of XIAP expression was evident in two maternal carriers, with significant skewing toward cells expressing normal XIAP. Bimodal distribution was also observed in a patient following HCT. Conclusions: Flow cytometric analysis of intracellular XIAP provides a rapid screening test for XLP due to XIAP deficiency. It also allows carrier detection and can be used to monitor donor versus recipient reconstitution following HCT. (C) 2009 Clinical Cytometry Society C1 [Marsh, Rebecca A.; Villanueva, Joyce; Marmer, Dan; Jordan, Michael B.; Filipovich, Alexandra H.; Bleesing, Jack J.] Cincinnati Childrens Hosp, Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. [Zhang, Kejian] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Snow, Andrew L.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Madden, Lisa; Mody, Rajen; Kitchen, Brenda] Univ Michigan, CS Mott Childrens Hosp, Div Pediat Hematol Oncol, Ann Arbor, MI 48109 USA. [Risma, Kimberly A.] Cincinnati Childrens Hosp, Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. RP Marsh, RA (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Hematol Oncol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM rebecca.marsh@cchmc.org RI Su, Helen/H-9541-2015; OI Su, Helen/0000-0002-5582-9110; Risma, Kimberly/0000-0003-0671-4859; Snow, Andrew/0000-0002-8728-6691 FU Histiocytosis Association of America; NIH [R03 1R03AI079797-01]; Intramural Research Program of the NIH, MAID FX Grant sponsor: Histiocytosis Association of America; Grant sponsor: NIH; Grant number: R03 1R03AI079797-01; Grant sponsor: (this research supported in part by) The Intramural Research Program of the NIH, MAID. NR 9 TC 25 Z9 27 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD SEP PY 2009 VL 76B IS 5 BP 334 EP 344 DI 10.1002/cyto.b.20473 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 489NI UT WOS:000269426400005 PM 19288545 ER PT J AU Pine, DS AF Pine, Daniel S. TI INTEGRATING RESEARCH ON DEVELOPMENT AND FEAR LEARNING: A VISION FOR CLINICAL NEUROSCIENCE? SO DEPRESSION AND ANXIETY LA English DT Article ID GENERALIZED ANXIETY DISORDER; ADOLESCENTS; DEPRESSION; AMYGDALA; CHILDREN; EXPRESSIONS; PREDICTORS; ACTIVATION; FACES; RISK C1 [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorder Program, Intramural Res Program, Bethesda, MD 20892 USA. [Pine, Daniel S.] NIMH, Emot & Dev Branch, Mood & Anxiety Disorder Program, Intramural Res Program, Bethesda, MD USA. [Pine, Daniel S.] New York State Psychiat Inst & Hosp, Dept Child & Adolescent Psychiat, New York, NY 10032 USA. [Pine, Daniel S.] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. RP Pine, DS (reprint author), NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorder Program, Intramural Res Program, Bethesda, MD 20892 USA. EM pined@mail.nih.gov NR 15 TC 12 Z9 12 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD SEP PY 2009 VL 26 IS 9 BP 775 EP 779 DI 10.1002/da.20595 PG 5 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 492UM UT WOS:000269685500001 PM 19731230 ER PT J AU Weimer, JM Yokota, Y Stanco, A Stumpo, DJ Blackshear, PJ Anton, ES AF Weimer, Jill M. Yokota, Yukako Stanco, Amelia Stumpo, Deborah J. Blackshear, Perry J. Anton, E. S. TI MARCKS modulates radial progenitor placement, proliferation and organization in the developing cerebral cortex SO DEVELOPMENT LA English DT Article DE Radial glia; Progenitors; Cerebral cortical development; MARCKS; Mouse; Laminar organization ID PROTEIN-KINASE-C; GLIAL-CELLS; NEURONAL MIGRATION; ADHERENS JUNCTIONS; ASYMMETRIC INHERITANCE; NEUROEPITHELIAL CELLS; MEMBRANE ASSOCIATION; SUBVENTRICULAR ZONE; NEURAL PROGENITORS; CORTICAL-NEURONS AB The radial glial cells serve as neural progenitors and as a migratory guide for newborn neurons in the developing cerebral cortex. These functions require appropriate organization and proliferation of the polarized radial glial scaffold. Here, we demonstrate in mice that the myristoylated alanine-rich C-kinase substrate protein (MARCKS), a prominent cellular substrate for PKC, modulates radial glial placement and expansion. Loss of MARCKS results in ectopic collection of mitotically active radial progenitors away from the ventricular zone (VZ) in the upper cerebral wall. Apical restriction of key polarity complexes [CDC42, beta-catenin (CTNNB1), N-cadherin (CDH2), myosin IIB (MYOIIB), aPKC zeta, LGL, PAR3, pericentrin, PROM1] is lost. Furthermore, the radial glial scaffold in Marcks null cortex is compromised, with discontinuous, non-radial processes apparent throughout the cerebral wall and deformed, bulbous, unbranched end-feet at the basal ends. Further, the density of radial processes within the cerebral cortex is reduced. These deficits in radial glial development culminate in aberrant positioning of neurons and disrupted cortical lamination. Genetic rescue experiments demonstrate, surprisingly, that phosphorylation of MARCKS by PKC is not essential for the role of MARCKS in radial glial cell development. By contrast, the myristoylation domain of MARCKS needed for membrane association is essential for MARCKS function in radial glia. The membrane-associated targeting of MARCKS and the resultant polarized distribution of signaling complexes essential for apicobasal polarity may constitute a critical event in the appropriate placement, proliferation and organization of polarized radial glial scaffold in the developing cerebral cortex. C1 [Weimer, Jill M.; Yokota, Yukako; Stanco, Amelia; Anton, E. S.] Univ N Carolina, Sch Med, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. [Weimer, Jill M.; Yokota, Yukako; Stanco, Amelia; Anton, E. S.] Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Stumpo, Deborah J.; Blackshear, Perry J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Anton, ES (reprint author), Univ N Carolina, Sch Med, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. EM anton@med.unc.edu FU NIH [MH060929]; NIH-NRSA [NS056686]; NIEHS FX This work was supported by an NIH grant (MH060929) to E. S. A., an NIH-NRSA fellowship (NS056686) to J. M. W., and, in part, by the Intramural Research Program of the NIH, NIEHS (PB). We thank Larysa Pevny for helpful comments and Ana Vargo and Eleanor Saunders for technical assistance. Deposited in PMC for release after 12 months. NR 86 TC 33 Z9 33 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 1 PY 2009 VL 136 IS 17 BP 2965 EP 2975 DI 10.1242/dev.036616 PG 11 WC Developmental Biology SC Developmental Biology GA 480ZG UT WOS:000268775400011 PM 19666823 ER PT J AU Koo, SK Hill, JK Hwang, CH Lin, ZS Millen, KJ Wu, DK AF Koo, Soo Kyung Hill, Jennifer K. Hwang, Chan Ho Lin, Zheng Shi Millen, Kathleen J. Wu, Doris K. TI Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear SO DEVELOPMENTAL BIOLOGY LA English DT Article DE LIM homeodomain; Inner ear development; Fgf3; Transcription factor; Neurogenic fate ID NAIL-PATELLA SYNDROME; ROOF PLATE FORMATION; MUTANT MICE; CELL FATE; MOLECULAR-MECHANISMS; TARGETED DISRUPTION; PATTERNING DEFECTS; VESTIBULAR NEURONS; VERTEBRATE LIMB; HOMEOBOX GENE AB Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional nullmutant, dreher (dr(J)/dr(J)), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a's role as a selector gene. More importantly, while all three primary fates of the inner ear-neural, sensory, and non-sensory-are specified in dr(J)/dr(J), normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct. Published by Elsevier Inc. C1 [Koo, Soo Kyung; Hill, Jennifer K.; Hwang, Chan Ho; Lin, Zheng Shi; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. [Millen, Kathleen J.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Wu, DK (reprint author), Natl Inst Deafness & Other Commun Disorders, 5 Res Court,Rm 2B34, Rockville, MD 20850 USA. EM wud@nidcd.nih.gov FU NIH [R01 NS044262] FX We thank Matthew Chang and Lydia Lui for generating the 3-D images, Brad Buran for contributing to Lmx1a expression study, Anne Lindgren and Yuriko Mishima for assistance with embryo collection, and Drs. Quifu Ma and Randy Johnson for riboprobes. We appreciate Drs. Bernd Fritzsch, David Nichols, and Zheng-Yi Chan sharing their results prior to publication. We also thank members of theWu lab and Drs. Thomas Friedman and Robert Morell for their insightful comments. K. J. M supported by NIH R01 NS044262. NR 58 TC 28 Z9 28 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 1 PY 2009 VL 333 IS 1 BP 14 EP 25 DI 10.1016/j.ydbio.2009.06.016 PG 12 WC Developmental Biology SC Developmental Biology GA 526AO UT WOS:000272260100002 PM 19540218 ER PT J AU Li, Y Piatigorsky, J AF Li, Yan Piatigorsky, Joram TI Targeted Deletion of Dicer Disrupts Lens Morphogenesis, Corneal Epithelium Stratification, and Whole Eye Development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Dicer; microRNA; lens development ID EMBRYONIC STEM-CELLS; MICRORNA BIOGENESIS; VESICLE SEPARATION; GENE-EXPRESSION; MOUSE OOCYTES; MICE LACKING; DIFFERENTIATION; APOPTOSIS; RNAS; INDUCTION AB Dicer, a ribonuclease essential for miRNA processing, is expressed abundantly in developing mouse cornea and lens. We studied the roles of Dicer and miRNAs in eye development by conditionally deleting the Dicer gene in the mouse lens and corneal epithelium. Adult Dicer conditional null (DicerCN) mice had severe microphthalmia with no discernible lens and a poorly stratified corneal epithelium. Targeted deletion of Dicer effectively inhibited miRNA processing in the developing lens at 12.5 day of embryogenesis (E12.5). Lens development initiated normally but underwent progressive dystrophy between E14.5 and E18.5. Microarray analysis revealed activation of P53 signaling in DicerCN lenses at E13.5, consistent with increased apoptosis and reduced cell proliferation between E12.5 and E14.5. Expression of Pax6 and other lens developmental transcription factors were not greatly affected between E12.5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development. Developmental Dynamics 238:2388-2400, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Li, Yan; Piatigorsky, Joram] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Li, Y (reprint author), NEI, Mol & Dev Biol Lab, NIH, 5625 Fishers Lane,1S02, Bethesda, MD 20892 USA. EM liyan2@mail.nih.gov; piatigorskyj@nei.nih.gov FU National Eye Institute, NIH FX Grant sponsor: National Eye Institute, NIH. NR 74 TC 32 Z9 35 U1 0 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD SEP PY 2009 VL 238 IS 9 BP 2388 EP 2400 DI 10.1002/dvdy.22056 PG 13 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 492UT UT WOS:000269686400024 PM 19681134 ER PT J AU Lowery, RL Zhang, Y Kelly, EA Lamantia, CE Harvey, BK Majewska, AK AF Lowery, Rebecca L. Zhang, Yu Kelly, Emily A. Lamantia, Cassandra E. Harvey, Brandon K. Majewska, Ania K. TI Rapid, Long-Term Labeling of Cells in the Developing and Adult Rodent Visual Cortex Using Double-Stranded Adeno-Associated Viral Vectors SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE AAV; labeling; visual cortex; imaging; GFP ID CENTRAL-NERVOUS-SYSTEM; RATE-LIMITING STEP; VIRUS VECTORS; GENE-TRANSFER; MOUSE-BRAIN; EFFICIENT TRANSDUCTION; IN-VIVO; TRANSGENE EXPRESSION; SINDBIS VECTOR; AAV SEROTYPES AB Chronic in vivo imaging studies of the brain require a labeling method that is fast, long-lasting, efficient, nontoxic, and cell-type specific. Over the last decade, adeno-associated virus (AAV) has been used to stably express fluorescent proteins in neurons in vivo. However, AAV's main limitation for many studies (such as those of neuronal development) is the necessity of second-strand DNA synthesis, which delays peak transgene expression. The development of double-stranded AAV (dsAAV) vectors has overcome this limitation, allowing rapid transgene expression. Here, we have injected different serotypes (1, 2, 6, 7, 8, and 9) of a dsAAV vector carrying the green fluorescent protein (GFP) gene into the developing and adult mouse visual cortex and characterized its expression. We observed labeling of both neurons and astrocytes with serotype-specific tropism. dsAAV-GFP labeling showed high levels of neuronal GFP expression as early as 2 days postinjection and as long as a month, surpassing conventional AAV's onset of expression and matching its longevity. Neurons labeled with dsAAV-GFP appeared structurally and electrophysiologically identical to nonlabeled neurons, suggesting that dsAAV-GFP is neither cytotoxic nor alters normal neuronal function. We also demonstrated that dsAAV-labeled cells can be imaged with subcellular resolution in vivo over multiple days. We conclude that dsAAV is an excellent vector for rapid labeling and long-term in vivo imaging studies of astrocytes and neurons on the single cell level within the developing and adult visual cortex. (C) 2009 Wiley Periodicals. Inc. Develop Neurobiol 69: 674-688, 2009 C1 [Lowery, Rebecca L.; Zhang, Yu; Kelly, Emily A.; Lamantia, Cassandra E.; Majewska, Ania K.] Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14642 USA. [Harvey, Brandon K.] Natl Inst Drug Abuse, Neural Protect & Regenerat Sect, IRP, Baltimore, MD USA. RP Majewska, AK (reprint author), Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14642 USA. EM ania_majewska@urmc.rochester.edu FU Intramural NIH HHS; NEI NIH HHS [R01 EY019277, R01 EY019277-01A1] NR 38 TC 9 Z9 9 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD SEP 1 PY 2009 VL 69 IS 10 BP 674 EP 688 DI 10.1002/dneu.20735 PG 15 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 482VG UT WOS:000268916600005 PM 19551873 ER PT J AU Stancakova, A Kuulasmaa, T Paananen, J Jackson, AU Bonnycastle, LL Collins, FS Boehnke, M Kuusisto, J Laakso, M AF Stancakova, Alena Kuulasmaa, Teemu Paananen, Jussi Jackson, Anne U. Bonnycastle, Lori L. Collins, Francis S. Boehnke, Michael Kuusisto, Johanna Laakso, Markku TI Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes With Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5,327 Nondiabetic Finnish Men SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; BETA-CELL FUNCTION; TCF7L2 GENE POLYMORPHISMS; POPULATION-BASED SAMPLE; GLUCOSE-TOLERANCE; INCREASED RISK; PREDIABETIC PHENOTYPES; PRO12ALA POLYMORPHISM; EUROPEAN POPULATIONS; PREVENTION PROGRAM AB OBJECTIVE-We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin. RESEARCH DESIGN AND METHODS-A total of 5,327 nondiabetic men (age 58 +/- 7 years, BMI 27.0 +/- 3.8 kg/m(2)) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium. RESULTS-Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, and MTNR1B) were significantly (P < 6.9 x 10(-4)) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P < 0.05) associated with early-phase insulin release, (InsAUC(0-30)/GluAUC(0-30)), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached -32% reduction in InsAUC(0-30)/GluAUC(0-30), in carriers of >= 11 vs. <= 3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, and TCF7L2) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs (KCNJ11, HHEX, and TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC(0-30)/GluAUC(0-30). Nine SNPs did not show any associations with examined traits. CONCLUSIONS-Eight type 2 diabetes-related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity. Diabetes 58:2129-2136, 2009 C1 [Stancakova, Alena; Kuulasmaa, Teemu; Paananen, Jussi; Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Stancakova, Alena; Kuulasmaa, Teemu; Paananen, Jussi; Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Bonnycastle, Lori L.