117 results on '"Barfield, R"'
Search Results
2. A Conserved 19-kDa Eimeria tenella Antigen Is a Profilin-like Protein
- Author
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Fetterer, R. H., Miska, K. B., Jenkins, M. C., and Barfield, R. C.
- Published
- 2004
3. Characterization of a Developmentally Regulated Oocyst Protein from Eimeria tenella
- Author
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Fetterer, R. H. and Barfield, R. C.
- Published
- 2003
4. Association between germline variants and somatic mutations in colorectal cancer.
- Author
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Barfield, R, Qu, C, Steinfelder, RS, Zeng, C, Harrison, TA, Brezina, S, Buchanan, DD, Campbell, PT, Casey, G, Gallinger, S, Giannakis, M, Gruber, SB, Gsur, A, Hsu, L, Huyghe, JR, Moreno, V, Newcomb, PA, Ogino, S, Phipps, AI, Slattery, ML, Thibodeau, SN, Trinh, QM, Toland, AE, Hudson, TJ, Sun, W, Zaidi, SH, Peters, U, Barfield, R, Qu, C, Steinfelder, RS, Zeng, C, Harrison, TA, Brezina, S, Buchanan, DD, Campbell, PT, Casey, G, Gallinger, S, Giannakis, M, Gruber, SB, Gsur, A, Hsu, L, Huyghe, JR, Moreno, V, Newcomb, PA, Ogino, S, Phipps, AI, Slattery, ML, Thibodeau, SN, Trinh, QM, Toland, AE, Hudson, TJ, Sun, W, Zaidi, SH, and Peters, U
- Abstract
Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.
- Published
- 2022
5. Identification and Characterization of a Serpin from Eimeria acervulina
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Fetterer, R. H., Miska, K. B., Jenkins, M. C., Barfield, R. C., and Lillehoj, H.
- Published
- 2008
6. Immunostimulating Complexes Incorporating Eimeria tenella Antigens and Plant Saponins as Effective Delivery System for Coccidia Vaccine Immunization
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Berezin, V. E., Bogoyavlenskiy, A. P., Tolmacheva, V. P., Makhmudova, N. R., Khudyakova, S. S., Levandovskaya, S. V., Omirtaeva, E. S., Zaitceva, I. A., Tustikbaeva, G. B., Ermakova, O. S., Aleksyuk, P. G., Barfield, R. C., Danforth, H. D., and Fetterer, R. H.
- Published
- 2008
7. Leading-Edge Vortex Improves Lift in Slow-Flying Bats
- Author
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Muijres, F. T., Johansson, L. C., Barfield, R., Wolf, M., Spedding, G. R., and Hedenström, A.
- Published
- 2008
- Full Text
- View/download PDF
8. Characterization of the Antigen SO7 during Development of Eimeria tenella
- Author
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Fetterer, R. H., Jenkins, M. C., Miska, K. B., and Barfield, R. C.
- Published
- 2007
9. Serine Protease Activity in Developmental Stages of Eimeria tenella
- Author
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Fetterer, R. H., Miska, K. B., Lillehoj, H., and Barfield, R. C.
- Published
- 2007
10. Partial Purification and Characterization of an Aminopeptidase from Eimeria tenella
- Author
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Fetterer, R. H., Miska, K. B., and Barfield, R. C.
- Published
- 2005
11. Discussion on the Electrical State of the Upper Atmosphere
- Author
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Rutherford, Ernest, Chapman, S., Wilson, C. T. R., Jackson, Henry, Appleton, E. V., Smith-Rose, R. L., Barfield, R. H., Eccles, W. H., Dobson, G. M. B., Simpson, G. C., and Lindemann, F. A.
- Published
- 1926
12. Further Measurements on Wireless Waves Received from the Upper Atmosphere
- Author
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Smith-Rose, R. L. and Barfield, R. H.
- Published
- 1927
13. An Investigation of Wireless Waves Arriving from the Upper Atmosphere
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Smith-Rose, R. L. and Barfield, R. H.
- Published
- 1926
14. On the Determination of the Directions of the Forces in Wireless Waves at the Earth's Surface
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Smith-Rose, R. L. and Barfield, R. H.
- Published
- 1925
15. Genetic architectures of proximal and distal colorectal cancer are partly distinct
- Author
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Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, Peters, U, Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, and Peters, U
- Abstract
OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
- Published
- 2021
16. A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study
- Author
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Plagnol, V, Dong, X, Su, Y-R, Barfield, R, Bien, SA, He, Q, Harrison, TA, Huyghe, JR, Keku, TO, Lindor, NM, Schafmayer, C, Chan, AT, Gruber, SB, Jenkins, MA, Kooperberg, C, Peters, U, Hsu, L, Plagnol, V, Dong, X, Su, Y-R, Barfield, R, Bien, SA, He, Q, Harrison, TA, Huyghe, JR, Keku, TO, Lindor, NM, Schafmayer, C, Chan, AT, Gruber, SB, Jenkins, MA, Kooperberg, C, Peters, U, and Hsu, L
- Abstract
Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.
- Published
- 2020
17. Sexual Behavior: Extreme Reduction of Postejaculatory Refractory Period by Midbrain Lesions in Male Rats
- Author
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Barfield, R. J., Wilson, Catherine, and McDonald, P. G.
- Published
- 1975
18. Ineffectiveness of Pineal Lesions on the Testis Cycle of a Finch
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Hamner, W. M. and Barfield, R. J.
