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1. Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047)

Author

Parker, C.C., Petersen, P.M., Cook, A.D., Clarke, N.W., Catton, C., Cross, W.R., Kynaston, H., Parulekar, W.R., Persad, R.A., Saad, F., Bower, L., Durkan, G.C., Logue, J., Maniatis, C., Noor, D., Payne, H., Anderson, J., Bahl, A.K., Bashir, F., Bottomley, D.M., Brasso, K., Capaldi, L., Chung, C., Cooke, P.W., Donohue, J.F., Eddy, B., Heath, C.M., Henderson, A., Henry, A., Jaganathan, R., Jakobsen, H., James, N.D., Joseph, J., Lees, K., Lester, J., Lindberg, H., Makar, A., Morris, S.L., Oommen, N., Ostler, P., Owen, L., Patel, P., Pope, A., Popert, R., Raman, R., Ramani, V., Røder, A., Sayers, I., Simms, M., Srinivasan, V., Sundaram, S., Tarver, K.L., Tran, A., Wells, P., Wilson, J., Zarkar, A.M., Parmar, M.K.B., and Sydes, M.R.

Published
2024
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4. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Author

Chee, J.M., Lanoue, L., Clary, D., Higgins, K., Bower, L., Flenniken, A., Guo, R., Adams, D.J., Bosch, F., Braun, R.E., Brown, S.D.M., Chin, H.J.G., Dickinson, M.E., Hsu, C.W., Dobbie, M., Gao, X., Galande, S., Grobler, A., Heaney, J.D., Herault, Y., de Angelis, M.H., Mammano, F., Nutter, L.M.J, Parkinson, H., Qin, C., Shiroishi, T., Sedlacek, R., Seong, J.K., Xu, Y., Brooks, B., McKerlie, C., Lloyd, K.C.K., Westerberg, H., and Moshiri, A.

Subjects
Cancer Research, Technology Platforms
Abstract

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Published
2023

5. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Author

Chee, J. M., Lanoue, L., Clary, D., Higgins, K., Bower, L., Flenniken, A., Guo, R., Adams, D. J., Bosch, F., Braun, R. E., Brown, S. D. M., Chin, H. J. G., Dickinson, M. E., Hsu, C. W., Dobbie, M., Gao, X., Galande, S., Grobler, A., Heaney, J. D., Herault, Y., de Angelis, M. H., Mammano, F., Nutter, L. M. J., Parkinson, H., Qin, C., Shiroishi, T., Sedlacek, R., Seong, J. K., Xu, Y., Ackert-Bicknell, C., Adams, D., Adoum, A. T., Aguilar-Pimentel, J. A., Akoma, U., Ali-Hadji, D., Amarie, O. V., André, P., Auburtin, A., Bam’Hamed, C., Beckers, J., Beig, J., Berberovic, Z., Bezginov, A., Birling, M. C., Boroviak, K., Bottomley, J., Bürger, A., Busch, D. H., Butterfield, N. C., Cacheiro, P., Calzada-Wack, J., Cambridge, E. L., Camilleri, S., Champy, M. F., Cater, H., Charles, P., Chesler, E. J., Cho, Y. L., Christiansen, A. E., Cipriani, V., Cockle, N., Codner, G., Creighton, A., Cruz, M., Curry, K. F., D’Souza, A., Danisment, O., Delbarre, D., Dewhurst, H. F., Doe, B., Dorr, A., Giesert, F., Duddy, G., Duffin, K., El Amri, A., Elrick, H., Eskandarian, M., Fray, M., Frost, A., Fuchs, H., Gailus-Durner, V., Gampe, K. K., Ganguly, M., Gannon, D., Garrett, L., Gertsenstein, M., Gleeson, D., Goodwin, L., Graw, J., Grimsrud, K., Haselimashhadi, H., Hobson, L., Hörlein, A., Hölter, S. M., Hong, S. H., Horner, N., Trainor, A. G., Huang, Z., Kane, C., and Katsman, Y.