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Laakso, M (reprint author), Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. EM markku.laakso@kuh.fi OI Paananen, Jussi/0000-0001-5100-4907 FU Academy of Finland [124243]; Finnish Heart Foundation; Finnish Diabetes Foundation; TEKES [1510/31/06]; Commission of the European Community [LSHM-CT-2004-512013]; National Institutes of Health [DK-62370]; National Human Genome Research Institute Intramural [1 Z01 HG000024] FX No potential conflicts of interest relevant to this article were reported. NR 49 TC 100 Z9 105 U1 0 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2009 VL 58 IS 9 BP 2129 EP 2136 DI 10.2337/db09-0117 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492JE UT WOS:000269650400023 PM 19502414 ER PT J AU Perreault, L Kahn, SE Christophi, CA Knowler, WC Hamman, RF AF Perreault, Leigh Kahn, Steven E. Christophi, Costas A. Knowler, William C. Hamman, Richard F. CA Diabet Prevention Program Res Grp TI Regression From Pre-Diabetes to Normal Glucose Regulation in the Diabetes Prevention Program SO DIABETES CARE LA English DT Article ID IMPAIRED FASTING GLUCOSE; LIFE-STYLE INTERVENTION; BETA-CELL FUNCTION; INSULIN-RESISTANCE; NATURAL-HISTORY; TOLERANCE; MELLITUS; SECRETION; EXERCISE; TRIAL AB OBJECTIVE - Participants in the Diabetes Prevention Program (DPP) randomized to intensive lifestyle modification (ILS) or metformin had a significantly reduced incidence of diabetes compared with those randomized to placebo, yet most were still at risk because they had pre-diabetes. We explored the effect of baseline characteristics, weight change, ILS, and metformin on regression from pre-diabetes to the lowest-risk state of normal glucose regulation (NGR) defined by American Diabetes Association criteria. RESEARCH DESIGN AND METHODS - The DPP was a prospective randomized trial. Cox proportional hazards modeling was used to identify predictors of regression from prediabetes to NGR over 3 years of follow-up. RESULTS - Lower baseline fasting (hazard ratio 1.52, P < 0.01) and 2-h (1.24, P < 0.01) glucose predicted regression to NGR, as did younger age (1.07, P < 0.01) and greater insulin secretion (1.09, P = 0.04). ILS (2.05, P < 0.01) and weight loss (1.34, P < 0.01) had significant and independent effects on regression. A nonsignificant trend for regression was also observed for metformin (1.25, P = 0.06), male sex (1.17, P = 0.08), and insulin sensitivity (1.07, P = 0.09). In those entering the study with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), male sex and insulin sensitivity predicted regression to isolated IFG, whereas ILS, metformin, female sex, and greater insulin secretion predicted regression to isolated IGT. CONCLUSIONS - insulin secretion, and other biologic processes retained with younger age, are key in restoring NGR in people with pre-diabetes. However, NGR may also be attained through weight loss and additional aspects of ILS. C1 [Perreault, Leigh] Univ Colorado, Dept Med, Div Endocrinol Diabet & Metab, Denver Sch Med, Aurora, CO USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Christophi, Costas A.] George Washington Univ, Ctr Biostat, Diabet Prevent Program, Coordinating Ctr, Rockville, MD USA. [Knowler, William C.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Div Intramural Res, Phoenix, AZ USA. [Hamman, Richard F.] Univ Colorado Denver, Dept Epidemiol, Colorado Sch Publ Hlth, Aurora, CO USA. EM dppmail@biostat.bsc.gwu.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; Henry M. Jackson Foundation FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the coordinating center for the design and conduct of the study and the collection, management, analysis, and interpretation of the data. The Southwestern American Indian centers were supported directly by the NIDDK and the Indian Health Service. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, and ADA. This research was also supported, in part, by the Intramural Research Program of the NIDDK. The Henry M. Jackson Foundation provided support services under subcontract with the coordinating center. NR 25 TC 54 Z9 54 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2009 VL 32 IS 9 BP 1583 EP 1588 DI 10.2337/dc09-0523 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492UY UT WOS:000269687100002 PM 19587364 ER PT J AU Kim, PS Woods, C Georgoff, P Crum, D Rosenberg, A Smith, M Hadigan, C AF Kim, Peter S. Woods, Christian Georgoff, Patrick Crum, Dana Rosenberg, Alice Smith, Margo Hadigan, Colleen TI A1C Underestimates Glycemia in HIV Infection SO DIABETES CARE LA English DT Article; Proceedings Paper CT 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 25, 2008 CL Washington, DC SP Infect Dis Soc Amer ID GLYCATED HEMOGLOBIN; POSITIVE PATIENTS; VALUES AB OBJECTIVE - The objective of this study was to determine the relationship between A1C and glycemia in HIV infection. RESEARCH DESIGN AND METHODS - We completed a prospective cross-sectional study of 100 HIV-infected adults with type 2 diabetes (77%) or fasting hyperglycemia (23%) with measured glucose, A1C, mean corpuscular Volume (MCV), and fructosamine. A total of 200 HIV-uninfected type 2 diabetic subjects matched for key demographic characteristics served as control subjects. RESULTS - Relative to the control subjects, A1C underestimated glucose by 29 +/- 4 mg/dl in the HIV-infected subjects. Current nucleoside reverse transcriptase inhibitors (NRTIs), higher MCV and hemoglobin, and lower HIV RNA and haptoglobin were associated With greater A1C-glucose discordance. However, only MCV and current NTRI use, in particular abacavir, remained significant predictors in multivariate analyses. Fructosamine more closely reflected glycemia in the HIV-infected subjects. CONCLUSIONS - A1C underestimates glycemia in HIV-infected patients and is related to NRTI use. Use of abacavir and increased MCV were key correlates in multivariate analyses. Fructosamine may be more appropriate in this setting. C1 [Kim, Peter S.; Rosenberg, Alice; Hadigan, Colleen] NIAID, NIH, Bethesda, MD 20892 USA. [Kim, Peter S.; Woods, Christian; Smith, Margo] Washington Hosp Ctr, Dept Infect Dis, Washington, DC 20010 USA. [Georgoff, Patrick; Crum, Dana] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Hadigan, C (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov FU Intramural NIH HHS NR 13 TC 38 Z9 40 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2009 VL 32 IS 9 BP 1591 EP 1593 DI 10.2337/dc09-0177 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492UY UT WOS:000269687100004 PM 19502538 ER PT J AU Sosenko, JM Palmer, JP Rafkin-Mervis, L Krischer, JP Cuthbertson, D Mahon, J Greenbaum, CJ Cowie, CC Skyler, JS AF Sosenko, Jay M. Palmer, Jerry P. Rafkin-Mervis, Lisa Krischer, Jeffrey P. Cuthbertson, David Mahon, Jeffery Greenbaum, Carla J. Cowie, Catherine C. Skyler, Jay S. CA Diabet Prevention Trial-Type 1 Stu TI Incident Dysglycemia and Progression to Type 1 Diabetes Among Participants in the Diabetes Prevention Trial-Type 1 SO DIABETES CARE LA English DT Article ID ANTIBODY-POSITIVE RELATIVES; IMPAIRED GLUCOSE-TOLERANCE; BETA-CELL FUNCTION; INSULIN; TRIAL-TYPE-1; INDIVIDUALS; PREDICTION; MELLITUS AB OBJECTIVE - We studied the incidence of dysglycemia and its prediction of the development of type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, we assessed whether dysglycemia was sustained. RESEARCH DESIGN AND METHODS - Participants (n = 515) in the Diabetes Prevention Trial-Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for type 1 diabetes prediction. RESULTS - Of 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month Visit was highly predictive of the development of type 1 diabetes, both in those aged <13 years (P < 0.001) and those aged >= 13 years (P < 0.01). Those aged <13 years with dysglycemia at the 6-month Visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis. CONCLUSIONS - ICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is Strongly predictive of type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of type 1 diabetes. C1 [Sosenko, Jay M.; Rafkin-Mervis, Lisa; Skyler, Jay S.] Univ Miami, Div Endocrinol, Miami, FL USA. [Palmer, Jerry P.] Univ Washington, Div Endocrinol Metab, Seattle, WA 98195 USA. [Krischer, Jeffrey P.] Univ S Florida, Div Informat & Biostat, Tampa, FL USA. [Cuthbertson, David] Univ S Florida, Pediat Epidemiol Ctr, Tampa, FL USA. [Mahon, Jeffery] Univ Western Ontario, Dept Epidemiol & Biostat, London, ON, Canada. [Greenbaum, Carla J.] Benaroya Res Inst Virginia Mason, Seattle, WA USA. [Cowie, Catherine C.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Sosenko, JM (reprint author), Univ Miami, Div Endocrinol, Miami, FL USA. EM jsosenko@med.miami.edu RI Skyler, Jay/F-4211-2016 NR 15 TC 22 Z9 22 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2009 VL 32 IS 9 BP 1603 EP 1607 DI 10.2337/dc08-2140 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492UY UT WOS:000269687100008 PM 19487644 ER PT J AU Saczynski, JS Siggurdsson, S Jonsson, PV Eiriksdottir, G Olafsdottir, E Kjartansson, O Harris, TB van Buchem, MA Gudnason, V Launer, LJ AF Saczynski, Jane S. Siggurdsson, Sigurdur Jonsson, Palmi V. Eiriksdottir, Gudny Olafsdottir, Elin Kjartansson, Olafur Harris, Tamara B. van Buchem, Mark A. Gudnason, Vilmundur Launer, Lenore J. TI Glycemic Status and Brain Injury in Older Individuals The Age Gene/Environment Susceptibility-Reykjavik Study SO DIABETES CARE LA English DT Article ID ENDOTHELIAL DYSFUNCTION; DIABETES-MELLITUS; DISEASE; EPIDEMIC; DEMENTIA; INSULIN; COHORT; RISK; MRI AB OBJECTIVE - To examine the association of glycemic status to magnetic resonance imaging indicators of brain pathological changes. RESEARCH DESIGN AND METHODS - This was a cross-sectional, population-based study of 4,415 men and women without dementia (mean age 76 years) participating in the Age Gene/Environment Susceptibility-Reykjavik Study. Glycemic status groups included the following: type 2 diabetes (self-report of diabetes, use of diabetes medications, or fasting blood glucose >= 7.0 mmol/l [11.1%]); impaired fasting glucose (IFG) (fasting blood glucose 5.6-6.9 mmol/l [36.2%]); and normoglycemic (52.7%). Outcomes were total brain volume, white and gray Matter volume, white matter lesion (WML) volume, and presence of cerebral infarcts. RESULTS - After adjustment for demographic and cardiovascular risk factors, participants with type 2 diabetes had significantly lower total brain volume (72.2 vs. 71.5%; P < 0.001) and lower gray and white matter volumes (45.1 vs. 44.9%, P < 0.01 and 25.7 vs. 25.3%, P < 0.001, respectively) and were more likely to have single (odds ratio 1.45 [95% CI 1.14-1.85]) or Multiple (2.27 [1.60-3.23]) cerebral infarcts compared with normoglycemic participants. Longer duration of type 2 diabetes was associated with lower total brain volume and gray and white matter volume, higher WML volume (all P(trend) < 0.05), and a greater likelihood of single and multiple cerebral infarcts (all P(trend) < 0.01). CONCLUSIONS - Type 2 diabetic participants have more pronounced brain atrophy and are more likely to have cerebral infarcts. Duration of type 2 diabetes is associated with brain changes, suggesting that type 2 diabetes has a cumulative effect on the brain. C1 [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA 01605 USA. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA USA. [Saczynski, Jane S.; Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Siggurdsson, Sigurdur; Jonsson, Palmi V.; Eiriksdottir, Gudny; Olafsdottir, Elin; Kjartansson, Olafur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Jonsson, Palmi V.; Kjartansson, Olafur; Gudnason, Vilmundur] Univ Iceland, Dept Med, Reykjavik, Iceland. [van Buchem, Mark A.] Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. RP Saczynski, JS (reprint author), Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA 01605 USA. EM jane.saczynski@umassmed.edu RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU National institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program, Hjartavernd FX This study was funded by the National institutes of Health (Contract N01-AG-12100), the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). NR 24 TC 25 Z9 26 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2009 VL 32 IS 9 BP 1608 EP 1613 DI 10.2337/dc08-2300 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492UY UT WOS:000269687100009 PM 19509008 ER PT J AU Nguyen, TT Alibrahim, E Islam, FMA Klein, R Klein, BEK Cotch, MF Shea, S Wong, TY AF Nguyen, Thanh T. Alibrahim, Ekaterina Islam, F. M. Amirul Klein, Ronald Klein, Barbara E. K. Cotch, Mary Frances Shea, Steven Wong, Tien Y. TI Inflammatory, Hemostatic, and Other Novel Biomarkers for Diabetic Retinopathy The Multi-Ethnic Study of Atherosclerosis SO DIABETES CARE LA English DT Article ID MICROVASCULAR COMPLICATIONS; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; HOMOCYSTEINE LEVELS; PLASMA-FIBRINOGEN; NEPHROPATHY; MARKERS; HOORN; ACTIVATION; COHORT AB OBJECTIVE - There are conflicting data regarding relationships of systemic biomarkers of inflammation, hemostasis, and homocysteine with diabetic retinopathy. We examined these relationships in the Multi-Ethnic Study of Atherosclerosis. RESEARCH DESIGN AND METHODS - A total of 921 participants with diabetes were included. Diabetic retinopathy was graded from retinal photographs. We defined two outcomes: any diabetic retinopathy and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse). Systemic markers analyzed were C-reactive protein, homocysteine, fibrinogen, plasmin-alpha(2)-antiplasmin complex (PAP), interleukin-6, D-dimer, factor VIII, serum creatinine, and urinary albumin-to-creatinine (UAC) ratio. RESULTS - Prevalence of diabetic retinopathy was 33.2% and vision-threatening diabetic retinopathy 7.1%. After adjusting for established risk factors (diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, and use of diabetes medications), fibrinogen (odds ratio 1.14 [95% CI 1.01-1.32], P = 0.05) and PAP (1.25 [1.05-1.50], P = 0.01) were associated With any diabetic retinopathy, while PAP (1.54 [1.13-2.11], P = 0.007) and homocysteine (1.57 [1.16-2.11], P = 0.003) were associated with vision-threatening diabetic retinopathy. Only PAP remained significant after additional adjustment for serum creatinine and UAC ratio. Area under receiver-operator characteristic curve (AUROC) for diabetic retinopathy was constructed for established and novel risk factors. Established risk factors accounted for a 39.2% increase Of the AUROC, whereas novel markers (fibrinogen, PAP, homocysteine, serum creatinine, and UAC ratio) only accounted for an additional 2.2%. CONCLUSIONS - There were few associations of novel markers of inflammation, hemostasis, and homocysteine with diabetic retinopathy after controlling for established risk factors. These data suggest that there is limited clinical use of these biomarkers for prediction of diabetic retinopathy. C1 [Nguyen, Thanh T.; Alibrahim, Ekaterina; Islam, F. M. Amirul; Wong, Tien Y.