- Published
- 1970
- Full Text
- View/download PDF
19. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
- Author
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Wu, L. (Lang), Shi, W. (Wei), Long, J. (Jirong), Guo, X. (Xingyi), Michailidou, K. (Kyriaki), Beesley, J. (Jonathan), Bolla, M. K. (Manjeet K.), Shu, X.-O. (Xiao-Ou), Lu, Y. (Yingchang), Cai, Q. (Qiuyin), Al-Ejeh, F. (Fares), Rozali, E. (Esdy), Wang, Q. (Qin), Dennis, J. (Joe), Li, B. (Bingshan), Zeng, C. (Chenjie), Feng, H. (Helian), Gusev, A. (Alexander), Barfield, R. T. (Richard T.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Barrdahl, M. (Myrto), Baynes, C. (Caroline), Beckmann, M. W. (Matthias W.), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Bojesen, S. E. (Stig E.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L. (Louise), Broberg, P. (Per), Brucker, S. Y. (Sara Y.), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Canzian, F. (Federico), Carter, B. D. (Brian D.), Castelao, J. E. (J. Esteban), Chang-Claude, J. (Jenny), Chen, X. (Xiaoqing), Cheng, T. D. (Ting-Yuan David), Christiansen, H. (Hans), Clarke, C. L. (Christine L.), Collee, M. (Margriet), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, D. (David), Cox, A. (Angela), Cross, S. S. (Simon S.), Cunningham, J. M. (Julie M.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doheny, K. F. (Kimberly F.), Dork, T. (Thilo), dos-Santos-Silva, I. (Isabel), Dumont, M. (Martine), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Eilber, U. (Ursula), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Eriksson, M. (Mikael), Fachal, L. (Laura), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fritschi, L. (Lin), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Closas, M. (Montserrat), Gaudet, M. M. (Mia M.), Ghoussaini, M. (Maya), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Harrington, P. (Patricia), Hein, A. (Alexander), Hicks, B. (Belynda), Hillemanns, P. (Peter), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Huang, G. (Guanmengqian), Humphreys, K. (Keith), Hunter, D. J. (David J.), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Johnson, N. (Nichola), Jones, K. (Kristine), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kerin, M. J. (Michael J.), Khusnutdinova, E. (Elza), Kosma, V.-M. (Veli-Matti), Kristensen, V. N. (Vessela N.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindstrom, S. (Sara), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loibl, S. (Sibylle), Lubinski, J. (Jan), Luccarini, C. (Craig), Lux, M. P. (Michael P.), MacInnis, R. J. (Robert J.), Maishman, T. (Tom), Kostovska, I. M. (Ivana Maleva), Mannermaa, A. (Arto), Manson, J. E. (Joann E.), Margolin, S. (Sara), Mavroudis, D. (Dimitrios), Meijers-Heijboer, H. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Meyer, J. (Jeffery), Mulligan, A. M. (Anna Marie), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olopade, O. I. (Olufunmilayo I.), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Prentice, R. (Ross), Presneau, N. (Nadege), Pylkäs, K. (Katri), Rack, B. (Brigitte), Radice, P. (Paolo), Rahman, N. (Nazneen), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Romm, J. (Jane), Rudolph, A. (Anja), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, R. J. (Rodney J.), Scott, C. G. (Christopher G.), Seal, S. (Sheila), Shah, M. (Mitul), Shrubsole, M. J. (Martha J.), Smeets, A. (Ann), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. (William), Taylor, J. A. (Jack A.), Terry, M. B. (Mary Beth), Tessier, D. C. (Daniel C.), Thomas, A. (Abigail), Thone, K. (Kathrin), Tollenaar, R. A. (Rob A. E. M.), Torres, D. (Diana), Truong, T. (Therese), Untch, M. (Michael), Vachon, C. (Celine), Van den Berg, D. (David), Vincent, D. (Daniel), Waisfisz, Q. (Quinten), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Whittemore, A. S. (Alice S.), Wildiers, H. (Hans), Willett, W. C. (Walter C.), Winqvist, R. (Robert), Wolk, A. (Alicja), Xia, L. (Lucy), Yang, X. R. (Xiaohong R.), Ziogas, A. (Argyrios), Ziv, E. (Elad), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Simard, J. (Jacques), Milne, R. L. (Roger L.), Edwards, S. L. (Stacey L.), Kraft, P. (Peter), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Wu, L. (Lang), Shi, W. (Wei), Long, J. (Jirong), Guo, X. (Xingyi), Michailidou, K. (Kyriaki), Beesley, J. (Jonathan), Bolla, M. K. (Manjeet K.), Shu, X.-O. (Xiao-Ou), Lu, Y. (Yingchang), Cai, Q. (Qiuyin), Al-Ejeh, F. (Fares), Rozali, E. (Esdy), Wang, Q. (Qin), Dennis, J. (Joe), Li, B. (Bingshan), Zeng, C. (Chenjie), Feng, H. (Helian), Gusev, A. (Alexander), Barfield, R. T. (Richard T.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Barrdahl, M. (Myrto), Baynes, C. (Caroline), Beckmann, M. W. (Matthias W.), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Bojesen, S. E. (Stig E.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L. (Louise), Broberg, P. (Per), Brucker, S. Y. (Sara Y.), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Canzian, F. (Federico), Carter, B. D. (Brian D.), Castelao, J. E. (J. Esteban), Chang-Claude, J. (Jenny), Chen, X. (Xiaoqing), Cheng, T. D. (Ting-Yuan David), Christiansen, H. (Hans), Clarke, C. L. (Christine L.), Collee, M. (Margriet), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, D. (David), Cox, A. (Angela), Cross, S. S. (Simon S.), Cunningham, J. M. (Julie M.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doheny, K. F. (Kimberly F.), Dork, T. (Thilo), dos-Santos-Silva, I. (Isabel), Dumont, M. (Martine), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Eilber, U. (Ursula), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Eriksson, M. (Mikael), Fachal, L. (Laura), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fritschi, L. (Lin), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Closas, M. (Montserrat), Gaudet, M. M. (Mia M.), Ghoussaini, M. (Maya), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Harrington, P. (Patricia), Hein, A. (Alexander), Hicks, B. (Belynda), Hillemanns, P. (Peter), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Huang, G. (Guanmengqian), Humphreys, K. (Keith), Hunter, D. J. (David J.), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Johnson, N. (Nichola), Jones, K. (Kristine), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kerin, M. J. (Michael J.), Khusnutdinova, E. (Elza), Kosma, V.-M. (Veli-Matti), Kristensen, V. N. (Vessela N.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindstrom, S. (Sara), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loibl, S. (Sibylle), Lubinski, J. (Jan), Luccarini, C. (Craig), Lux, M. P. (Michael P.), MacInnis, R. J. (Robert J.), Maishman, T. (Tom), Kostovska, I. M. (Ivana Maleva), Mannermaa, A. (Arto), Manson, J. E. (Joann E.), Margolin, S. (Sara), Mavroudis, D. (Dimitrios), Meijers-Heijboer, H. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Meyer, J. (Jeffery), Mulligan, A. M. (Anna Marie), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olopade, O. I. (Olufunmilayo I.), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Prentice, R. (Ross), Presneau, N. (Nadege), Pylkäs, K. (Katri), Rack, B. (Brigitte), Radice, P. (Paolo), Rahman, N. (Nazneen), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Romm, J. (Jane), Rudolph, A. (Anja), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, R. J. (Rodney J.), Scott, C. G. (Christopher G.), Seal, S. (Sheila), Shah, M. (Mitul), Shrubsole, M. J. (Martha J.), Smeets, A. (Ann), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. (William), Taylor, J. A. (Jack A.), Terry, M. B. (Mary Beth), Tessier, D. C. (Daniel C.), Thomas, A. (Abigail), Thone, K. (Kathrin), Tollenaar, R. A. (Rob A. E. M.), Torres, D. (Diana), Truong, T. (Therese), Untch, M. (Michael), Vachon, C. (Celine), Van den Berg, D. (David), Vincent, D. (Daniel), Waisfisz, Q. (Quinten), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Whittemore, A. S. (Alice S.), Wildiers, H. (Hans), Willett, W. C. (Walter C.), Winqvist, R. (Robert), Wolk, A. (Alicja), Xia, L. (Lucy), Yang, X. R. (Xiaohong R.), Ziogas, A. (Argyrios), Ziv, E. (Elad), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Simard, J. (Jacques), Milne, R. L. (Roger L.), Edwards, S. L. (Stacey L.), Kraft, P. (Peter), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), and Zheng, W. (Wei)
- Abstract
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
- Published
- 2018
20. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
- Author
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Wu, L., Shi, W., Long, J., Guo, X., Michailidou, K., Beesley, J., Bolla, M., Shu, X., Lu, Y., Cai, Q., Al-Ejeh, F., Rozali, E., Wang, Q., Dennis, J., Li, B., Zeng, C., Feng, H., Gusev, A., Barfield, R., Andrulis, I., Anton-Culver, H., Arndt, V., Aronson, K., Auer, P., Barrdahl, M., Baynes, C., Beckmann, M., Benitez, J., Bermisheva, M., Blomqvist, C., Bogdanova, N., Bojesen, S., Brauch, H., Brenner, H., Brinton, L., Broberg, P., Brucker, S., Burwinkel, B., Caldés, T., Canzian, F., Carter, B., Castelao, J., Chang-Claude, J., Chen, X., Cheng, T., Christiansen, H., Clarke, C., Collée, M., Cornelissen, S., Couch, F., Cox, D., Cox, A., Cross, S., Cunningham, J., Czene, K., Daly, M., Devilee, P., Doheny, K., Dörk, T., Dos-Santos-Silva, I., Dumont, M., Dwek, M., Eccles, D., Eilber, U., Eliassen, A., Engel, C., Eriksson, M., Fachal, L., Fasching, P., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, Lin, Gabrielson, M., Wu, L., Shi, W., Long, J., Guo, X., Michailidou, K., Beesley, J., Bolla, M., Shu, X., Lu, Y., Cai, Q., Al-Ejeh, F., Rozali, E., Wang, Q., Dennis, J., Li, B., Zeng, C., Feng, H., Gusev, A., Barfield, R., Andrulis, I., Anton-Culver, H., Arndt, V., Aronson, K., Auer, P., Barrdahl, M., Baynes, C., Beckmann, M., Benitez, J., Bermisheva, M., Blomqvist, C., Bogdanova, N., Bojesen, S., Brauch, H., Brenner, H., Brinton, L., Broberg, P., Brucker, S., Burwinkel, B., Caldés, T., Canzian, F., Carter, B., Castelao, J., Chang-Claude, J., Chen, X., Cheng, T., Christiansen, H., Clarke, C., Collée, M., Cornelissen, S., Couch, F., Cox, D., Cox, A., Cross, S., Cunningham, J., Czene, K., Daly, M., Devilee, P., Doheny, K., Dörk, T., Dos-Santos-Silva, I., Dumont, M., Dwek, M., Eccles, D., Eilber, U., Eliassen, A., Engel, C., Eriksson, M., Fachal, L., Fasching, P., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, Lin, and Gabrielson, M.
- Abstract
© 2018 The Author(s) The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
- Published
- 2018
21. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer
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Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Brotzman, M, Buechler, MW, Bueno-de-Mesquita, HB, Bugert, P, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Chung, C, Cotterchio, M, Costello, E, Elena, J, Funel, N, Gaziano, JM, Giese, NA, Goggins, M, Gorman, MJ, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Henderson, BE, Holly, EA, Hu, N, Hunter, DJ, Innocenti, F, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, LaCroix, A, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Nakamura, Y, Oberg, AL, Owzar, K, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Piepoli, A, Porta, M, Real, FX, Riboli, E, Rothman, N, Scarpa, A, Shu, X-O, Silverman, DT, Soucek, P, Sund, M, Talar-Wojnarowska, R, Taylor, PR, Theodoropoulos, GE, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Wu, C, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stolzenberg-Solomon, RS, Amundadottir, LT, Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Brotzman, M, Buechler, MW, Bueno-de-Mesquita, HB, Bugert, P, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Chung, C, Cotterchio, M, Costello, E, Elena, J, Funel, N, Gaziano, JM, Giese, NA, Goggins, M, Gorman, MJ, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Henderson, BE, Holly, EA, Hu, N, Hunter, DJ, Innocenti, F, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, LaCroix, A, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Nakamura, Y, Oberg, AL, Owzar, K, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Piepoli, A, Porta, M, Real, FX, Riboli, E, Rothman, N, Scarpa, A, Shu, X-O, Silverman, DT, Soucek, P, Sund, M, Talar-Wojnarowska, R, Taylor, PR, Theodoropoulos, GE, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Wu, C, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stolzenberg-Solomon, RS, and Amundadottir, LT
- Abstract
We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
- Published
- 2014
22. DNA methylation signatures in the Normative Aging Study:Epigenome-wide association analyses of air pollution exposure,biological aging, metabolism, and lung function decline
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Carmona, J, Barfield, R, Just, A, Colicino, E, Testa, P, Pafundi, P, Mehta, A, Peng, C, Chen, J, Schwartz, J, Lin, X, Baccarelli, A, Carmona, JJ, Barfield, RT, Just, AC, Mehta, AJ, Baccarelli, A., PAFUNDI, PIA CLARA, Carmona, J, Barfield, R, Just, A, Colicino, E, Testa, P, Pafundi, P, Mehta, A, Peng, C, Chen, J, Schwartz, J, Lin, X, Baccarelli, A, Carmona, JJ, Barfield, RT, Just, AC, Mehta, AJ, Baccarelli, A., and PAFUNDI, PIA CLARA
- Abstract
Epigenetic modifications may serve as indicators of past toxic exposures and predict future disease risk. We propose to discover and validate novel methylomic biomarkers of air pollution exposure and related phenotypic outcomes of interest. Our understanding about the complex interplay of epigene-environment interactions remains rudimentary, and it often based on high-exposure animal models. This array-based methylomics study employs the Normative Aging Study (NAS) cohort, followed for over 40+ years, to identify key epigenetic pathways in humans; the Illumina HumanMethylation450 BeadChip was used to query the methylation status of ~480K CpG sites across the human genome. These epigenetic marks may aid in the early diagnosis and prevention of air pollution-related diseases and the study of basic biological processes in vivo.