Subjects
Serine-glycine biosynthesis, Mouse, Eye development, Physiology, Cell Biology, Plant Science, General Biochemistry, Genetics and Molecular Biology, CPLANE, IMPC, MAC spectrum, Structural Biology, General Agricultural and Biological Sciences, Ecology, Evolution, Behavior and Systematics, Developmental Biology, Biotechnology
Abstract

Background Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Results Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Conclusions Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Published
2023

6. Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma

Author

Noble, F., Lloyd, M. A., Turkington, R., Griffiths, E., OʼDonovan, M., OʼNeill, J. R., Mercer, S., Parsons, S. L., Fitzgerald, R. C., Underwood, T. J., Noorani, A., Fels Elliott, R., Abdullahi, Z., de la Rue, R., Bornschein, J., MacRae, S., Nutzinger, B., Grehan, N., Contino, G., Crawte, J., Edwards, P. A. W., Miremadi, A., Malhotra, S., Hayden, A., Walker, R., Peters, C., Hannah, G., Hardwick, R., Davies, J., Ford, H., Gilligan, D., Safranek, P., Hindmarsh, A., Sujendran, V., Carroll, N., McManus, D., Hayes, S. J., Ang, Y., Preston, S. R., Oakes, S., Bagwan, I., Skipworth, R. J. E., Save, V., Hupp, T. R., Puig, S., Bedford, M., Taniere, P., Whiting, J., Byrne, J., Kelly, J., Owsley, J., Crichton, C., Barr, H., Shepherd, N., Old, O., Lagergren, J., Gossage, J., Davies, A., Chang, F., Zylstra, J., Sanders, G., Berrisford, R., Harden, C., Bunting, D., Lewis, M., Cheong, E., Kumar, B., Saunders, J. H., Soomro, I. N., Vohra, R., Duffy, J., Kaye, P., Grabowska, A., Lovat, L., Haidry, R., Eneh, V., Igali, L., Welch, I., Scott, M., Sothi, S., Suortamo, S., Lishman, S., Beardsmore, D., Sutaria, R., Secrier, M., Eldridge, M.D., Bower, L., Lynch, A. G., and Tavaré, S.

Published
2017
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7. PD-0798 Development and results of a patient-reported treatment experience questionnaire on a 1.5 T MR-Linac

Author

Barnes, H., primary, Alexander, S., additional, Bower, L., additional, Ehlers, J., additional, Gani, C., additional, Herbert, T., additional, Lawes, R., additional, Krause, P., additional, øller, M., additional, Morgan, T., additional, Nowee, M., additional, Smith, G., additional, van Triest, B., additional, Tyagi, N., additional, Whiteside, L., additional, and McNair, H., additional

Published
2021
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8. Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction

Author

Bornschein, J, Wernisch, L, Secrier, M, Miremadi, A, Perner, J, MacRae, S, O'Donovan, M, Newton, R, Menon, S, Bower, L, Eldridge, MD, Devonshire, G, Cheah, C, Turkington, R, Hardwick, RH, Selgrad, M, Venerito, M, Malfertheiner, P, Fitzgerald, RC, Noorani, A, Elliott, RF, Edwards, PAW, Grehan, N, Nutzinger, B, Crawte, J, Chettouh, H, Contino, G, Li, X, Gregson, E, Zeki, S, De la Rue, R, Malhotra, S, Tavare, S, Lynch, AG, Smith, ML, Davies, J, Crichton, C, Carroll, N, Safranek, P, Hindmarsh, A, Sujendran, V, Hayes, SJ, Ang, Y, Preston, SR, Oakes, S, Bagwan, I, Save, V, Skipworth, RJE, Hupp, TR, O'Neill, JR, Tucker, O, Beggs, A, Taniere, P, Puig, S, Underwood, TJ, Noble, F, Owsley, J, Barr, H, Shepherd, N, Old, O, Lagergren, J, Gossage, J, Davies, A, Chang, F, Zylstra, J, Goh, V, Ciccarelli, FD, Sanders, G, Berrisford, R, Harden, C, Bunting, D, Lewis, M, Cheong, E, Kumar, B, Parsons, SL, Soomro, I, Kaye, P, Saunders, J, Lovat, L, Haidry, R, Eneh, V, Igali, L, Scott, M, Sothi, S, Suortamo, S, Lishman, S, Hanna, GB, Peters, CJ, and Grabowska, A

Subjects
Oncology, Cancer Research, Esophageal Neoplasms, esophageal adenocarcinoma, gastroesophageal junction, SUBTYPES, Transcriptome, Molecular Cancer Biology, 0302 clinical medicine, Gene expression, Prospective Studies, BILE-ACIDS, SIGNATURE, Prognosis, Immunohistochemistry, Phenotype, medicine.anatomical_structure, 030220 oncology & carcinogenesis, OCCAMS Consortium, Adenocarcinoma, Esophagogastric Junction, Life Sciences & Biomedicine, EXPRESSION, medicine.medical_specialty, Biology, CLASSIFICATION, Siewert classification, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stomach Neoplasms, Internal medicine, gene expression profiling, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Esophagus, Science & Technology, Anatomical location, IDENTIFICATION, Gene Expression Profiling, gastric cancer, PATHWAYS, medicine.disease, Gene expression profiling, ESOPHAGUS, GASTRIC-CANCER
Abstract

Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment‐naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina‐HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune‐response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed., What's new? Adenocarcinomas that arise at the junction between the esophagus and the stomach are currently classified based on location. Here, the authors looked at patterns of gene expression of these cancers. They found that gastro‐esophageal junction adenocarcinomas can be sorted into three biological subtypes, independent of location, based on gene expression. Group 1 cancers have boosted stomach‐specific genes that combat the effects of acid reflux. Group 2 tumors express genes characteristic to the intestinal tract, and the genes active in Group 3 relate to inflammation. The differences in biological pathway expression means that these differences could be used to improve treatment.

Published
2019

9. Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics

Author

Li, X, Francies, H, Secrier, M, Perner, J, Miremadi, A, Galeano-Dalmau, N, Barendt, W, Letchford, L, Leyden, G, Goffin, E, Barthorpe, A, Lightfoot, H, Chen, E, Gilbert, J, Noorani, A, Devonshire, G, Bower, L, Grantham, A, Macrae, S, Grehan, N, Wedge, D, Fitzgerald, R, Garnett, M, Fitzgerald, Rebecca [0000-0002-3434-3568], and Apollo - University of Cambridge Repository

Subjects
Male, DNA Copy Number Variations, Esophageal Neoplasms, Science, DNA Mutational Analysis, Adenocarcinoma, Article, Clonal Evolution, Inhibitory Concentration 50, Humans, Precision Medicine, lcsh:Science, Aged, Aged, 80 and over, Manchester Cancer Research Centre, Sequence Analysis, RNA, ResearchInstitutes_Networks_Beacons/mcrc, Receptor Protein-Tyrosine Kinases, Middle Aged, Organoids, Karyotyping, Mutation, lcsh:Q, Female, Drug Screening Assays, Antitumor, Transcriptome
Abstract

Esophageal adenocarcinoma (EAC) incidence is increasing while 5-year survival rates remain less than 15%. A lack of experimental models has hampered progress. We have generated clinically annotated EAC organoid cultures that recapitulate the morphology, genomic, and transcriptomic landscape of the primary tumor including point mutations, copy number alterations, and mutational signatures. Karyotyping of organoid cultures has confirmed polyclonality reflecting the clonal architecture of the primary tumor. Furthermore, subclones underwent clonal selection associated with driver gene status. Medium throughput drug sensitivity testing demonstrates the potential of targeting receptor tyrosine kinases and downstream mediators. EAC organoid cultures provide a pre-clinical tool for studies of clonal evolution and precision therapeutics., Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate and lacks robust preclinical models for use in research. Here, the authors show that newly derived organoids recapitulate the transcriptomic, genetic, and morphological landscape of the primary EAC tumors and provide a platform to test drug sensitivity and study tumor clonality.

Published
2018

10. OC-0469: MR-guided online adaptive radiotherapy for muscle invasive bladder cancer: First UK experience

Author

Hunt, A., primary, Hanson, I., additional, Dunlop, A., additional, Bower, L., additional, Barnes, H., additional, Chick, J., additional, Herbert, T., additional, Lawes, R., additional, McNair, H., additional, Mitchell, A., additional, Mohajer, J., additional, Morgan, T., additional, Smith, G., additional, Nill, S., additional, Oelfke, U., additional, Huddart, R., additional, and Hafeez, S., additional

Published
2020
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14. Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Author