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Shea, Steven] Columbia Univ, Sch Med, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Sch Med, Dept Epidemiol, New York, NY USA. [Shea, Steven] Columbia Univ, Sch Publ Hlth, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. RP Wong, TY (reprint author), Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. EM twong@unimelb.edu.au OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung, and Blood institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; National Institutes of Health (NIH) [R01HL69979-03, Z01EY403] FX This research was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood institute. Additional support was provided by National Institutes of Health (NIH) Grants R01HL69979-03 (to K.R. and W.T.Y.) and the NIH Intramural Program Award Z01EY403 (to M.F.C.). NR 25 TC 51 Z9 52 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2009 VL 32 IS 9 BP 1704 EP 1709 DI 10.2337/dc09-0102 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492UY UT WOS:000269687100027 PM 19549733 ER PT J AU McNeely, MJ McClelland, RL Bild, DE Jacobs, DR Tracy, RP Cushman, M Goff, DC Astor, BC Shea, S Siscovick, DS AF McNeely, Marguerite J. McClelland, Robyn L. Bild, Diane E. Jacobs, David R., Jr. Tracy, Russell P. Cushman, Mary Goff, David C., Jr. Astor, Brad C. Shea, Steven Siscovick, David S. TI The Association Between A1C and Subclinical Cardiovascular Disease The Multi-Ethnic Study of Atherosclerosis SO DIABETES CARE LA English DT Article ID INTIMA-MEDIA THICKNESS; CORONARY-HEART-DISEASE; CAROTID ATHEROSCLEROSIS; DIABETES-MELLITUS; FASTING GLUCOSE; PLASMA-GLUCOSE; RISK-FACTORS; POPULATION; INDIVIDUALS; MESA AB OBJECTIVE - To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI. RESEARCH DESIGN AND METHODS - This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose >= 7.0 mmol/l or use of diabetes medication), aged 47-86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, Systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI. RESULTS - Compared with those in the lowest quartile for A1C ([mean +/- SD] 5.0 +/- 0.2%), participants in the highest quartile (6.0 +/- 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, L e association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11). CONCLUSIONS - In this multiethnic cohort, there were small, Positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women. C1 [McNeely, Marguerite J.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bild, Diane E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, Oslo, Norway. [Tracy, Russell P.; Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Goff, David C., Jr.] Wake Forest Univ, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Goff, David C., Jr.] Wake Forest Univ, Dept Internal Med, Winston Salem, NC 27109 USA. [Astor, Brad C.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Astor, Brad C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Dept Epidemiol, New York, NY USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP McNeely, MJ (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. EM mcneely@u.washington.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169] FX D.C.G. received grant support from Merck, has been an editorial consultant for the American Medical Association (Deputy Editor, Archives of Internal Medicine), and has been a scientific consultant for Scientific Evidence. No other potential conflicts of interest relevant to this article were reported. NR 23 TC 35 Z9 36 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2009 VL 32 IS 9 BP 1727 EP 1733 DI 10.2337/dc09-0074 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 492UY UT WOS:000269687100032 PM 19549732 ER PT J AU Curtis, J Lipke, S Effland, S Dickinson, B McCabe, A Russell, B Russell, M Bloomquist, P Wilson, C AF Curtis, Jeffrey Lipke, Suzanne Effland, Shirley Dickinson, Bridget McCabe, Alberta Russell, Bernadine Russell, Marie Bloomquist, Paul Wilson, Charlton TI Effectiveness and Safety of Medication Adjustments by Nurse Case Managers to Control Hyperglycemia SO DIABETES EDUCATOR LA English DT Article ID HEALTH MAINTENANCE ORGANIZATION; GLYCEMIC CONTROL; DIABETIC-PATIENTS; CARE; INSULIN AB Purpose The purpose of this study was to determine the safety and effectiveness of implementing standing orders for nurse case managers to adjust antihyperglycemic medications. Methods A retrospective cohort design was used to assess outcomes in American Indian and Alaska Native people who received case management and medication adjustment and those who received only standard primary care. Patients with diabetes and evidence of keeping regular follow-up appointments for diabetes care (N = 2345) who all had baseline A1C >= 7.0% were divided into 3 mutually exclusive groups for analysis: (1) those seen only by primary care providers (PCP; n = 1574); (2) those seen by nurse case managers (NCM; in addition to primary care) for diabetes education services only (n = 711); and (3) those who, in addition to a PCP and NCM visit, had medications adjusted by the nurse case managers (MA; n = 60). Outcome variables were number of visits with documentation of hypoglycemia (safety) and rate of A1C change (effectiveness). Results Documented hypoglycemia occurred more frequently with more intensive treatment. The MA group experienced the greatest rate of hypoglycemic events. The difference in hypoglycemia incidence between the groups was significant, but the number of events was small. Glycemic control improved most rapidly in the MA group, even after adjusting for potentially confounding variables. Conclusions In this setting, hypoglycemia occurs infrequently in all groups, but at higher rates with more intensive treatment. Nurse case management, whether with or without medication adjustment, is effective in improving short-term glucose control. C1 [Curtis, Jeffrey] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Lipke, Suzanne; Effland, Shirley; Dickinson, Bridget; McCabe, Alberta; Russell, Bernadine; Russell, Marie; Bloomquist, Paul; Wilson, Charlton] Phoenix Indian Med Ctr, Div Ctr Excellence, Phoenix, AZ USA. RP Curtis, J (reprint author), 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM jfcurtis@mail.nih.gov FU Special Diabetes Programs for Indians [5H1D9400171-06]; NIH; NIDDK FX This project was made possible by funding from the Special Diabetes Programs for Indians Grant # 5H1D9400171-06 and was supported in part by the Intramural Research Program of the NIH, NIDDK. The authors would like to acknowledge Ms Audrey Lynch for her expert data management assistance and Dr Clinton Mason, Dr Robert Hanson, and Dr William Knowler for their assistance in statistical programming and analysis. NR 21 TC 4 Z9 4 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 J9 DIABETES EDUCATOR JI Diabetes Educ. PD SEP PY 2009 VL 35 IS 5 BP 851 EP 856 DI 10.1177/0145721709343677 PG 6 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 498UT UT WOS:000270170300015 PM 19713556 ER PT J AU Prokopenko, I Dupuis, J Langenberg, C Saxena, R Soranzo, N Jackson, AU Wheeler, E Glazer, NL Magi, R Bouatia-Naji, N Florez, JC Barroso, I AF Prokopenko, I. Dupuis, J. Langenberg, C. Saxena, R. Soranzo, N. Jackson, A. U. Wheeler, E. Glazer, N. L. Maegi, R. Bouatia-Naji, N. Florez, J. C. Barroso, I. CA MAGIC Investigators TI Novel genetic loci implicated in fasting glucose homeostasis and their impact on related metabolic traits SO DIABETOLOGIA LA English DT Meeting Abstract CT 45th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 30-OCT 02, 2009 CL Vienna, AUSTRIA SP European Assoc Study Diabet C1 [Prokopenko, I.; Maegi, R.] WTCHG, Oxford, England. [Prokopenko, I.; Maegi, R.] OCDEM, Oxford, England. [Dupuis, J.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Dupuis, J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Langenberg, C.] MRC Epidemiol Unit, Cambridge, England. [Saxena, R.; Florez, J. C.] Broad Inst Harvard, Cambridge, MA 02138 USA. [Saxena, R.; Florez, J. C.] MIT, Cambridge, MA 02139 USA. [Saxena, R.; Florez, J. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Soranzo, N.; Wheeler, E.; Barroso, I.] Wellcome Trust Sanger Inst, Cambridge, England. [Soranzo, N.] Kings Coll London, London, England. [Jackson, A. U.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Glazer, N. L.] Univ Michigan, Seattle, WA USA. [Bouatia-Naji, N.] CNRS, UMR8090, Lille, France. RI BOUATIA-NAJI, NABILA/D-5863-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2009 VL 52 MA 76 BP S38 EP S38 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 487HK UT WOS:000269262400076 ER PT J AU Shamekh, R Patterson, AD Eichler, GS Krausz, KW Li, F Aslam, S Weinstein, JN Hansen, BC Idle, JR Gonzalez, FJ AF Shamekh, R. Patterson, A. D. Eichler, G. S. Krausz, K. W. Li, F. Aslam, S. Weinstein, J. N. Hansen, B. C. Idle, J. R. Gonzalez, F. J. TI Metabolomic profile delineates potential defect in renal transporter function in the proximal tubule of monkeys with diabetic nephropathy SO DIABETOLOGIA LA English DT Meeting Abstract CT 45th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 30-OCT 02, 2009 CL Vienna, AUSTRIA SP European Assoc Study Diabet C1 [Shamekh, R.; Hansen, B. C.] Univ S Florida, St Petersburg, FL 33701 USA. [Patterson, A. D.; Krausz, K. W.; Li, F.; Gonzalez, F. J.] NIH, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Eichler, G. S.; Weinstein, J. N.] NCI, NIH, Genom & Bioinformat Grp, Bethesda, MD 20892 USA. [Aslam, S.] Univ S Florida, Off Clin Res, Tampa, FL USA. [Idle, J. R.] Charles Univ Prague, Inst Pharmacol, Prague, Czech Republic. RI Hansen, Barbara/J-8723-2012; Patterson, Andrew/G-3852-2012 OI Hansen, Barbara/0000-0001-9646-3525; Patterson, Andrew/0000-0003-2073-0070 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2009 VL 52 MA 1050 BP S412 EP S412 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 487HK UT WOS:000269262401048 ER PT J AU Thorsson, B Olafsdottir, E Aspelund, T Sigurdsson, G Benediktsson, R Harris, TB Launer, LJ Eiriksdottir, G Gudnason, V AF Thorsson, B. Olafsdottir, E. Aspelund, T. Sigurdsson, G. Benediktsson, R. Harris, T. B. Launer, L. J. Eiriksdottir, G. Gudnason, V. TI Changes in life expectancy of people with type 2 diabetes relative to non-diabetics over the last 40 years, from Reykjavik-AGES Study SO DIABETOLOGIA LA English DT Meeting Abstract CT 45th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 30-OCT 02, 2009 CL Vienna, AUSTRIA SP European Assoc Study Diabet C1 [Thorsson, B.; Olafsdottir, E.; Aspelund, T.; Sigurdsson, G.; Benediktsson, R.; Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Olafsdottir, E.; Aspelund, T.