- Published
- 2013
23. Quality of Life Project – An Oral Presentation
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Caraher, R.B.J., primary, Little, K., additional, Kurtzberg, J., additional, Guess, C., additional, Barfield, R., additional, Saini, S., additional, and Paul, M.L., additional
- Published
- 2011
- Full Text
- View/download PDF
24. 211: Haploidentical Stem Cell Transplantation Using T- and B-Lymphocyte Depleted Grafts Following Reduced Intensity Conditioning for Wiskott-Aldrich Syndrome
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Kasow, K.A., primary, Madden, R., additional, Barfield, R., additional, Leung, W., additional, and Hale, G.A., additional
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- 2008
- Full Text
- View/download PDF
25. 473: Rabbit ATG (thymoglobulin r) Pharmacokinetics in Pediatric Patients Receiving a Matched Unrelated Donor Bone Marrow Transplantation
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Call, S.K., primary, Kasow, K., additional, Barfield, R., additional, Leung, W., additional, Madden, R., additional, Horwitz, E., additional, Woodard, P., additional, Yusuf, U., additional, Panetta, J.C., additional, Baker, S., additional, Handgretinger, R., additional, Rodman, J., additional, and Hale, G.A., additional
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- 2008
- Full Text
- View/download PDF
26. A one-step large-scale method for T- and B-cell depletion of mobilized PBSC for allogeneic transplantation.
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Barfield, R. C., Otto, M., Houston, J., Holladay, M., Geiger, T., Martin, J., Leimig, T., Gordon, P., Chen, X., and Handgretinger, R.
- Subjects
- *
T cells , *B cells , *HOMOGRAFTS , *LYMPHOPROLIFERATIVE disorders , *STEM cells , *PEOPLE with diabetes - Abstract
Background The presence of T and B cells in allogeneic grafts contributes to GvHD and to EBV-associated lymphoproliferative disease (LPD). Depletion of T and B cells from the graft decreases the risk of these complications. Methods T and B cells were depleted from mobilized peripheral stem cells from volunteer donors (n=5) using anti-CD3 and anti-CD19 Abs conjugated to magnetic microbeads, and the CliniMACS device. The function of the stem cells after depletion was evaluated using colony assays and non-obese diabetic (NOD)/SCID repopulating experiments. Results The mean mononuclear cell (MNC) count prior to T- and B-cell depletion was 2.19×10 10 (range 1.48-3.53). After depletion, the mean percentage of contaminating T cells was 0.02% (range 0.01-0.04%) with a mean log 10 depletion of 3.4 (range 3-3.8). The mean percentage of contaminating B cells was 0.1% (range 0.01-0.4%) with a mean log 10 depletion of 2.2 (range 1.4-3). The mean recovery of CD3- and CD19-negative MNCs after depletion was 70% (range 54-88%) and the mean recovery of CD34 + stem cells was 69% (range 52-98%). The mean number of natural killer (NK) cells after T- and B-cell depletion was 5.2×10 8 (range 2-10×10 8 ). In vitro colony assays and in vivo NOD/SCID repopulation assays showed no negative impact of this method on the function of the hematopoietic stem cells. Discussion Our results show that the CliniMACS system can be used to efficiently deplete PBSC of T and B cells simultaneously, without adverse effect on the graft. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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27. Rabbit anti-thymocyte globulin (rATG;thymoglobulin®) pharmacokinetics in pediatric patients receiving a hematopoietic stem cell transplant (HSCT)
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Hale, G.A., Call, S.K., Handgretinger, R., Horwitz, E., Kasow, K., Barfield, R., Yusuf, U., Woodard, P., Leung, W., and Rodman, J.
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- 2006
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28. A review of the use of topotecan for mobilization of peripheral blood stem cells in autologous hematopoietic stem cell transplantation
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Pring, K., Hale, G., Barfield, R., Horwitz, E., Kasow, K., Leung, W., Woodard, P., Yusuf, U., and Handgretinger, R.
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- 2006
- Full Text
- View/download PDF
29. Woods and Wireless
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BARFIELD, R. H., primary
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- 1928
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30. Coastal Refraction of Wireless Waves
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BARFIELD, R. H., primary
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- 1925
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31. Effect of a Large Number of Receiving Aerials on the Propagation of Wireless Waves
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BARFIELD, R. H., primary
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- 1927
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32. Rabbit ATG (thymoglobulin r) Pharmacokinetics in Pediatric Patients Receiving a Matched Unrelated Donor Bone Marrow Transplantation
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Call, S.K., Kasow, K., Barfield, R., Leung, W., Madden, R., Horwitz, E., Woodard, P., Yusuf, U., Panetta, J.C., Baker, S., Handgretinger, R., Rodman, J., and Hale, G.A.
- Published
- 2008
- Full Text
- View/download PDF
33. Haploidentical Stem Cell Transplantation Using T- and B-Lymphocyte Depleted Grafts Following Reduced Intensity Conditioning for Wiskott-Aldrich Syndrome
- Author
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Kasow, K.A., Madden, R., Barfield, R., Leung, W., and Hale, G.A.