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Sigurdsson, G.; Benediktsson, R.] Landspitali Univ Hosp, Reykjavik, Iceland. [Harris, T. B.; Launer, L. J.] NIA, NIH, Bethesda, MD 20892 USA. RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2009 VL 52 MA 294 BP S125 EP S125 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 487HK UT WOS:000269262400293 ER PT J AU Ashktorab, H Nouraie, M Hosseinkhah, F Lee, E Rotimi, C Smoot, D AF Ashktorab, Hassan Nouraie, Mehdi Hosseinkhah, Fatemeh Lee, Edward Rotimi, Charles Smoot, Duane TI A 50-Year Review of Colorectal Cancer in African Americans: Implications for Prevention and Treatment SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Colorectal; Cancer; Retrospective; Review; African Americans ID BLACK-WHITE DIFFERENCES; HUMAN LARGE-INTESTINE; LARGE-BOWEL CANCER; COLON-CANCER; SOCIOECONOMIC-STATUS; UNITED-STATES; RACIAL DISPARITIES; PHYSICAL-ACTIVITY; INCIDENCE RATES; SURVIVAL AB African-Americans (AA) have the highest rate of colorectal cancer (CRC) incidence and mortality in the US. CRC in AA is more advanced and right-sided. Although screening has been shown to reduce mortality from CRC in the general US population, AA continue to experience a disproportionately higher CRC death compared to other ethnic groups. This study aimed at assessing the trend of CRC in AA, focusing on the changing pattern of in situ tumors in this ethnic group and how observed trends may guide current and future preventive and treatment strategies. All pathologic reports from 1959 to 2006 in Howard University Hospital (n = 150,000) were reviewed manually. The pathology reports showing colorectal cancer were carefully reviewed and selected by a GI pathologist. Intraepithelial or intramucosal carcinomas were diagnosed as in situ carcinoma. Reviewed pathological information were entered into Microsoft Excel and checked for duplication and missing data. Differences in situ and advanced cancer by sex, histology, location, and years of diagnosis were assessed by Chi-square test. A total of 1,753 CRC cases were diagnosed in this period. About 56% of the cases were female and 51% of the tumors were left-sided. Mean (SD) age was 66 (13) years. The frequency of in situ tumor was 5.8% in this period. There was no statistically significant difference between in situ and advance tumor by age, sex, and tumor location. The rate of in situ tumor peaked in the 1990s at 8.5% (P = 0.0001). We observed a decade-to-decade increasing rate of right-sided tumors, which started at 36% in the period 1959-1970 and peaked in the period of 2001-2006 at 60% (P = 0.0001). The recent increasing number of advanced and right-sided tumor in our study is concordant with SEER data and has great importance in developing CRC prevention and treatment strategies for AA population. C1 [Ashktorab, Hassan; Nouraie, Mehdi; Hosseinkhah, Fatemeh; Smoot, Duane] Howard Univ, Coll Med, Dept Med, Washington, DC 20060 USA. [Ashktorab, Hassan; Nouraie, Mehdi; Hosseinkhah, Fatemeh; Smoot, Duane] Howard Univ, Coll Med, Ctr Canc, Washington, DC 20060 USA. [Lee, Edward] Howard Univ, Coll Med, Dept Pathol, Washington, DC 20060 USA. [Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Ashktorab, H (reprint author), Howard Univ, Coll Med, Dept Med, 2041 Georgia Ave NW, Washington, DC 20060 USA. EM hashktorab@howard.edu FU National Cancer Institute, NIH [CA102681]; Center for Research on Genomics and Global Health; Howard University GCRC FX This work was supported by Grant # CA102681, funded by the National Cancer Institute, NIH, the Center for Research on Genomics and Global Health, and Howard University GCRC. NR 37 TC 10 Z9 11 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD SEP PY 2009 VL 54 IS 9 BP 1985 EP 1990 DI 10.1007/s10620-009-0866-5 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 474ZP UT WOS:000268324000025 PM 19554449 ER PT J AU Schug, TT Li, XL AF Schug, Thaddeus T. Li, Xiaoling TI PPAR delta-mediated macrophage activation: a matter of fat SO DISEASE MODELS & MECHANISMS LA English DT Editorial Material ID INSULIN-RESISTANCE; ADIPOSE-TISSUE; OBESITY; POLARIZATION; INFLAMMATION C1 [Schug, Thaddeus T.; Li, Xiaoling] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Schug, TT (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM schugt@niehs.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 J9 DIS MODEL MECH JI Dis. Model. Mech. PD SEP-OCT PY 2009 VL 2 IS 9-10 BP 421 EP 422 DI 10.1242/dmm.003913 PG 2 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 507TH UT WOS:000270877300001 PM 19726795 ER PT J AU Anderson, AL Reid, MS Li, SH Holmes, T Shemanski, L Slee, A Smith, EV Kahn, R Chiang, NR Vocci, F Ciraulo, D Dackis, C Roache, JD Salloum, IM Somoza, E Urschel, HC Elkashef, AM AF Anderson, Ann L. Reid, Malcolm S. Li, Shou-Hua Holmes, Tyson Shemanski, Lynn Slee, April Smith, Edwina V. Kahn, Roberta Chiang, Nora Vocci, Frank Ciraulo, Domenic Dackis, Charles Roache, John D. Salloum, Ihsan M. Somoza, Eugene Urschel, Harold C., III Elkashef, Ahmed M. TI Modafinil for the treatment of cocaine dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article; Proceedings Paper CT 69th Annual Meeting of the College-of-Problems-on-Drug-Dependence CY JUN 19, 2007 CL Quebec City, CANADA SP Coll Problems Drug Dependence DE Modafinil; Cocaine-related disorders; Alcoholism; Pharmacotherapy; Risk factors ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DOUBLE-BLIND; TRIAL; BEHAVIOR AB Aim: Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo. Methods: This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200 mg, and 69 to modafinil 400 mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days. Results: The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p > 0.79). However, two secondary outcomes showed significant effects by modafinil 200 mg: the maximum number of consecutive non-use days for cocaine (p = 0.02), and a reduction in craving (p = 0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p < 0.02). Conclusions: These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving. Published by Elsevier Ireland Ltd. C1 [Anderson, Ann L.; Li, Shou-Hua; Smith, Edwina V.; Kahn, Roberta; Chiang, Nora; Vocci, Frank; Elkashef, Ahmed M.] Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. [Reid, Malcolm S.] NYU, Sch Med, Dept Psychiat, New York, NY 10010 USA. [Holmes, Tyson] Stanford Univ, Div Biostat, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Shemanski, Lynn; Slee, April] Axio Res Corp, Seattle, WA 98121 USA. [Ciraulo, Domenic] Boston Med Ctr, Boston, MA 02118 USA. [Dackis, Charles] Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. [Roache, John D.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Salloum, Ihsan M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Somoza, Eugene] CinARC Clin Res Trials, Cincinnati, OH 45220 USA. [Urschel, Harold C., III] Res Amer, Dallas, TX 75234 USA. RP Anderson, AL (reprint author), Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, 6001 Execut Blvd,Rm 4149, Bethesda, MD 20892 USA. EM aa135m@nih.gov OI Ciraulo, Domenic/0000-0001-7706-8765 FU Intramural NIH HHS [Z99 DA999999]; NIDA NIH HHS [N01DA-3-8838] NR 27 TC 111 Z9 113 U1 2 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2009 VL 104 IS 1-2 BP 133 EP 139 DI 10.1016/j.drugalcdep.2009.04.015 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 478TK UT WOS:000268611000019 PM 19560290 ER PT J AU Tahlan, K Boshoff, HI AF Tahlan, K. Boshoff, H. I. TI NEW CELL WALL BIOSYNTHESIS INHIBITORS UNDER ACTIVE DEVELOPMENT FOR TUBERCULOSIS SO DRUGS OF THE FUTURE LA English DT Review ID RESISTANT MYCOBACTERIUM-TUBERCULOSIS; VITRO ANTIMYCOBACTERIAL ACTIVITY; BETA-LACTAM ANTIBIOTICS; ACID CONDENSING ENZYME; KETOACYL-ACP SYNTHASE; IN-VITRO; NITROIMIDAZOPYRAN PA-824; ANTITUBERCULOSIS AGENTS; CAPURAMYCIN ANALOGS; CATALASE PEROXIDASE AB Tuberculosis caused by the bacterial pathogen Mycobacterium tuberculosis is a major human disease predominantly affecting the developing world. The complex lifestyle and cell wall of M. tuberculosis confer intrinsic resistance to most commonly used antibacteriols, often requiring the use of specialized antituberculosis drugs for the treatment of the disease. Coinfection with human immunodeficiency virus (HIV) and tuberculosis is cause for growing worldwide concern, and the emergence of multidrug-resistant and extensively drug-resistant tuberculosis further complicates the situation. Therefore, there is a demand for new antituberculosis drugs to combat the disease. Fortunately, characteristics that import uniqueness and complexity to the mycobacteriol cell wall also make it on attractive target for drug development. The current review describes some of the cell wall inhibitors under active development for the treatment of tuberculosis. C1 [Tahlan, K.; Boshoff, H. I.] NIH, TB Res Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Tahlan, K (reprint author), NIH, TB Res Sect, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. EM tahlank@niaid.nih.gov NR 104 TC 4 Z9 4 U1 0 U2 1 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD SEP PY 2009 VL 34 IS 9 BP 739 EP 748 DI 10.1358/dof.2009.34.9.1410444 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 561NE UT WOS:000274983500005 ER PT J AU Cappuzzo, F Coudert, B Wierzbicki, R Park, K Custers, F Curbera, GA Giaccone, G Hilbe, W Klingelschmitt, G Ciuleanu, TE AF Cappuzzo, F. Coudert, B. Wierzbicki, R. Park, K. Custers, F. Curbera, G. A. Giaccone, G. Hilbe, W. Klingelschmitt, G. Ciuleanu, T. E. TI Overall survival analyses from the SATURN phase III placebo-controlled study of erlotinib as first-line maintenance therapy in advanced non-small-cell lung cancer (NSCLC) SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th ECCO/34th ESMO Multidisciplinary Congress CY SEP 20-24, 2009 CL Berlin, GERMANY SP ECCO, ESMO C1 [Ciuleanu, T. E.] Inst Oncol Ion Chiricuta, Cluj Napoca, Romania. [Hilbe, W.] Univ Innsbruck Hosp, A-6020 Innsbruck, Austria. [Klingelschmitt, G.] F Hoffmann La Roche Ltd, Stat, Basel, Switzerland. [Giaccone, G.] NIH, Bethesda, MD 20892 USA. [Curbera, G. A.] Med Oncol Serv Hosp Juan Canalejo, La Coruna, Spain. [Custers, F.] Atrium Med Ctr, Heerlen, Netherlands. [Park, K.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Wierzbicki, R.] RS McLaughlin Durham Reg Canc Ctr, Oshawa, ON, Canada. [Coudert, B.] Ctr George Francois Leclerc, Dijon, France. [Cappuzzo, F.] Ist Clin Humanitas, Rozzano Milano, Italy. RI Ciuleanu, Tudor Eliade/C-3996-2011 NR 0 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 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 3 BP 13 EP 13 PG 1 WC Oncology SC Oncology GA 504VD UT WOS:000270645000036 ER PT J AU Giaccone, G AF Giaccone, G. TI The role of biomarkers in selecting the right targeted agent to combine with chemotherapy SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Giaccone, G.] NCI, Med Oncol Branch CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 15 EP 15 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645900048 ER PT J AU Simon, R AF Simon, R. TI The need for robust statistical designs to bring biomarkers to the clinic SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Simon, R.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 42 EP 42 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645900141 ER PT J AU Simon, R AF Simon, R. TI Integration of diagnostic markers into the development process of targeted agents SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Simon, R.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 82 EP 82 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645900278 ER PT J AU Dittfeld, C Peickert, S Dietrich, A Grade, M Ried, T Kunz-Schughart, LA AF Dittfeld, C. Peickert, S. Dietrich, A. Grade, M. Ried, T. Kunz-Schughart, L. A. TI Response of CD133+/- subpopulations of CRC cell lines to radio- and chemotherapy SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Dittfeld, C.; Peickert, S.; Dietrich, A.; Kunz-Schughart, L. A.] OncoRay Ctr Radiat Res Oncol, Dresden, Germany. [Grade, M.] Univ Med, Dept Gen & Visceral Surg, Gottingen, Germany. [Ried, T.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 97 EP 97 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645900321 ER PT J AU Martinelli, F Maringwa, J Quinten, C Coens, C Cleeland, C Mendoza, T Reeve, B Shiling, Q Wang, S Bottomley, A AF Martinelli, F. Maringwa, J. Quinten, C. Coens, C. Cleeland, C. Mendoza, T. Reeve, B. Shiling, Q. Wang, S. Bottomley, A. TI Factor analysis of the Health-Related Quality of Life indicators of the QLQ-C30 in 6798 cancer patients SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Martinelli, F.; Maringwa, J.; Quinten, C.; Coens, C.; Bottomley, A.] EORTC, Brussels, Belgium. [Cleeland, C.; Mendoza, T.; Shiling, Q.; Wang, S.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Reeve, B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 175 EP 175 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645900591 ER PT J AU Bryce, J Catania, G Falanga, M Callegaro, L Liptrott, S Feroce, I Colussi, A Grosso, D Connola, M AF Bryce, J. Catania, G. Falanga, M. Callegaro, L. Liptrott, S. Feroce, I. Colussi, A. Grosso, D. Connola, M. TI Creating an oncology nurse cooperative research group: the GIRC experience SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Bryce, J.] Natl Canc Inst, Clin Trials Unit, Naples, Italy. [Catania, G.] Natl Canc Inst, Genoa, Italy. [Falanga, M.] SG Moscati Hosp, Avellino, Italy. [Callegaro, L.] Hosp San Raffaele, I-20132 Milan, Italy. [Liptrott, S.; Feroce, I.] European Inst Oncol, Milan, Italy. [Colussi, A.] Natl Canc Inst, Aviano, Italy. [Grosso, D.] Veneto Canc Inst, Padua, Italy. RI CATANIA, GIANLUCA/C-5845-2016 OI CATANIA, GIANLUCA/0000-0002-0862-071X NR 0 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 239 EP 239 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645901126 ER PT J AU Godfrey, WR Blumenstein, BA Schuetz, TJ Glode, LM Bilhartz, DL Gulley, JL Arlen, PM Schlom, J Laus, R Kantoff, PW AF Godfrey, W. R. Blumenstein, B. A. Schuetz, T. J. Glode, L. M. Bilhartz, D. L. Gulley, J. L. Arlen, P. M. Schlom, J. Laus, R. Kantoff, P. W. TI Further analysis of a Phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC) SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Godfrey, W. R.] Bavarian Nord ImmunoTherapeut, Clin Dev, Mountain View, CA USA. [Blumenstein, B. A.] Trial Architecture Consulting, Washington, DC USA. [Schuetz, T. J.] Therion Biol, Clin Dev, Boston, MA USA. [Glode, L. M.] Univ Colorado, Denver, CO 80202 USA. [Bilhartz, D. L.] Urol Associates, Nashville, TN USA. [Schlom, J.] NCI, Lab Tumor Immunobiol, Bethesda, MD 20892 USA. [Kantoff, P. W.] Dana Farber Canc Inst, Boston, MA 02115 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 406 EP 406 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645902012 ER PT J AU Cappuzzo, F Coudert, B Wierzbicki, R Park, K Custers, F Curbera, GA Giaccone, G Hilbe, W Klingelschmitt, G Ciuleanu, T AF Cappuzzo, F. Coudert, B. Wierzbicki, R. Park, K. Custers, F. Curbera, G. A. Giaccone, G. Hilbe, W. Klingelschmitt, G. Ciuleanu, T. CA SATURN Investigators TI A phase III study of erlotinib as maintenance therapy in NSCLC to delay progression following first-line chemotherapy (SATURN) SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology CY SEP 20-24, 2009 CL Berlin, GERMANY SP European Canc Org, European Soc Med Oncol C1 [Cappuzzo, F.] IRCCS, Ist Clin Humanitas, Rozzano, 20892, Italy. [Coudert, B.] Ctr Georges Francois Leclerc, A-6020 Dijon, France. [Wierzbicki, R.] RS McLaughlin Durham Reg Canc Ctr, CH-4002 Oshawa, ON, Canada. [Park, K.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Custers, F.] Atrium Med Ctr, Heerlen, Netherlands. [Curbera, G. A.] Hosp Juan Canalejo, La Coruna, Spain. [Giaccone, G.] NIH, Bethesda, MD USA. [Hilbe, W.] Univ Innsbruck Hosp, Innsbruck, Austria. [Klingelschmitt, G.] F Hoffmann La Roche & Co Ltd, Basel, Switzerland. [Ciuleanu, T.] Inst Oncol Ion Chiricuta, Cluj Napoca, Romania. RI Ciuleanu, Tudor Eliade/C-3996-2011 NR 0 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 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD SEP PY 2009 VL 7 IS 2 BP 553 EP 553 PG 1 WC Oncology SC Oncology GA 504VM UT WOS:000270645902503 ER PT J AU Race, B Meade-White, KD Miller, MW Barbian, KD Rubenstein, R LaFauci, G Cervenakova, L Favara, C Gardner, D Long, D Parnell, M Striebel, J Priola, SA Ward, A Williams, ES Race, R Chesebro, B AF Race, Brent Meade-White, Kimberly D. Miller, Michael W. Barbian, Kent D. Rubenstein, Richard LaFauci, Giuseppe Cervenakova, Larisa Favara, Cynthia Gardner, Donald Long, Dan Parnell, Michael Striebel, James Priola, Suzette A. Ward, Anne Williams, Elizabeth S. Race, Richard Chesebro, Bruce TI Susceptibilities of Nonhuman Primates to Chronic Wasting Disease SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; PRION PROTEIN EXPRESSION; DEER ODOCOILEUS-HEMIONUS; CAPTIVE MULE DEER; TRANSGENIC MICE; SPONGIFORM ENCEPHALOPATHY; TRANSMISSION; HUMANS; VARIANT; ELK AB Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy, or prion disease, that affects deer, elk, and moose. Human susceptibility to CWD remains unproven. despite likely exposure to CWD-infected cervids. We used 2 nonhuman primate species, cynomolgus macaques and squirrel monkeys, as human models for CWD susceptibility. CWD was inoculated into these 2 species by intracerebral and oral routes. After intracerebral inoculation of squirrel monkeys, 7 of 8 CWD isolates induced a clinical wasting syndrome within 33-53 months. The monkeys, brains showed spongiform encephalopathy and protease-resistant prion protein (PrPres) diagnostic of prion disease. After oral exposure, 2 squirrel monkeys had PrPres in brain, spleen, and lymph nodes at 69 months postinfection. In contrast, cynomolgus macaques have not shown evidence of clinical disease as of 70 months postinfection. Thus, these 2 species differed in susceptibility to CWD. Because humans are evolutionarily closer to macaques than to squirrel monkeys, they may also be resistant to CWD. C1 [Race, Brent] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. [Miller, Michael W.] Colorado Div Wildlife, Ft Collins, CO 80526 USA. [Rubenstein, Richard] SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. [LaFauci, Giuseppe] New York State Inst Basic Res Dev Disabil, Staten Isl, NY 10314 USA. [Cervenakova, Larisa] Amer Red Cross, Rockville, MD USA. [Williams, Elizabeth S.] Univ Wyoming, Laramie, WY 82071 USA. RP Race, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM raceb@niaid.nih.g FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This study was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 38 TC 51 Z9 51 U1 2 U2 13 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2009 VL 15 IS 9 BP 1366 EP 1376 DI 10.3201/eid1509.090253 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 490NK UT WOS:000269507500005 PM 19788803 ER PT J AU Brown, MA Troyer, JL Pecon-Slattery, J Roelke, ME O'Brien, SJ AF Brown, Meredith A. Troyer, Jennifer L. Pecon-Slattery, Jill Roelke, Melody E. O'Brien, Stephen J. TI Genetics and Pathogenesis of Feline Infectious Peritonitis Virus SO EMERGING INFECTIOUS DISEASES LA English DT Article ID TRANSMISSIBLE GASTROENTERITIS CORONAVIRUS; ENTERIC CORONAVIRUS; SEQUENCE ALIGNMENT; SPIKE PROTEIN; TROPISM; CATS; VIRULENCE; CHEETAHS; MUTATION; GENOME AB Feline coronavirus (FCoV) is endemic in feral cat populations and cat colonies, frequently preceding outbreaks of fatal feline infectious peritonitis (FIP). FCoV exhibits 2 biotypes: the pathogenic disease and a benign infection with feline enteric coronavirus (FECV). Uncertainty remains regarding whether genetically distinctive avirulent and virulent forms coexist or whether an avirulent form mutates in vivo, causing FIR To resolve these alternative hypotheses, we isolated viral sequences from FCoV-infected clinically healthy and sick cats (8 FIP cases and 48 FECV-asymptomatic animals); 735 sequences from 4 gene segments were generated and subjected to phylogenetic analyses. Viral sequences from healthy cats were distinct from sick cats on the basis of genetic distances observed in the membrane and nonstructural protein 7b genes. These data demonstrate distinctive circulating virulent and avirulent strains in natural populations. In addition, 5 membrane protein amino acid residues with functional potential differentiated healthy cats from cats with FIR These findings may have potential as diagnostic markers for virulent FIP-associated FCoV. C1 [Brown, Meredith A.] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Troyer, Jennifer L.; Roelke, Melody E.] SAIC Frederick Inc, Frederick, MD USA. RP Brown, MA (reprint author), NCI, Lab Genom Div, Frederick, MD 21702 USA. EM brownmer@gmail.com RI Troyer, Jennifer/B-8415-2012 FU National Cancer Institute; National Institutes of Health [N01-CO-12400]; National Institutes of Health; Center for Cancer Research FX This study was supported in part by the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400; and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 34 TC 42 Z9 42 U1 1 U2 24 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2009 VL 15 IS 9 BP 1445 EP 1452 DI 10.3201/eid1509.081573 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 490NK UT WOS:000269507500015 PM 19788813 ER PT J AU Schultz, MG Morens, DM AF Schultz, Myron G. Morens, David M. TI Charles-Jules-Henri Nicolle SO EMERGING INFECTIOUS DISEASES LA English DT Biographical-Item C1 [Schultz, Myron G.] Ctr Dis Control & Prevent, Atlanta, GA 30303 USA. [Morens, David M.] NIH, Bethesda, MD 20892 USA. RP Schultz, MG (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE, Atlanta, GA 30303 USA. EM mgs1@cdc.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2009 VL 15 IS 9 BP 1520 EP 1522 DI 10.3201/eid1509.090891 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 490NK UT WOS:000269507500034 ER PT J AU Berglund, ED Li, CY Bina, HA Lynes, SE Michael, MD Shanafelt, AB Kharitonenkov, A Wasserman, DH AF Berglund, Eric D. Li, Candice Y. Bina, Holly A. Lynes, Sara E. Michael, M. Dodson Shanafelt, Armen B. Kharitonenkov, Alexei Wasserman, David H. TI Fibroblast Growth Factor 21 Controls Glycemia via Regulation of Hepatic Glucose Flux and Insulin Sensitivity SO ENDOCRINOLOGY LA English DT Article ID BETA-KLOTHO; PPAR-ALPHA; METABOLIC DISEASES; FGF21; FIBROBLAST-GROWTH-FACTOR-21; ACTIVATION; FGF-21; GLUCOKINASE; STATES; MOUSE AB Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator shown to improve glycemic control. However, the molecular and functional mechanisms underlying FGF21-mediated improvements in glycemic control are not completely understood. We examined FGF21 effects on insulin sensitivity and glucose fluxes upon chronic (daily injection for 8 d) and acute (6 h infusion) administration in ob/+ and ob/ob mice. Results show that chronic FGF21 ameliorated fasting hyperglycemia in ob/ob mice via increased glucose disposal and improved hepatic insulin sensitivity. Acute FGF21 suppressed hepatic glucose production, increased liver glycogen, lowered glucagon, and improved glucose clearance in ob/+ mice. These effects were blunted in ob/ob mice. Neither chronic nor acute FGF21 altered skeletal muscle or adipose tissue glucose uptake in either genotype. In conclusion, FGF21 has potent glycemic effects caused by hepatic changes in glucose flux and improved insulin sensitivity. Thus, these studies define mechanisms underlying anti-hyperglycemic actions of FGF21 and support its therapeutic potential. (Endocrinology 150: 4084-4093, 2009) C1 [Berglund, Eric D.; Li, Candice Y.; Lynes, Sara E.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, NIH, Nashville, TN 37232 USA. [Bina, Holly A.; Michael, M. Dodson; Shanafelt, Armen B.; Kharitonenkov, Alexei] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Berglund, ED (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, 2200 Pierce Ave,702 Light Hall, Nashville, TN 37232 USA. EM berglunde@gmail.com FU National Institutes of Health [RO1 DK-50277, U24 DK-59637, T32 DK-07563] FX This work was supported by grants from the National Institutes of Health (RO1 DK-50277 to D. H. W., U24 DK-59637 to the Vanderbilt MMPC, and T32 DK-07563 to E. D. B.). NR 33 TC 131 Z9 136 U1 2 U2 14 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2009 VL 150 IS 9 BP 4084 EP 4093 DI 10.1210/en.2009-0221 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 485XV UT WOS:000269159800014 PM 19470704 ER PT J AU Crocker, MK Yanovski, JA AF Crocker, Melissa K. Yanovski, Jack A. TI Pediatric Obesity: Etiology and Treatment SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Review DE Overweight; Differential diagnosis; Pharmacotherapy; Bariatric surgery; Adiposity; Leptin ID EARLY-ONSET OBESITY; BODY-MASS INDEX; GENOME-WIDE ASSOCIATION; CONGENITAL LEPTIN DEFICIENCY; GASTRIC BYPASS-SURGERY; EXPERT COMMITTEE RECOMMENDATIONS; RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; PLACEBO-CONTROLLED TRIAL; GLUCAGON-LIKE PEPTIDE-1 AB This article reviews factors that contribute to excessive weight gain in children and outlines current knowledge regarding approaches for treating pediatric obesity. Most of the known genetic causes of obesity primarily increase energy intake. Genes regulating the leptin signaling pathway are particularly important for human energy homeostasis. Obesity is a chronic disorder that requires long-term strategies for management. The foundation for all treatments for pediatric obesity remains restriction of energy intake with lifestyle modification. There are few long-term studies of pharmacotherapeutic interventions for pediatric obesity. Bariatric surgical approaches are the most efficacious treatment but, because of their potential risks, are reserved for those with the most significant complications of obesity. C1 [Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US PHS, Dept Hlth & Human Serv,Unit Growth & Obes, Program Dev Endocrinol & Genet,NIH, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US PHS, Dept Hlth & Human Serv,Unit Growth & Obes, Program Dev Endocrinol & Genet,NIH, 9000 Rockville Pike,Hatfield Clin Res Ctr,Room 1-, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Child Health and Human Development; United States Public Health Service, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Yanovski is a Commissioned Officer in the United States Public Health Service, Department of Health and Human Services. Unit on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, 9000 Rockville Pike, Hatfield Clinical Research Center, Room 1-3330, IVISC 1103, Bethesda, MD, 20892-1103, USA NR 158 TC 28 Z9 29 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD SEP PY 2009 VL 38 IS 3 BP 525 EP + DI 10.1016/j.ecl.2009.06.007 PG 26 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 499HN UT WOS:000270209400006 PM 19717003 ER PT J AU Fang, F Quinlan, P Ye, W Barber, MK Umbach, DM Sandler, DP Kamel, F AF Fang, Fang Quinlan, Patricia Ye, Weimin Barber, Marie K. Umbach, David M. Sandler, Dale P. Kamel, Freya TI Workplace Exposures and the Risk of Amyotrophic Lateral Sclerosis SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE amyotrophic lateral sclerosis; chemicals; relative risk; risk factors; workplace exposures ID MOTOR-NEURON-DISEASE; CIGARETTE-SMOKING; OCCUPATIONAL EXPOSURES; ETHYLENE-GLYCOL; LEAD-EXPOSURE; N-HEXANE; ASSOCIATION; ALS; MORTALITY; DIAGNOSIS AB BACKGROUND: Occupation has been suggested to play a role in amyotrophic lateral sclerosis (ALS) etiology, but detailed information on the importance of specific workplace exposures is lacking. OBJECTIVES: Our aim was to assess the relationship between workplace exposures and the risk of ALS and to evaluate potential interactions between these exposures and smoking. METHODS: We conducted a case-control study in New England between 1993 and 1996, comprising 109 cases and 253 controls who completed a structured interview covering occupations and workplace exposures. Unconditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for ALS. Analyses were conducted among the entire study population and after stratification by smoking. RESULTS: We observed a higher risk of ALS for construction workers excluding supervisors (OR 2.9; 95% Cl, 1.2-7.2) and precision metal workers (OR = 3.5; 95% Cl, 1.2-10.5). Self-reported exposures to paint strippers; cutting, cooling, or lubricating oils; antifreeze or coolants; mineral or white spirits; and dry cleaning agents each appeared to be associated with a 60-90% higher risk. Specific chemicals related to a > 50% increase in risk of ALS included aliphatic chlorinated hydrocarbons, glycols, glycol ethers, and hexane. Relative risks associated with these workplace exposures and chemicals were greater among nonsmokers and persisted in mutually adjusted models. CONCLUSIONS: Our data suggest that certain occupations and workplace exposures may be associated with increased risk of ALS. These results need to be confirmed in independent populations. C1 [Fang, Fang; Sandler, Dale P.; Kamel, Freya] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Fang, Fang; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Quinlan, Patricia] Univ Calif San Francisco, Dept Med, Div Occupat & Environm Med, San Francisco, CA USA. [Barber, Marie K.] WESTAT Corp, Durham, NC USA. [Umbach, David M.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kamel, F (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov RI Ye, Weimin/A-5939-2008; OI Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES049005, Z01 ES49005-15] NR 39 TC 34 Z9 37 U1 2 U2 9 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 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2009 VL 117 IS 9 BP 1387 EP 1392 DI 10.1289/ehp.0900580 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 490EE UT WOS:000269479900026 PM 19750102 ER PT J AU Saldana, TM Basso, O Baird, DD Hoppin, JA Weinberg, CR Blair, A Alavanja, MCR Sandler, DP AF Saldana, Tina M. Basso, Olga Baird, Donna D. Hoppin, Jane A. Weinberg, Clarice R. Blair, Aaron Alavanja, Michael C. R. Sandler, Dale P. TI Pesticide Exposure and Hypertensive Disorders during Pregnancy SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE pesticide exposure; preeclampsia; pregnancy-induced hypertension ID GESTATIONAL DIABETES-MELLITUS; AGRICULTURAL HEALTH; INSULIN-RESISTANCE; BLOOD-PRESSURE; UNITED-STATES; PREECLAMPSIA; WOMEN; OUTCOMES; WORKERS; RISK AB BACKGROUND: Hypertensive disorders of pregnancy, including pregnancy- induced hypertension (PIH) and preeclampsia (PE), complicate 2-8% of pregnancies. Few studies have examined environmental risk factors in relation to these conditions. OBJECTIVES: Our goal was to examine whether pesticide exposure during pregnancy was associated with hypertensive disorders of pregnancy. METHODS: We analyzed self-reported data from 11,274 wives of farmers enrolled in the Agricultural Health Study (AHS) between 1993 and 1997. Using logistic regression models, we estimated the adjusted odds ratios (AORs) for PIH and PE associated with pesticide-related activities during the first trimester of pregnancy. RESULTS: First-trimester residential and agricultural activities with potential exposure to pesticides were associated with both PIH [residential AOR = 1.27; 95% confidence interval (CI), 1.02-1.60; agricultural AOR = 1.60; 95% Cl, 1.05-2.45] and PE (residential AOR = 1.32; 95% CI, 1.02-1.70; agricultural AOR = 2.07; 95% Cl, 1.34-3.21). CONCLUSIONS: Exposure to pesticides during pregnancy may increase the risk of hypertensive disorders of pregnancy. Laboratory research may provide insights into relationships between pesticide exposure and hypertensive diseases of pregnancy. C1 [Saldana, Tina M.] Social & Sci Syst Inc, Durham, NC 27703 USA. [Saldana, Tina M.; Basso, Olga; Baird, Donna D.; Hoppin, Jane A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Weinberg, Clarice R.] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Blair, Aaron; Alavanja, Michael C. R.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Saldana, TM (reprint author), Social & Sci Syst Inc, 1009 Slater Rd,Suite 120, Durham, NC 27703 USA. EM saldana@niehs.nih.gov RI Basso, Olga/E-5384-2010; Baird, Donna/D-5214-2017; OI Basso, Olga/0000-0001-9298-4921; Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS; NCI NIH HHS [Z01 CP010119, Z01 CP010119-12]; NIEHS NIH HHS [Z01 ES 049030-11, Z01 ES049030] NR 37 TC 11 Z9 11 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2009 VL 117 IS 9 BP 1393 EP 1396 DI 10.1289/ehp.0900672 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 490EE UT WOS:000269479900027 PM 19750103 ER PT J AU Hofmann, JN Keifer, MC Furlong, CE De Roos, AJ Farin, FM Fenske, RA van Belle, G Checkoway, H AF Hofmann, Jonathan N. Keifer, Matthew C. Furlong, Clement E. De Roos, Anneclaire J. Farin, Federico M. Fenske, Richard A. van Belle, Gerald Checkoway, Harvey TI Serum Cholinesterase Inhibition in Relation to Paraoxonase-1 (PON1) Status among Organophosphate-Exposed Agricultural Pesticide Handlers SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE agriculture; cholinesterase; farmworkers; gene-environment interaction; organophosphates; paraoxonase; pesticides ID CHLORPYRIFOS-OXON; POLYMORPHISM; GENE; SUSCEPTIBILITY; ASSOCIATION; TOXICITY; WORKERS; HEALTH; ACETYLCHOLINESTERASE; SENSITIVITY AB BACKGROUND: Animal studies have demonstrated that low paraoxonase-1 (PON1) status (i.e., low catalytic efficiency and/or low plasma PON1 activity) is associated with neurotoxic effects after exposure to several organophosphate (OP) insecticides. However, few human studies have investigated associations between PON1 status and intermediate end points, such as serum cholinesterase [butyrylcholinesterase (BuChE)] inhibition, among OP-exposed individuals. OBJECTIVES: We evaluated the relation between plasma PON1 status and BuChE inhibition among OP-exposed agricultural pesticide handlers. METHODS: Agricultural pesticide handlers in Washington State were recruited during the 2006 and 2007 spray seasons when they were seen for follow-up ChE testing by collaborating medical providers as part of a statewide monitoring program. Blood samples were collected from 163 participants and tested for PON1 status based on plasma PON1 activity [arylesterase (AREase)] and PON1 Q192R genotype. We evaluated percent change in BuChE activity from baseline level in relation to PON1 status. RESULTS: We observed significantly greater BuChE inhibition among QQ homozygotes relative to RR homozygotes (p = 0.036). Lower levels of plasma PON1 activity were significantly associated with greater BuChE inhibition (p = 0.004). These associations remained after adjustment for year, days since baseline test, age, and OP exposure in the last 30 days. CONCLUSIONS: We found that both low PON1 catalytic efficiency (i.e., the Q192 alloform) and low plasma PON1 activity were associated with BuChE inhibition among OP-exposed agricultural pesticide handlers. Corroborative findings from future studies with prospective collection of blood samples for PON1 testing, more sensitive markers of OP-related effects, and larger sample sizes are needed. C1 [Hofmann, Jonathan N.; De Roos, Anneclaire J.; Checkoway, Harvey] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Keifer, Matthew C.; Farin, Federico M.; Fenske, Richard A.; van Belle, Gerald; Checkoway, Harvey] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Furlong, Clement E.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Furlong, Clement E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [van Belle, Gerald] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Hofmann, JN (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8109,MSC 7240, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov FU Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health [U50OH07544, T420H008433]; National Institute of Environmental Health Sciences [P30ES07033, T32ES07262, P42ES04696, ES009883] FX Financial support was provided by Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (U50OH07544 and T420H008433) and National Institute of Environmental Health Sciences (P30ES07033, T32ES07262, P42ES04696, and ES009883). NR 48 TC 21 Z9 24 U1 0 U2 4 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 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2009 VL 117 IS 9 BP 1402 EP 1408 DI 10.1289/ehp.0900682 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 490EE UT WOS:000269479900029 PM 19750105 ER PT J AU McGlynn, KA Guo, XG Graubard, BI Brock, JW Klebanoff, MA Longnecker, MP AF McGlynn, Katherine A. Guo, Xuguang Graubard, Barry I. Brock, John W. Klebanoff, Mark A. Longnecker, Matthew P. TI Maternal Pregnancy Levels of Polychlorinated Biphenyls and Risk of Hypospadias and Cryptorchidism in Male Offspring SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE cryptorchidism; hypospadias; polychlorinated biphenyls; testicular dysgenesis syndrome ID MALE REPRODUCTIVE FUNCTION; HUMAN SEMEN QUALITY; DIOXIN-LIKE PCBS; ORGANOCHLORINE CONTAMINANTS; PRENATAL EXPOSURE; HUMAN-MILK; DIBENZOFURANS; POPULATION; FERTILITY; CONGENERS AB BACKGROUND: The etiologies of the male urogenital anomalies cryptorchidism and hypospadias are poorly understood. It has been suggested, however, that in utero hormone levels may be related to risk. Endocrine-disrupting chemicals, including polychlorinated biphenyl (PCB) compounds, may alter hormone levels and thereby affect the fetus. OBJECTIVES: To examine whether in utero PCB exposure is related to cryptorchidism and hypospadias, we examined PCB levels among pregnant women enrolled in the Collaborative Perinatal Project (CPP). METHODS: The CPP enrolled pregnant women at 12 U.S. medical centers between 1959 and 1965. For the present research, we analyzed third-trimester serum samples from the mothers of 230 sons with cryptorchidism, 201 sons with hypospadias, and 593 sons with neither condition. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression and examined the associations of each anomaly with individual PCB congener levels, sum of PCBs, and several functional groupings of PCBs. RESULTS: In general, the ORs for cryptorchidism or hypospadias showed no notable associations with individual PCB congener levels or functional groupings of PCBs. However, the ORs and 95% CIs for the sum of PCBs associated with hypospadias were as follows: 0-1.9 mu g/L, reference group; 2-2.9 mu g/L, OR = 1.57, 95% Cl, 1.05-2.34; 3-3.9 mu g/L, OR = 1.45, 95% Cl, 0.90-2.34; and >= 4.0 mu g/L, OR = 1.69, 95% Cl, 1.06-2.68; p-value for trend = 0.08. CONCLUSIONS: Given the large number of associations examined, these findings do not strongly support the hypothesis that PCBs are associated with cryptorchidism or hypospadias. Because population serum PCB levels at the time of sample collection were considerably higher than levels at present, it is unlikely that current PCB exposure is related to the development of either anomaly. C1 [McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Guo, Xuguang] Westat Corp, Durham, NC USA. [Brock, John W.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Klebanoff, Mark A.] Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP McGlynn, KA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS Suite 550,6120 Execut Blvd, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural Research Programs of the National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences of the National Institutes of Health (NIH); Centers for Disease Control and Prevention (CDC) FX Support for this research was provided by the Intramural Research Programs of the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH) and by the Centers for Disease Control and Prevention (CDC). NR 42 TC 37 Z9 38 U1 0 U2 4 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 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2009 VL 117 IS 9 BP 1472 EP 1476 DI 10.1289/ehp.0800389 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 490EE UT WOS:000269479900040 PM 19750116 ER PT J AU Keim, SA Branum, AM Klebanoff, MA Zemel, BS AF Keim, Sarah A. Branum, Amy M. Klebanoff, Mark A. Zemel, Babette S. TI Maternal Body Mass Index and Daughters' Age at Menarche SO EPIDEMIOLOGY LA English DT Article ID FOR-GESTATIONAL-AGE; LOW-BIRTH-WEIGHT; ADOLESCENT GIRLS; BREAST-CANCER; UNITED-STATES; PUBERTY; GROWTH; CHILDREN; HEIGHT; WOMEN AB Background: The role of intergenerational influences on age at menarche has not been explored far beyond the association between mothers' and daughters' menarcheal ages. Small size at birth and childhood obesity have been associated with younger age at menarche, but the influence of maternal overweight or obesity on daughters' age at menarche has not been thoroughly examined. Methods: In a follow-up study of the prospective Collaborative Perinatal Project, grown daughters were asked in 1987-1991 for their age at menarche. Data from the original Collaborative Perinatal Project (1959-1966) included their mothers' height and prepregnancy weight. In the follow-up study, 597 of 627 daughters had complete menarche and maternal data available and were included in the present analysis. We used polytomous logistic regression to examine the association between maternal overweight (body mass index [BMI] = 25-29.9 km/m(2)) or obesity (BMI >= 30) and daughter's age at menarche (<= 12, 12, 13, 14 + years). Results: Compared with those whose mothers had a BMI less than 25, daughters of obese mothers experienced younger age at menarche (OR for menarche at <= 12 years = 3.1 [1.1-9.2]). This association remained after adjusting for maternal age at menarche, maternal parity, socioeconomic status, race, and study site (OR = 3.3 [1.1-10.0]). Effect estimates for maternal overweight were close to the null. There was limited evidence of mediation by small for gestational age or BMI at age 7. Conclusions: Maternal obesity is associated with younger menarcheal age among daughters in this study, possibly via unmeasured shared factors. C1 [Keim, Sarah A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study Program Off, Bethesda, MD USA. [Keim, Sarah A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Branum, Amy M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Off Anal & Epidemiol, Infant Child & Womens Hlth Stat Branch, Hyattsville, MD 20782 USA. [Branum, Amy M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Klebanoff, Mark A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Zemel, Babette S.] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. RP Keim, SA (reprint author), 6100 Execut Blvd,Suite 3A01, Bethesda, MD 20892 USA. EM Keim@nih.gov RI Zemel, Babette/D-1117-2009; Keim, Sarah/F-8929-2013 OI Keim, Sarah/0000-0003-3490-3649 FU Intramural NIH HHS [Z01 HD000334-21]; NICHD NIH HHS [N01-HD-7-2909] NR 40 TC 23 Z9 23 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2009 VL 20 IS 5 BP 677 EP 681 DI 10.1097/EDE.0b013e3181b093ce PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 485EJ UT WOS:000269103500011 PM 19602980 ER PT J AU Klebanoff, MA Zhang, J Zhang, CL Levine, RJ AF Klebanoff, Mark A. Zhang, Jun Zhang, Cuilin Levine, Richard J. TI Maternal Serum Theobromine and the Development of Preeclampsia SO EPIDEMIOLOGY LA English DT Article ID GESTATIONAL-AGE BIRTH; CAFFEINE METABOLISM; PREGNANCY; RISK; HYPERTENSION; ESTROGEN; COCOA; PARAXANTHINE; CHOCOLATE; EXPOSURE AB Background: Preeclampsia, a disorder with prominent cardiovascular manifestations, is a cause of maternal, fetal, and infant morbidity and mortality. Chocolate contains compounds that may promote cardiovascular health. A recent study found chocolate consumption during pregnancy, and, particularly, increasing cord serum concentration of theobromine (the primary methylxanthine alkaloid in chocolate), to be associated with reduced occurrence of preeclampsia. Methods: We studied 2769 women who comprised the control group from a case-control study of caffeine metabolites and spontaneous abortion nested within the Collaborative Perinatal Project. These women were pregnant between 1959 and 1966, with liveborn infants of at least 28 weeks' gestation. Serum was drawn at <20 weeks and >26 weeks' gestation, and assayed for theobromine by high-performance liquid chromatography. Odds ratios (ORs) for preeclampsia were estimated using logistic regression, and adjusted for age, education, prepregnant weight, race, parity, smoking, and gestation at blood draw. Results: Preeclampsia occurred in 68 (2.9%) of 2105 eligible women. Adjusted ORs for preeclampsia were near unity across most third-trimester theobromine concentrations. Adjusted ORs for preeclampsia according to theobromine concentration in serum at <20 weeks' gestation increased with increases in concentration, although estimates were imprecise. Conclusion: This study does not support the previous finding that chocolate consumption is associated with a reduced occurrence of preeclampsia. Unmeasured confounding or reverse causation may account for the positive association between early-pregnancy theobromine and preeclampsia. C1 [Klebanoff, Mark A.; Zhang, Jun; Zhang, Cuilin; Levine, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. RP Klebanoff, MA (reprint author), NICHD, Epidemiol Branch, Dept Hlth & Human Serv, NIH, 6100 Bldg,7B05, Bethesda, MD 20892 USA. EM mk90h@nih.gov