- Published
- 2008
- Full Text
- View/download PDF
34. DNA methylation signatures in the Normative Aging Study:Epigenome-wide association analyses of air pollution exposure,biological aging, metabolism, and lung function decline
- Author
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Carmona, JJ, Barfield, RT, Just, AC, Colicino, E, Testa, P, Mehta, AJ, Peng, C, Chen, J, Schwartz, J, Lin, X, Baccarelli, A., PAFUNDI, PIA CLARA, Carmona, J, Barfield, R, Just, A, Colicino, E, Testa, P, Pafundi, P, Mehta, A, Peng, C, Chen, J, Schwartz, J, Lin, X, and Baccarelli, A
- Subjects
SECS-S/01 - STATISTICA ,aging, pollution, GWAS, R Cran ,MED/01 - STATISTICA MEDICA - Abstract
Epigenetic modifications may serve as indicators of past toxic exposures and predict future disease risk. We propose to discover and validate novel methylomic biomarkers of air pollution exposure and related phenotypic outcomes of interest. Our understanding about the complex interplay of epigene-environment interactions remains rudimentary, and it often based on high-exposure animal models. This array-based methylomics study employs the Normative Aging Study (NAS) cohort, followed for over 40+ years, to identify key epigenetic pathways in humans; the Illumina HumanMethylation450 BeadChip was used to query the methylation status of ~480K CpG sites across the human genome. These epigenetic marks may aid in the early diagnosis and prevention of air pollution-related diseases and the study of basic biological processes in vivo.
- Published
- 2013
35. Maternal immunity shapes biomarkers of germinal center development in HIV-exposed uninfected infants.
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Yin L, Venturi GM, Barfield R, Fischer BM, Kim-Chang JJ, Chan C, De Paris K, Goodenow MM, and Sleasman JW
- Subjects
- Humans, Female, Pregnancy, Infant, Newborn, Adult, Infant, HIV-1 immunology, Infectious Disease Transmission, Vertical, Cytokines blood, Male, Immunity, Maternally-Acquired, HIV Infections immunology, Biomarkers blood, Germinal Center immunology, Pregnancy Complications, Infectious immunology
- Abstract
Introduction: HIV-exposed uninfected (HEU) infants exhibit elevated pro-inflammatory biomarkers that persist after birth. However, comprehensive assessments of bioprofiles associated with immune regulation and development in pregnant women with HIV (PWH) and HEU infants has not been performed. Maternal immunity in PWH may be imprinted on their HEU newborns, altering immune bioprofiles during early immune development., Methods: Cryopreserved paired plasma samples from 46 HEU infants and their mothers enrolled in PACTG 316, a clinical trial to prevent perinatal HIV-1 transmission were analyzed. PWH received antiretrovirals (ARV) and had either fully suppressed or unsuppressed viral replication. Maternal blood samples obtained during labor and infant samples at birth and 6 months were measured for 21 biomarkers associated with germinal centers (GC), macrophage activation, T-cell activation, interferon gamma (IFN-γ)-inducible chemokines, and immune regulatory cytokines using Mesoscale assays. Pregnant women without HIV (PWOH) and their HIV unexposed uninfected (HUU) newborns and non-pregnant women without HIV (NPWOH) served as reference groups. Linear regression analysis fitted for comparison among groups and adjusted for covariant(s) along with principal component analysis performed to assess differences among groups., Results: Compared with NPWOH, PWOH displayed higher levels of GC, macrophage, and regulatory biomarkers. PWH compared to PWOH displayed elevated GC, T cell activation, and IFN-γ-inducible chemokines biomarkers at delivery. Similar to their mothers, HEU infants had elevated GC, macrophage, and IFN-γ-inducible chemokines, as well as elevated anti-inflammatory cytokines, IL-10 and IL-1RA. Across all mother/newborn dyads, multiple biomarkers positively correlated, providing further evidence that maternal inflammation imprints on newborn bioprofiles. By 6 months, many HEU biomarkers normalized to levels similar to HUU infants, but some GC and inflammatory biomarkers remained perturbed. Bioprofiles in PWH and HEU infants were similar regardless of the extent of maternal viral suppression by ARV., Conclusions: GC immune pathways are perturbed in HEU newborns, but immune regulatory responses down regulate inflammation during early infancy, indicating a transient inflammatory effect. However, several GC biomarkers that may alter immune development remain perturbed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yin, Venturi, Barfield, Fischer, Kim-Chang, Chan, De Paris, Goodenow and Sleasman.)
- Published
- 2024
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36. Multivalent cytomegalovirus glycoprotein B nucleoside modified mRNA vaccines did not demonstrate a greater antibody breadth.
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Wang HY, Li L, Nelson CS, Barfield R, Valencia S, Chan C, Muramatsu H, Lin PJC, Pardi N, An Z, Weissman D, and Permar SR
- Abstract
Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female rabbits with monovalent (gB-1), bivalent (gB-1+gB-3), or pentavalent (gB-1+gB-2+gB-3+gB-4+gB-5) gB lipid nanoparticle-encapsulated nucleoside-modified RNA (mRNA-LNP) vaccines. The multivalent vaccine groups did not demonstrate a higher magnitude or breadth of the IgG response to the gB ectodomain or cell-associated gB compared to that of the monovalent vaccine. Also, the multivalent vaccines did not show an increase in the breadth of neutralization activity and antibody-dependent cellular phagocytosis against HCMV strains encoding distinct gB genotypes. Interestingly, peripheral blood mononuclear cell-derived gB-2-specific T-cell responses elicited by multivalent vaccines were of a higher magnitude compared to that of monovalent vaccinated animals against a vaccine-mismatched gB genotype at peak immunogenicity. Yet, no statistical differences were observed in T cell response against gB-3 and gB-5 variable regions among the three vaccine groups. Our data suggests that the inclusion of multivalent gB antigens is not an effective strategy to increase the breadth of anti-HCMV gB antibody and T cell responses. Understanding how to increase the HCMV vaccine protection breadth will be essential to improve the vaccine efficacy., (© 2024. The Author(s).)
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- 2024
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37. Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.
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Tuyishime M, Spreng RL, Hueber B, Nohara J, Goodman D, Chan C, Barfield R, Beck WE, Jha S, Asdell S, Wiehe K, He MM, Easterhoff D, Conley HE, Hoxie T, Gurley T, Jones C, Adhikary ND, Villinger F, Thomas R, Denny TN, Moody MA, Tomaras GD, Pollara J, Reeves RK, and Ferrari G
- Subjects
- Animals, Humans, Macaca mulatta, Killer Cells, Natural, Multivariate Analysis, Cluster Analysis, Receptors, Fc metabolism, Antibodies, Monoclonal
- Abstract
Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tuyishime, Spreng, Hueber, Nohara, Goodman, Chan, Barfield, Beck, Jha, Asdell, Wiehe, He, Easterhoff, Conley, Hoxie, Gurley, Jones, Adhikary, Villinger, Thomas, Denny, Moody, Tomaras, Pollara, Reeves and Ferrari.)