FU National Institutes of Health, NICHD [1 Z01 HD000383-18 SPR]; [NO1-HD-7-3262] FX Supported by Contract NO1-HD-7-3262, and Intramural funds (1 Z01 HD000383-18 SPR) from the National Institutes of Health, NICHD. NR 28 TC 15 Z9 15 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2009 VL 20 IS 5 BP 727 EP 732 DI 10.1097/EDE.0b013e3181aba664 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 485EJ UT WOS:000269103500019 PM 19535985 ER PT J AU Crane, PK Gibbons, LE Arani, K Nguyen, V Rhoads, K McCurry, SM Launer, L Masaki, K White, L AF Crane, Paul K. Gibbons, Laura E. Arani, Keerthi Nguyen, Viet Rhoads, Kristoffer McCurry, Susan M. Launer, Lenore Masaki, Kamal White, Lon TI Midlife Use of Written Japanese and Protection From Late Life Dementia SO EPIDEMIOLOGY LA English DT Article ID ALZHEIMERS-DISEASE; AMERICAN MEN; COGNITIVE RESERVE; KAME PROJECT; KING COUNTY; HAWAII; PERFORMANCE; PREVALENCE; CALIFORNIA; DIAGNOSIS AB Background: The cognitive reserve hypothesis would predict that use of written Japanese should confer protection against dementia because of the complexity of its ideograms compared with written English. We sought to test this hypothesis in analyses from a longitudinal study of Japanese-American men. Methods: Participants were second-generation Japanese-American men (Nisei) on the island of Oahu, Hawaii, who were seen in 1965 and in subsequent examinations to detect dementia beginning in 1991-1993. Use of spoken and written Japanese was self-reported in 1965 (Analyses 1 and 2), and midlife use of written Japanese and written English was self-reported in 1994-1996 (Analysis 3). We analyzed prevalent dementia outcomes in 1991-1993 (Analysis 1, n = 3 139) using logistic regression, and incident dementia outcomes in 1994-2002 (Analysis 2, n = 2299) and in 1997-2002 (Analysis 3, n = 1655) using Cox proportional hazards regression. Dementia outcomes included all-cause dementia, probable and possible Alzheimer disease, and probable vascular dementia. We adjusted models for probable and possible confounders. Results: Participants who reported proficiency with written Japanese were older and had lower incomes. For Analysis 1, there were 154 prevalent cases of dementia, 74 of Alzheimer disease, and 43 of vascular dementia; for Analysis 2, 236 incident cases of dementia, 138 of Alzheimer disease, and 45 of vascular dementia; and for Analysis 3, 125 incident cases of dementia, 80 of Alzheimer disease, and 20 of vascular dementia. There was no relationship in adjusted models between self-reported proficiency with written Japanese and any dementia outcomes. Conclusions: Proficiency with written Japanese does not appear to be protective for dementia. C1 [Crane, Paul K.; Gibbons, Laura E.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Arani, Keerthi; Nguyen, Viet] Univ Washington, Sch Med, Seattle, WA 98195 USA. [Rhoads, Kristoffer] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [McCurry, Susan M.] Univ Washington, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Launer, Lenore] NIA, Neuroepidemiol Branch, Bethesda, MD 20892 USA. [Masaki, Kamal; White, Lon] Kuakini Med Ctr, Honolulu, HI USA. [Masaki, Kamal; White, Lon] Pacific Hlth Res Inst, Honolulu, HI USA. RP Crane, PK (reprint author), Univ Washington, Harborview Med Ctr, Box 359780,325 9th Ave, Seattle, WA 98104 USA. EM pcrane@u.washington.edu RI Crane, Paul/C-8623-2014; OI Crane, Paul/0000-0003-4278-7465 FU Alzheimer's Association Investigator Initiated Research Grant; National Institute on Aging (NIA) [N01-AG-4-2149, U01-AG-1-9349-01, 1-R01-AG17155-01A1, 1RO1 AG19349-01]; National Heart, Lung, and Blood Institute [N01-HC-05102]; [P50 AG05136] FX Supported by an Alzheimer's Association Investigator Initiated Research Grant (P.K.C., PI). Additional support was provided from P50 AG05136 (to L.E.G.) (M. Raskind, PI). Data collection was supported by the National Institute on Aging (NIA) Contract N01-AG-4-2149, NIA grant U01-AG-1-9349-01, NIA grant 1-R01-AG17155-01A1, NIA grant 1RO1 AG19349-01, and National Heart, Lung, and Blood Institute Contract N01-HC-05102. NR 27 TC 24 Z9 24 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2009 VL 20 IS 5 BP 766 EP 774 DI 10.1097/EDE.0b013e3181b09332 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 485EJ UT WOS:000269103500025 PM 19593152 ER PT J AU Shariff-Marco, S Gee, GC Breen, N Willis, G Reeve, BB Grant, D Ponce, NA Krieger, N Landrine, H Williams, DR Alegria, M Mays, VM Johnson, TP Brown, ER AF Shariff-Marco, Salma Gee, Gilbert C. Breen, Nancy Willis, Gordon Reeve, Bryce B. Grant, David Ponce, Ninez A. Krieger, Nancy Landrine, Hope Williams, David R. Alegria, Margarita Mays, Vickie M. Johnson, Timothy P. Brown, E. Richard TI A MIXED-METHODS APPROACH TO DEVELOPING A SELF-REPORTED RACIAL/ETHNIC DISCRIMINATION MEASURE FOR USE IN MULTIETHNIC HEALTH SURVEYS SO ETHNICITY & DISEASE LA English DT Article DE Cross-Cultural Comparison; Discrimination; Survey Methods ID ASIAN-AMERICAN; ETHNIC DISCRIMINATION; PSYCHOMETRIC PROPERTIES; NATIONAL LATINO; RACISM; STRESS; PERCEPTIONS; VALIDATION; OUTCOMES; RACE AB Objective: The development of measures of self-reported racial/ethnic discrimination is an active area of research, but few measures have been validated across multiple racial/ethnic and language groups. Our goal is to develop and evaluate a discrimination measure that is appropriate for use in surveys of racially and ethnically diverse populations. Methods: To develop our measure, we employ a mixed-methods approach for survey research, drawing from both qualitative and quantitative traditions, including literature review, cognitive testing, psychometric analyses, behavior coding as well as two rounds of field testing using a split-sample design. We tested our new measure using two different approaches to elicit self-reported experiences of racial/ethnic discrimination. Results: Our new measure captures four dimensions of racial/ethnic discrimination: 1) frequency of encounters with discrimination across several domains (eg, medical care, school, work, street and other public places); 2) timing of exposure (eg recent, lifetime); 3) appraisal of discrimination as stressful; and 4) responses to discrimination. Conclusions: Because of the growing interest in measurement of racial/ethnic discrimination in health surveys, we think this report on the methods informing the development and testing of the discrimination module that will be used on the California Health Interview Survey would be useful to other researchers. The application of mixed methods to rigorously test the validity and reliability of our instrument proves to be a good roadmap for measuring racial/ethnic discrimination in multicultural and multilingual populations. (Ethn Dis. 2009;19:447-453) C1 [Shariff-Marco, Salma] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Shariff-Marco, Salma] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Gee, Gilbert C.; Ponce, Ninez A.; Mays, Vickie M.; Brown, E. Richard] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA USA. [Grant, David; Ponce, Ninez A.; Brown, E. Richard] Univ Calif Los Angeles, Ctr Hlth Policy & Res, Los Angeles, CA USA. [Krieger, Nancy; Williams, David R.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Landrine, Hope] Amer Canc Soc, Atlanta, GA 30329 USA. [Alegria, Margarita] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Johnson, Timothy P.] Univ Illinois, Chicago, IL USA. [Mays, Vickie M.] Univ Calif Los Angeles, Ctr Res Educ Training & Strateg Commun Minor Hlth, Los Angeles, CA USA. RP Shariff-Marco, S (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4009C,MSC 7344, Bethesda, MD 20892 USA. EM shariffs@mail.nih.gov OI Ponce, Ninez/0000-0001-5151-6718 FU NIH Office of Behavioral Social Sciences Research; National Cancer Institute; National Center for Minority Health and Health Disparities [MD 000508] FX We would like to thank the NIH Office of Behavioral Social Sciences Research for funding the field test and NCI Division of Cancer Control and Population Sciences for providing staff for this project. We Would also like to acknowledge the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute for providing financial support for S. Shariff-Marco in her post-doctoral fellowship; Westat for their work on the cognitive interviews and behavior coding; and the Collaborative Psychiatric Epidemiology Stirveys project for providing access to data from the National Survey of American Life, and the National Latino and Asian American Survey. Support for this work was a so provided by the National Center for Minority Health and Health Disparities (MD 000508).; We would also like to acknowledge Dr. David Takeuchi for his participation as a member of the panel of external advisors for this research project and Drs. Martin Brown and Rachel Ballard-Barbash fo r their thoughtful reviews of our manuscript. NR 33 TC 14 Z9 14 U1 4 U2 14 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2009 VL 19 IS 4 BP 447 EP 453 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 530XA UT WOS:000272624700012 PM 20073147 ER PT J AU Sumner, AE AF Sumner, Anne E. TI "HALF THE DSYLIPIDEMIA OF INSULIN RESISTANCE" IS THE DSYLIPIDEMIA OF INSULIN-RESISTANT BLACKS SO ETHNICITY & DISEASE LA English DT Editorial Material DE Triglyceride; High Density Lipoprotein-Cholesterol; Metabolic Syndrome; Insulin Resistance; Blacks ID NUTRITION EXAMINATION SURVEY; INCIDENT DIABETES-MELLITUS; METABOLIC SYNDROME; LIPOPROTEIN-LIPASE; HYPERTRIGLYCERIDEMIC WAIST; TRIGLYCERIDE LEVELS; ETHNIC-DIFFERENCES; AFRICAN-AMERICANS; NATIONAL-HEALTH; ADIPOSE-TISSUE C1 [Sumner, Anne E.] NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov FU Intramural NIH HHS [ZIA DK047023-09] NR 23 TC 10 Z9 10 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2009 VL 19 IS 4 BP 462 EP 465 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 530XA UT WOS:000272624700014 PM 20073149 ER PT J AU Lora, CM Daviglus, ML Kusek, JW Porter, A Ricardo, AC Go, AS Lash, JP AF Lora, Claudia M. Daviglus, Martha L. Kusek, John W. Porter, Anna Ricardo, Ana C. Go, Alan S. Lash, James P. TI CHRONIC KIDNEY DISEASE IN UNITED STATES HISPANICS: A GROWING PUBLIC HEALTH PROBLEM SO ETHNICITY & DISEASE LA English DT Article DE Chronic Kidney Disease; Hispanics; Health Care Disparities ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; STAGE RENAL-DISEASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; SURVEY NHANES-III; METABOLIC SYNDROME; MEXICAN-AMERICANS; US POPULATION; HEMODIALYSIS-PATIENTS; RACIAL-DIFFERENCES AB Hispanics are the fastest growing minority group in the United States. The incidence of end-stage renal disease (ESRD) in Hispanics is higher than non-Hispanic Whites and Hispanics with chronic kidney disease (CKD) are at increased risk for kidney failure. Likely contributing factors to this burden of disease include diabetes and metabolic syndrome, both are common among Hispanics. Access to health care, quality of care, and barriers due to language, health literacy and acculturation may also play a role. Despite the importance of this public health problem, only limited data exist about Hispanics with CKD. We review the epidemiology of CKD in US Hispanics, identify the factors that may be responsible for this growing health problem, and suggest gaps in our understanding which are suitable for future investigation. (Ethn Dis. 2009;19:466-472) C1 [Lora, Claudia M.; Porter, Anna; Ricardo, Ana C.; Lash, James P.] Univ Illinois, Dept Med, Nephrol Sect, Chicago, IL 60612 USA. [Go, Alan S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, San Francisco, CA USA. [Daviglus, Martha L.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Evanston, IL 60208 USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Lora, CM (reprint author), Univ Illinois, Dept Med, Nephrol Sect, 820 S Wood St,M-C 793, Chicago, IL 60612 USA. EM Clora1@uic.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [5U01DK60980, R01 DK72231]; Research Supplements to Promote Diversity in Health-Related Research; Jose Arruda Fellowship FX This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK60980, R01 DK72231 JPL). During the performance of this work, C Lora, MD was supported in part by Research Supplements to Promote Diversity in Health-Related Research (National Center for Minority Health and Health Disparities) and by the Jose Arruda Fellowship (Acute Dialysis Services Association, Inc.) NR 78 TC 24 Z9 24 U1 0 U2 5 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2009 VL 19 IS 4 BP 466 EP 472 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 530XA UT WOS:000272624700015 PM 20073150 ER PT J AU Conen, D Chae, CU Guralnik, JM Glynn, RJ AF Conen, D. Chae, C. U. Guralnik, J. M. Glynn, R. J. TI Influence of blood pressure and blood pressure change on the risk of congestive heart failure in the elderly SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Conen, D.] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Chae, C. U.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Guralnik, J. M.] NIA, Bethesda, MD 20892 USA. [Glynn, R. J.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD SEP PY 2009 VL 30 SU 1 BP 11 EP 12 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TH UT WOS:000208702601035 ER PT J AU O'Donoghue, M Morrow, D Braunwald, E Sloan, S Domanski, M Sabatine, M AF O'Donoghue, M. Morrow, D. Braunwald, E. Sloan, S. Domanski, M. Sabatine, M. TI Prognostic utility of lipoprotein(a) in patients with stable coronary artery disease SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [O'Donoghue, M.; Morrow, D.; Braunwald, E.; Sloan, S.; Sabatine, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Domanski, M.