- Published
- 2023
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38. Prevalence and significance of clonal hematopoiesis of indeterminate potential in lung transplant recipients.
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Swaminathan AC, Barfield R, Zhang M, Povysil G, Chen C, Frankel C, Kelly F, McKinney M, Todd JL, Allen A, and Palmer SM
- Subjects
- Humans, Transplant Recipients, Prevalence, Lung, Clonal Hematopoiesis, Lung Transplantation adverse effects
- Abstract
Background: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition of somatic mutations that leads to an expanded blood cell clone, has been associated with development of a pro-inflammatory state. An enhanced or dysregulated inflammatory response may contribute to rejection after lung transplantation, however the prevalence of CHIP in lung recipients and influence of CHIP on allograft outcomes is unknown., Methods: We analyzed whole-exome sequencing data in 279 lung recipients to detect CHIP, defined by pre-specified somatic mutations in 74 genes known to promote clonal expansion of hematopoietic stem cells. We compared the burden of acute rejection (AR) over the first post-transplant year in lung recipients with vs. without CHIP using multivariable ordinal regression. Multivariate Cox proportional hazards models were used to assess the association between CHIP and CLAD-free survival. An exploratory analysis evaluated the association between the number of CHIP-associated variants and chronic lung allograft dysfunction (CLAD)-free survival., Results: We detected 64 CHIP-associated mutations in 45 individuals (15.7%), most commonly in TET2 (10.8%), DNMT3A (9.2%), and U2AF1 (9.2%). Patients with CHIP tended to be older but did not significantly differ from patients without CHIP in terms of race or native lung disease. Patients with CHIP did not have a higher incidence of AR over the first post-transplant year (p = 0.45) or a significantly increased risk of death or CLAD (adjusted HR 1.25, 95% CI 0.88-1.78). We did observe a significant association between the number of CHIP variants and CLAD-free survival, specifically patients with 2 or more CHIP-associated variants had an increased risk for death or CLAD (adjusted HR 3.79, 95% CI 1.98-7.27)., Conclusions: Lung recipients have a higher prevalence of CHIP and a larger variety of genes with CHIP-associated mutations compared with previous reports for the general population. CHIP did not increase the risk of AR, CLAD, or death in lung recipients., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2023
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39. Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model.
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Otero CE, Barfield R, Scheef E, Nelson CS, Rodgers N, Wang HY, Moström MJ, Manuel TD, Sass J, Schmidt K, Taher H, Papen C, Sprehe L, Kendall S, Davalos A, Barry PA, Früh K, Pollara J, Malouli D, Chan C, Kaur A, and Permar SR
- Subjects
- Animals, Female, Humans, Pregnancy, Macaca mulatta, Antibody Formation, Viral Load, Placenta, Antibodies, Viral, Glycoproteins metabolism, Infectious Disease Transmission, Vertical, Immunoglobulin G metabolism, Cytomegalovirus physiology, Cytomegalovirus Infections
- Abstract
Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n = 15), CD4+ T cell-depleted with (n = 6) and without (n = 6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings., Competing Interests: SRP provides individual consulting services to Moderna, Merck, Dynavax, Pfizer, GlaxoSmithKline (CMV vaccines) and HOOKIPA Biotech GmbH. She has also led sponsored research programs with Merck Vaccines and Moderna. Oregon Health Sciences University, KF and DM have a substantial financial interest in Vir Biotechnology, Inc. a company that may have a commercial interest in the results of this research and technology. KF and DM are co-inventors of several patents licensed to Vir Biotechnology. KF is also consultants to Vir Biotechnology, Inc. All potential conflicts of interest have been reviewed and managed by OHSU. These competing interests will not alter our adherence to PLOS policies on data and material sharing., (Copyright: © 2023 Otero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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40. Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV.
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Hansen SG, Womack JL, Perez W, Schmidt KA, Marshall E, Iyer RF, Cleveland Rubeor H, Otero CE, Taher H, Vande Burgt NH, Barfield R, Randall KT, Morrow D, Hughes CM, Selseth AN, Gilbride RM, Ford JC, Caposio P, Tarantal AF, Chan C, Malouli D, Barry PA, Permar SR, Picker LJ, and Früh K
- Subjects
- Animals, Humans, Macaca mulatta, Gene Expression, Cytomegalovirus genetics, Simian Immunodeficiency Virus
- Abstract
Rhesus cytomegalovirus-based (RhCMV-based) vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory-based (EM-biased) CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex-E (MHC-E) instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the antihost intrinsic immunity factor phosphoprotein 71 (pp71). Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506 analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high-frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RMs at doses of ≥ 1 × 106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.
- Published
- 2023
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41. Neuroimaging and immunological features of neurocognitive function related to substance use in people with HIV.
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Murdoch DM, Barfield R, Chan C, Towe SL, Bell RP, Volkheimer A, Choe J, Hall SA, Berger M, Xie J, and Meade CS
- Subjects
- Humans, Cross-Sectional Studies, Neuroimaging, Cognition, HIV Infections complications, Substance-Related Disorders complications
- Abstract
This study sought to identify neuroimaging and immunological factors associated with substance use and that contribute to neurocognitive impairment (NCI) in people with HIV (PWH). We performed cross-sectional immunological phenotyping, neuroimaging, and neurocognitive testing on virally suppressed PWH in four substance groups: cocaine only users (COC), marijuana only users (MJ), dual users (Dual), and Non-users. Participants completed substance use assessments, multimodal MRI brain scan, neuropsychological testing, and blood and CSF sampling. We employed a two-stage analysis of 305 possible biomarkers of cognitive function associated with substance use. Feature reduction (Kruskal Wallis p-value < 0.05) identified 53 biomarkers associated with substance use (22 MRI and 31 immunological) for model inclusion along with clinical and demographic variables. We employed eXtreme Gradient Boosting (XGBoost) with these markers to predict cognitive function (global T-score). SHapley Additive exPlanations (SHAP) values were calculated to rank features for impact on model output and NCI. Participants were 110 PWH with sustained HIV viral suppression (33 MJ, 12 COC, 22 Dual, and 43 Non-users). The ten highest ranking biomarkers for predicting global T-score were 4 neuroimaging biomarkers including functional connectivity, gray matter volume, and white matter integrity; 5 soluble biomarkers (plasma glycine, alanine, lyso-phosphatidylcholine (lysoPC) aC17.0, hydroxy-sphingomyelin (SM.OH) C14.1, and phosphatidylcholinediacyl (PC aa) C28.1); and 1 clinical variable (nadir CD4 count). The results of our machine learning model suggest that substance use may indirectly contribute to NCI in PWH through both metabolomic and neuropathological mechanisms., (© 2022. Journal of NeuroVirology, Inc.)