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD SEP PY 2009 VL 30 SU 1 BP 481 EP 481 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TH UT WOS:000208702604155 ER PT J AU Koh, K Quon, M AF Koh, K. Quon, M. TI Additive beneficial effects of atorvastatin combined with amlodipine therapy in hypertensive patients SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Koh, K.] Gachon Univ, Inchon, South Korea. [Quon, M.] NIH, Diabet Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD SEP PY 2009 VL 30 SU 1 BP 722 EP 722 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TH UT WOS:000208702606045 ER PT J AU Tocchetti, CG Donzelli, S Flores-Santana, W Betocchi, S Chiariello, M Stuehr, DJ Kass, DA Wink, DA Paolocci, N AF Tocchetti, C. G. Donzelli, S. Flores-Santana, W. Betocchi, S. Chiariello, M. Stuehr, D. J. Kass, D. A. Wink, D. A. Paolocci, N. TI Heme-catalyzed generation of nitroxyl modulates contractility in cardiac myocytes SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 [Tocchetti, C. G.; Betocchi, S.; Chiariello, M.] Univ Naples Federico II, Azienda Osped, Naples, Italy. [Donzelli, S.; Flores-Santana, W.; Wink, D. A.] NCI, NIH, Bethesda, MD 20892 USA. [Stuehr, D. J.] Lerner Res Inst, Cleveland, OH USA. [Kass, D. A.; Paolocci, N.] Johns Hopkins Univ, Baltimore, MD USA. RI Betocchi, Sandro/N-9647-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD SEP PY 2009 VL 30 SU 1 BP 956 EP 957 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V28TH UT WOS:000208702607424 ER PT J AU Bergeron-Sawitzke, J Gold, B Olsh, A Schlotterbeck, S Lemon, K Visvanathan, K Allikmets, R Dean, M AF Bergeron-Sawitzke, Julie Gold, Bert Olsh, Adam Schlotterbeck, Sarah Lemon, Kendal Visvanathan, Kala Allikmets, Rando Dean, Michael TI Multilocus analysis of age-related macular degeneration SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE age-related macular degeneration; complement; ARMS2; HTRA1 ID COMPLEMENT FACTOR-H; EYE DISEASE; RISK; SMOKING; GENES; CFH; POLYMORPHISMS; METAANALYSIS; ASSOCIATION; MACULOPATHY AB Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD. European Journal of Human Genetics (2009) 17, 1190-1199; doi:10.1038/ejhg.2009.23; published online 4 March 2009 C1 [Gold, Bert; Olsh, Adam; Schlotterbeck, Sarah; Lemon, Kendal; Dean, Michael] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Bergeron-Sawitzke, Julie] SAIC Frederick, Basic Sci Program, Human Genet Sect, Frederick, MD USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10027 USA. RP Dean, M (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Bldg 560,Room 21-18, Frederick, MD 21702 USA. EM dean@ncifcrf.gov RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; SAIC-Frederick [NO1-CO-12400]; National Eye Institute [EY13435, EY017404]; Macula Vision Research Foundation; Wallach Foundation; Elyachar Foundation; Kaplen Foundation; Wigdeon Point Charitable Foundation; Research to Prevent Blindness FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and SAIC-Frederick under contract no. NO1-CO-12400 and with grants from the National Eye Institute EY13435 and EY017404 (RA); the Macula Vision Research Foundation; Wallach Foundation (RA); Elyachar Foundation (RA); Kaplen Foundation (RA); Wigdeon Point Charitable Foundation (RA); and an unrestricted grant to the Department of Ophthalmology, Columbia University, from Research to Prevent Blindness. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be marked as an advertisement in accordance with 18 USC Section 1734 solely to indicate this fact. NR 30 TC 55 Z9 55 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2009 VL 17 IS 9 BP 1190 EP 1199 DI 10.1038/ejhg.2009.23 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 489VA UT WOS:000269449900015 PM 19259132 ER PT J AU Kulandasamy, R Adhikari, AV Stables, JP AF Kulandasamy, Ravi Adhikari, Airody Vasudeva Stables, James P. TI Synthesis and anticonvulsant activity of some new bishydrazones derived from 3,4-dipropyloxythiophene SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Thiophene; Bishydrazones; Epilepsy; Anticonvulsants; Toxicity ID MAXIMAL ELECTROSHOCK; PARTIAL EPILEPSY; AGENTS; SEMICARBAZONES; DERIVATIVES; MODELS AB A series of new 3,4-dipropyloxy-N(2),N(5)-bis(substituted)thiophene-2,5-dicarbohydrazides (4-30) were synthesized from ethyl thiodiglycolate and diethyloxalate through multistep reactions. Following Dieckmann-Komppa reaction, the required precursor 3,4-dihydroxythiophene-2,5-diester (1) was prepared. This was derivatized with propyl bromide and further converted to corresponding hydrazide (3), which was finally transformed to targeted hydrazones (4-30) by conventional methods. The newly synthesized compounds were characterized using FT-IR, (1)H and (13)C NMR, EI-MS and elemental analyses. The anticonvulsant activity of all the title compounds was investigated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scMET) models and their neurotoxicity was also evaluated. Some of the selected compounds were subjected to 6 Hz test in order to evaluate their uncover activities. Compound 3,4-dipropyloxy-N(2),N(5)-bis[1-(2-thienyl)ethylidene]thiophene-2,5-dicarbohydrazide (15) has emerged as a lead in this series with less neurotoxicity. (C) 2009 Elsevier Masson SAS. All rights reserved. C1 [Kulandasamy, Ravi; Adhikari, Airody Vasudeva] Natl Inst Technol Karnataka, Dept Chem, Mangalore 575025, Karnataka, India. [Stables, James P.] NIH, Preclin Pharmacol Sect, Epilepsy Branch, Bethesda, MD 20892 USA. RP Adhikari, AV (reprint author), Natl Inst Technol Karnataka, Dept Chem, Mangalore 575025, Karnataka, India. EM avchem@nitk.ac.in NR 25 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP PY 2009 VL 44 IS 9 BP 3672 EP 3679 DI 10.1016/j.ejmech.2009.02.009 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 480OE UT WOS:000268744700039 PM 19286282 ER PT J AU Jinde, S Belforte, JE Yamamoto, J Wilson, MA Tonegawa, S Nakazawa, K AF Jinde, Seiichiro Belforte, Juan E. Yamamoto, Jun Wilson, Matthew A. Tonegawa, Susumu Nakazawa, Kazu TI Lack of kainic acid-induced gamma oscillations predicts subsequent CA1 excitotoxic cell death SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE CA3; epilepsy research; GABA; mouse; NMDA receptors ID HIGH-FREQUENCY OSCILLATIONS; HIPPOCAMPAL SHARP WAVES; TEMPORAL-LOBE EPILEPSY; NMDA RECEPTORS; NEOCORTICAL EPILEPSY; GABAERGIC INHIBITION; BEHAVING RAT; INTERNEURON NETWORKS; POTASSIUM CHANNEL; RIPPLE COMPLEXES AB Gamma oscillations are a prominent feature of hippocampal network activity, but their functional role remains debated, ranging from mere epiphenomena to being crucial for information processing. Similarly, persistent gamma oscillations sometimes appear prior to epileptic discharges in patients with mesial temporal sclerosis. However, the significance of this activity in hippocampal excitotoxicity is unclear. We assessed the relationship between kainic acid (KA)-induced gamma oscillations and excitotoxicity in genetically engineered mice in which N-methyl-d-aspartic acid receptor deletion was confined to CA3 pyramidal cells. Mutants showed reduced CA3 pyramidal cell firing and augmented sharp wave-ripple activity, resulting in higher susceptibility to KA-induced seizures, and leading to strikingly selective neurodegeneration in the CA1 subfield. Interestingly, the increase in KA-induced gamma-aminobutyric acid (GABA) levels, and the persistent 30-50-Hz gamma oscillations, both of which were observed in control mice prior to the first seizure discharge, were abolished in the mutants. Consequently, on subsequent days, mutants manifested prolonged epileptiform activity and massive neurodegeneration of CA1 cells, including local GABAergic neurons. Remarkably, pretreatment with the potassium channel blocker alpha-dendrotoxin increased GABA levels, restored gamma oscillations, and prevented CA1 degeneration in the mutants. These results demonstrate that the emergence of low-frequency gamma oscillations predicts increased resistance to KA-induced excitotoxicity, raising the possibility that gamma oscillations may have potential prognostic value in the treatment of epilepsy. C1 [Jinde, Seiichiro; Belforte, Juan E.; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, Mood & Anxiety Disorders Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Yamamoto, Jun; Wilson, Matthew A.; Tonegawa, Susumu] MIT, Picower Inst Learning & Memory, RIKEN MIT Ctr Neural Circuit Genet, Cambridge, MA 02139 USA. [Tonegawa, Susumu] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Nakazawa, K (reprint author), NIMH, Unit Genet Cognit & Behav, Mood & Anxiety Disorders Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM nakazawk@mail.nih.gov RI Nakazawa, Kazutoshi/J-6195-2015 OI Nakazawa, Kazutoshi/0000-0001-5699-9093 FU National Institute of Mental Health; NIH [R01-MH078821]; Japan Society for the Promotion of Science (JSPS) FX We thank Linus D. Sun and Catherine J. Cravens for technical assistance, Brian Condie and John Rubenstein for providing GAD67 cDNA plasmid, and Gyorgy Buzsaki, Dax Hoffman, Karen N. Gale, Brita Fritsch, Kim Christian and Ioline Henter for valuable advice and critical reading of this manuscript. This research was supported by the Intramural Research Program of the National Institute of Mental Health and by NIH Grant R01-MH078821 to S. Tonegawa. S. Jinde was supported, in part, by a Japan Society for the Promotion of Science (JSPS) fellowship. NR 78 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD SEP PY 2009 VL 30 IS 6 BP 1036 EP 1055 DI 10.1111/j.1460-9568.2009.06896.x PG 20 WC Neurosciences SC Neurosciences & Neurology GA 494HT UT WOS:000269803200009 PM 19735292 ER PT J AU Panico, MM Lang, L Greco, A Greco, A Gargiulo, S Larobina, M Del Vecchio, S Zannetti, A Zaccaro, L Zaccaro, L Del Gatto, A Saviano, M Alfano, B Salvatore, M AF Panico, M. M. Lang, L. Greco, A. Greco, A. Gargiulo, S. Larobina, M. Del Vecchio, S. Zannetti, A. Zaccaro, L. Zaccaro, L. Del Gatto, A. Saviano, M. Alfano, B. Salvatore, M. TI New high yield HPLC purification with ethanol of 18F-RGDEchi and directly injection in mice SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract C1 [Panico, M. M.; Larobina, M.; Zannetti, A.; Zaccaro, L.; Zaccaro, L.; Del Gatto, A.; Saviano, M.; Alfano, B.] Univ Naples Federico II, CNR, IBB, Naples, Italy. [Lang, L.] NIH, Bethesda, MD 20892 USA. [Greco, A.; Greco, A.] Univ Naples Federico II, CEINGE, Dip Sci Biomorfol & Funz, Naples, Italy. [Gargiulo, S.; Del Vecchio, S.; Salvatore, M.] Univ Naples Federico II, Dip Sc Biomorfol & Funz, Naples, Italy. RI Salvatore, Marco/K-8083-2016 OI Salvatore, Marco/0000-0001-9734-7702 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD SEP PY 2009 VL 36 SU 2 BP S353 EP S353 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V28OT UT WOS:000208690801468 ER PT J AU Runyon, SP Orr, M Navarro, HA Kepler, JA Rogawski, MA Kaminski, RM Cook, CE AF Runyon, Scott P. Orr, Matthew Navarro, Hernan A. Kepler, John A. Rogawski, Michael A. Kaminski, Rafal M. Cook, C. Edgar TI 17 beta-Nitro-5 alpha-androstan-3 alpha-ol and its 3 beta-methyl derivative: Neurosteroid analogs with potent anticonvulsant and anxiolytic activities SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Neurosteroid; Allopregnanolone; GABA(A) receptor; Anticonvulsant; Anxiolytic; Bioisostere ID AMINOBUTYRIC ACID(A) RECEPTOR; MODULATE GABA(A) RECEPTORS; NEUROACTIVE STEROIDS; ANESTHETIC STEROIDS; EPIMERIZATION; MECHANISMS; DRUGS; MICE AB Many 17-substituted androstan-3 alpha-ol analogs act as positive allosteric modulators of GABA(A) receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17 beta-acetyl; 1) is among the most potent of these. Here we demonstrate that 3 alpha-hydroxy-17 beta-nitro-5 alpha-androstane (2b) and its 3 beta-methyl analog (3 alpha-hydroxy-3 beta-methyl-17 beta-nitro-5 alpha-androstane; 2c) modulate GABA(A) receptors as assessed by [(35)S]t-butylbicyclo-phosphorothionate and [(3)H] flunitrazepam binding with potencies equivalent to or greater than 1. These compounds also had potencies equivalent to or greater than 1 in the pentylenetetrazol and 6 Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3 beta-hydroxy, 3 alpha-desmethyl analog (2a) was devoid of activity on GABA(A) receptors in vitro but had moderate activity in the seizure models, possibly as a result of epimerization in vivo at the 3-position. This conclusion was supported by the lack of in vivo activity of the 3 beta-hydroxy, 3 alpha-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17 beta-position of 5 alpha-androstan-3 alpha-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABA(A) receptors. (C) 2009 Elsevier B.V. All rights reserved. C1 [Runyon, Scott P.; Orr, Matthew; Navarro, Hernan A.; Kepler, John A.; Cook, C. Edgar] Res Triangle Inst, Ctr Organ & Med Chem, Res Triangle Pk, NC 27709 USA. [Rogawski, Michael A.] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [Kaminski, Rafal M.] NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Runyon, SP (reprint author), Res Triangle Inst, Ctr Organ & Med Chem, POB 12194, Res Triangle Pk, NC 27709 USA. EM srunyon@rti.org RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU NIDA NIH HHS [L30 DA032053] NR 26 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 1 PY 2009 VL 617 IS 1-3 BP 68 EP 73 DI 10.1016/j.ejphar.2009.06.052 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 495CO UT WOS:000269867400011 PM 19577558 ER PT J AU Vitiello, B Correll, C van Zwieten-Boot, B Zuddas, A Parellada, M Arango, C AF Vitiello, Benedetto Correll, Christoph van Zwieten-Boot, Barbara Zuddas, Alessandro Parellada, Mara Arango, Celso TI Antipsychotics in children and adolescents: Increasing use, evidence for efficacy and safety concerns SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Review DE Antipsychotics; Children; Adolescents; Safety; Efficacy ID DISRUPTIVE BEHAVIOR DISORDERS; EARLY-ONSET SCHIZOPHRENIA; NEW-GENERATION ANTIPSYCHOTICS; RANDOMIZED CONTROLLED-TRIAL; TERM RISPERIDONE TREATMENT; INDUCED WEIGHT-GAIN; DOUBLE-BLIND; 2ND-GENERATION ANTIPSYCHOTICS; OPEN-LABEL; 1ST-EPISODE PSYCHOSIS AB Second-generation antipsychotics (SGA) are increasingly used to treat children and adolescents. The European College of Neuro-psychopharmacology convened an expert panel to review relevant efficacy and safety data, and identify needs for further research. Controlled studies support the short-term efficacy of several SGA for treating psychosis, mania, and aggression within certain diagnostic categories. Except for clozapine, no clinically significant superiority in efficacy has been demonstrated for any specific antipsychotic, including both first- and second-generation agents, in children and adolescents. Major differences exist, however, with respect to type and severity of adverse effects; therefore the choice of treatment is primarily guided by tolerability and safety considerations. Children appear to be at higher risk than adults for a number of adverse effects, such as extrapyramidal symptoms and metabolic and endocrine abnormalities. While the safety profile during acute and intermediate treatment has been evaluated, the distal ben