- Published
- 2023
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42. Self-assembling peptide nanofiber HIV vaccine elicits robust vaccine-induced antibody functions and modulates Fc glycosylation.
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Chen JL, Fries CN, Berendam SJ, Rodgers NS, Roe EF, Wu Y, Li SH, Jain R, Watts B, Eudailey J, Barfield R, Chan C, Moody MA, Saunders KO, Pollara J, Permar SR, Collier JH, and Fouda GG
- Subjects
- Animals, Glycosylation, HIV Antibodies, Immunoglobulin Fc Fragments genetics, Immunoglobulin G, Vaccines, Subunit, AIDS Vaccines, HIV Infections prevention & control, HIV-1, Nanofibers
- Abstract
To develop vaccines for certain key global pathogens such as HIV, it is crucial to elicit both neutralizing and non-neutralizing Fc-mediated effector antibody functions. Clinical evidence indicates that non-neutralizing antibody functions including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) contribute to protection against several pathogens. In this study, we demonstrated that conjugation of HIV Envelope (Env) antigen gp120 to a self-assembling nanofiber material named Q11 induced antibodies with higher breadth and functionality when compared to soluble gp120. Immunization with Q11-conjugated gp120 vaccine (gp120-Q11) demonstrated higher tier 1 neutralization, ADCP, and ADCC as compared to soluble gp120. Moreover, Q11 conjugation altered the Fc N-glycosylation profile of antigen-specific antibodies, leading to a phenotype associated with increased ADCC in animals immunized with gp120-Q11. Thus, this nanomaterial vaccine strategy can enhance non-neutralizing antibody functions possibly through modulation of immunoglobulin G Fc N-glycosylation.
- Published
- 2022
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43. Association between germline variants and somatic mutations in colorectal cancer.
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Barfield R, Qu C, Steinfelder RS, Zeng C, Harrison TA, Brezina S, Buchanan DD, Campbell PT, Casey G, Gallinger S, Giannakis M, Gruber SB, Gsur A, Hsu L, Huyghe JR, Moreno V, Newcomb PA, Ogino S, Phipps AI, Slattery ML, Thibodeau SN, Trinh QM, Toland AE, Hudson TJ, Sun W, Zaidi SH, and Peters U
- Subjects
- Allelic Imbalance, Genetic Predisposition to Disease, Germ Cells pathology, Humans, Polymorphism, Single Nucleotide, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Germ-Line Mutation
- Abstract
Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC., (© 2022. The Author(s).)
- Published
- 2022
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44. Genetic Regulation of DNA Methylation Yields Novel Discoveries in GWAS of Colorectal Cancer.
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Barfield R, Huyghe JR, Lemire M, Dong X, Su YR, Brezina S, Buchanan DD, Figueiredo JC, Gallinger S, Giannakis M, Gsur A, Gunter MJ, Hampel H, Harrison TA, Hopper JL, Hudson TJ, Li CI, Moreno V, Newcomb PA, Pai RK, Pharoah PDP, Phipps AI, Qu C, Steinfelder RS, Sun W, Win AK, Zaidi SH, Campbell PT, Peters U, and Hsu L
- Subjects
- Epigenomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Proteins, Quantitative Trait Loci, Colorectal Neoplasms genetics, DNA Methylation
- Abstract
Background: Colorectal cancer has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the interrelationship of germline genetics, DNAm, and colorectal cancer risk., Methods: We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1,355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants ± 1 Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with colorectal cancer risk based on genome-wide association studies (GWAS) of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with colorectal cancer risk., Results: Of the 142 known colorectal cancer GWAS loci, 47 were identified as meQTLs. We identified four novel colorectal cancer-associated loci (NID2, ATXN10, KLHDC10, and CEP41) that reside over 1 Mb outside of known colorectal cancer loci and 10 secondary signals within 1 Mb of known loci., Conclusions: Leveraging information of DNAm regulation into genetic association of colorectal cancer risk reveals novel pathways in colorectal cancer tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed., Impact: Using genotype, DNAm, and GWAS, we identified four new colorectal cancer risk loci. We studied the landscape of genetic regulation of DNAm via single-SNP and multi-SNP meQTL analyses., (©2022 American Association for Cancer Research.)
- Published
- 2022
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45. Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies.
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Liu Z, Shen J, Barfield R, Schwartz J, Baccarelli AA, and Lin X
- Abstract
In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel's test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this paper, we show that the null distribution of Sobel's test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful Divide-Aggregate Composite-null Test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron's empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the type I error rate and outperformed Sobel's test and the joint significance test for detecting mediation effects. We applied the DACT method to the US Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from -0.18 to -0.79 and false discovery rate controlled at level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors.
- Published
- 2022
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46. HIV envelope antigen valency on peptide nanofibers modulates antibody magnitude and binding breadth.
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Fries CN, Chen JL, Dennis ML, Votaw NL, Eudailey J, Watts BE, Hainline KM, Cain DW, Barfield R, Chan C, Moody MA, Haynes BF, Saunders KO, Permar SR, Fouda GG, and Collier JH
- Subjects
- Animals, Female, Germinal Center immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 metabolism, Herpes Simplex Virus Vaccines immunology, Immunoglobulin G blood, Mice, Inbred C57BL, T-Lymphocytes, Helper-Inducer immunology, Mice, HIV Antibodies metabolism, HIV Antigens immunology, HIV Envelope Protein gp120 chemistry, HIV Envelope Protein gp120 immunology, Nanofibers chemistry
- Abstract
A major challenge in developing an effective vaccine against HIV-1 is the genetic diversity of its viral envelope. Because of the broad range of sequences exhibited by HIV-1 strains, protective antibodies must be able to bind and neutralize a widely mutated viral envelope protein. No vaccine has yet been designed which induces broadly neutralizing or protective immune responses against HIV in humans. Nanomaterial-based vaccines have shown the ability to generate antibody and cellular immune responses of increased breadth and neutralization potency. Thus, we have developed supramolecular nanofiber-based immunogens bearing the HIV gp120 envelope glycoprotein. These immunogens generated antibody responses that had increased magnitude and binding breadth compared to soluble gp120. By varying gp120 density on nanofibers, we determined that increased antigen valency was associated with increased antibody magnitude and germinal center responses. This study presents a proof-of-concept for a nanofiber vaccine platform generating broad, high binding antibody responses against the HIV-1 envelope glycoprotein., (© 2021. The Author(s).)
- Published
- 2021
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47. Intake of Dietary Fruit, Vegetables, and Fiber and Risk of Colorectal Cancer According to Molecular Subtypes: A Pooled Analysis of 9 Studies.
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Hidaka A, Harrison TA, Cao Y, Sakoda LC, Barfield R, Giannakis M, Song M, Phipps AI, Figueiredo JC, Zaidi SH, Toland AE, Amitay EL, Berndt SI, Borozan I, Chan AT, Gallinger S, Gunter MJ, Guinter MA, Harlid S, Hampel H, Jenkins MA, Lin Y, Moreno V, Newcomb PA, Nishihara R, Ogino S, Obón-Santacana M, Parfrey PS, Potter JD, Slattery ML, Steinfelder RS, Um CY, Wang X, Woods MO, Van Guelpen B, Thibodeau SN, Hoffmeister M, Sun W, Hsu L, Buchanan DD, Campbell PT, and Peters U
- Subjects
- Case-Control Studies, Colorectal Neoplasms pathology, CpG Islands, DNA Methylation, Female, Humans, Male, Microsatellite Instability, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, Risk Factors, Colorectal Neoplasms etiology, Colorectal Neoplasms prevention & control, Dietary Fiber pharmacology, Fruit, Vegetables
- Abstract
Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF -mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF -wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF -wildtype, and KRAS -wildtype tumors ( P
trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF -mutated, or KRAS -mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported., (©2020 American Association for Cancer Research.)- Published
- 2020
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48. A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study.
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Dong X, Su YR, Barfield R, Bien SA, He Q, Harrison TA, Huyghe JR, Keku TO, Lindor NM, Schafmayer C, Chan AT, Gruber SB, Jenkins MA, Kooperberg C, Peters U, and Hsu L
- Subjects
- Colorectal Neoplasms pathology, Computational Biology, Gene Expression Regulation, Neoplastic genetics, Genetic Variation genetics, Genotype, Humans, Models, Statistical, Phenotype, Polymorphism, Single Nucleotide genetics, Colorectal Neoplasms genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Quantitative Trait Loci genetics
- Abstract
Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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49. Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.
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Cade BE, Chen H, Stilp AM, Louie T, Ancoli-Israel S, Arens R, Barfield R, Below JE, Cai J, Conomos MP, Evans DS, Frazier-Wood AC, Gharib SA, Gleason KJ, Gottlieb DJ, Hillman DR, Johnson WC, Lederer DJ, Lee J, Loredo JS, Mei H, Mukherjee S, Patel SR, Post WS, Purcell SM, Ramos AR, Reid KJ, Rice K, Shah NA, Sofer T, Taylor KD, Thornton TA, Wang H, Yaffe K, Zee PC, Hanis CL, Palmer LJ, Rotter JI, Stone KL, Tranah GJ, Wilson JG, Sunyaev SR, Laurie CC, Zhu X, Saxena R, Lin X, and Redline S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cell Adhesion Molecules, Neuronal genetics, Computational Biology, Extracellular Matrix Proteins genetics, Female, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Humans, Hypoxia blood, Hypoxia genetics, Male, Middle Aged, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Nerve Tissue Proteins genetics, Oxygen blood, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reelin Protein, Serine Endopeptidases genetics, Sleep Apnea Syndromes blood, Sleep Apnea Syndromes genetics, Young Adult, Hexokinase genetics, Interleukin-18 Receptor alpha Subunit genetics, Oxyhemoglobins metabolism, Sleep genetics
- Abstract
Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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50. Reclassification of genetic-based risk predictions as GWAS data accumulate.
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Krier J, Barfield R, Green RC, and Kraft P
- Subjects
- Algorithms, Breast Neoplasms genetics, Computer Simulation, Diabetes Mellitus, Type 2 genetics, Female, Genome-Wide Association Study methods, Humans, Male, Odds Ratio, Prostatic Neoplasms genetics, Cardiovascular Diseases genetics, Computational Biology methods, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Disease risk assessments based on common genetic variation have gained widespread attention and use in recent years. The clinical utility of genetic risk profiles depends on the number and effect size of identified loci, and how stable the predicted risks are as additional loci are discovered. Changes in risk classification for individuals over time would undermine the validity of common genetic variation for risk prediction. In this analysis, we quantified reclassification of genetic risk based on past and anticipated future GWAS data., Methods: We identified disease-associated SNPs via the NHGRI GWAS catalog and recent large scale genome-wide association study (GWAS). We calculated the genomic risk for a simulated cohort of 100,000 individuals based on a multiplicative odds ratio model using cumulative GWAS-identified SNPs at four time points: 2007, 2009, 2011, and 2013. Individuals were classified as Higher Risk (population adjusted odds >2), Average Risk (between 0.5 and 2), and Lower Risk (<0.5) for each time point and we compared classifications between time points for breast cancer (BrCa), prostate cancer (PrCa), diabetes mellitus type 2 (T2D), and cardiovascular heart disease (CHD). We estimated future reclassification using the anticipated number of undiscovered SNPs., Results: Risk reclassification occurred for all four phenotypes from 2007 to 2013. During the most recent interval (2011-2013), the degree of risk reclassification ranged from 16.3 % for CHD to 24.4 % for PrCa. Many individuals classified as Higher Risk at earlier time points were subsequently reclassified into a lower risk category. From 2011 to 2013, the degree of such downward risk reclassification ranged from 24.9% for T2D to 55% for CHD. The percent of individuals classified as Higher Risk increased as more SNPs were discovered, ranging from an increase of 5% for CHD to 9% for PrCa from 2007 to 2013. Reclassification continued to occur when we modeled the discovery of anticipated SNPs based on doubling current sample size., Conclusion: Risk estimates from common genetic variation show large reclassification rates. Identifying disease-associated SNPs facilitates the clinically relevant task of identifying higher-risk individuals. However, the large amount of reclassification that we demonstrated in individuals initially classified as Higher Risk but later as Average Risk or Lower Risk, suggests that caution is currently warranted in basing clinical decisions on common genetic variation for many complex diseases.
- Published
- 2016
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