Mourikis, TP, Benedetti, L, Foxall, E, Temelkovski, D, Nulsen, J, Perner, J, Cereda, M, Lagergren, J, Howell, M, Yau, C, Fitzgerald, RC, Scaffidi, P, Noorani, A, Edwards, PAW, Elliott, RF, Grehan, N, Nutzinger, B, Hughes, C, Fidziukiewicz, E, Bornschein, J, MacRae, S, Crawte, J, Northrop, A, Contino, G, Li, X, De la Rue, R, Katz-Summercorn, A, Abbas, S, Loureda, D, O'Donovan, M, Miremadi, A, Malhotra, S, Tripathi, M, Tavare, S, Lynch, AG, Eldridge, M, Secrier, M, Bower, L, Devonshire, G, Jammula, S, Davies, J, Crichton, C, Carroll, N, Safranek, P, Hindmarsh, A, Sujendran, V, Hayes, SJ, Ang, Y, Sharrocks, A, Preston, SR, Oakes, S, Bagwan, I, Save, V, Skipworth, RJE, Hupp, TR, O'Neill, JR, Tucker, O, Beggs, A, Taniere, P, Puig, S, Underwood, TJ, Walker, RC, Grace, BL, Barr, H, Shepherd, N, Old, O, Gossage, J, Davies, A, Chang, F, Zylstra, J, Mahadeva, U, Goh, V, Sanders, G, Berrisford, R, Harden, C, Lewis, M, Cheong, E, Kumar, B, Parsons, SL, Soomro, I, Kaye, P, Saunders, J, Lovat, L, Haidry, R, Igali, L, Scott, M, Sothi, S, Suortamo, S, Lishman, S, Hanna, GB, Peters, CJ, Moorthy, K, Grabowska, A, Turkington, R, McManus, D, Khoo, D, Fickling, W, Ciccarelli, FD, Mourikis, Thanos P. [0000-0002-8026-8837], Foxall, Elizabeth [0000-0003-1995-5547], Scaffidi, Paola [0000-0002-3642-4193], and Apollo - University of Cambridge Repository

Subjects
EXPRESSION, SELECTION, 631/67, DATABASE, PROTEIN, 38/90, 631/67/69, 13/109, VARIANTS, 13/44, GERMLINE, MD Multidisciplinary, 38/23, 38/22, 38/88, Science & Technology, 631/67/1504/1477, article, Multidisciplinary Sciences, 13/31, BARRETTS-ESOPHAGUS, REPLICATION, PATTERNS, 38/77, Science & Technology - Other Topics, UPDATE, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
Abstract

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.

Published
2019

20. The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

Author

Frankell, AM, Jammula, S, Li, X, Contino, G, Killcoyne, S, Abbas, S, Perner, J, Bower, L, Devonshire, G, Cocks, E, Grehan, N, Mok, J, O'Donovan, M, MacRae, S, Eldridge, MD, Tavare, S, Fitzgerald, RC, Noorani, A, Edwards, PAW, Grehanl, N, Nutzinger, B, Hughes, CI, Fidziukiewicz, E, Northrop, A, De la Rue, R, Katz-Summercorn, A, Loureda, D, Miremadi, A, Malhotra, S, Tripathi, M, Lynch, AG, Eldridge, M, Secrier, M, Davies, J, Crichton, C, Carro, N, Safranek, P, Hindmarsh, A, Sujendran, V, Hayes, SJ, Ang, Y, Sharrocks, A, Preston, SR, Oakes, S, Bagwan, I, Save, V, Skipworth, RJE, Hupp, TR, ONeill, JR, Tucker, O, Beggs, A, Taniere, P, Puig, S, Underwood, T, Walker, RC, Grace, BL, Barr, H, Shepherd, N, Old, O, Lagergren, J, Gossage, J, Davies, A, Chang, F, Zylstra, J, Mahadeva, U, Goh, V, Ciccarelli, FD, Sanders, G, Berrisford, R, Harden, C, Lewis, M, Cheong, E, Kumar, B, Parsons, SL, Soomro, I, Kaye, P, Saunders, J, Lovat, L, Haidry, R, Igali, L, Scott, M, Sothi, S, Suortamo, S, Lishman, S, Hanna, GB, Moorthy, K, Peters, CJ, Grabowska, A, Turkington, R, McManus, D, Coleman, H, Khoo, D, and Fickling, W

Subjects
Male, Oncology, Mutation rate, Esophageal Neoplasms, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Exome, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Mutation, GATA4, Incidence (epidemiology), Genomics, CANCER, Cell Cycle Gene, Gene Expression Regulation, Neoplastic, Cohort, Adenocarcinoma, Female, Life Sciences & Biomedicine, Silent mutation, medicine.medical_specialty, CARCINOMA, DNA Copy Number Variations, Biology, Article, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, Genetics, Carcinoma, medicine, Humans, Gene, SIGNATURES, 030304 developmental biology, Science & Technology, Gene Expression Profiling, PATHWAYS, Cancer, SOMATIC MUTATIONS, 06 Biological Sciences, medicine.disease, COMPREHENSIVE MOLECULAR CHARACTERIZATION, PD-1 BLOCKADE, Gene expression profiling, PATTERNS, DRIVER, Cancer research, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, 030217 neurology & neurosurgery, ACQUIRED-RESISTANCE, Developmental Biology
Abstract

Esophageal Adenocarcinoma (EAC) is a poor prognosis cancer type with rapidly rising incidence. Our understanding of genetic events which drive EAC development is limited and there are few molecular biomarkers for prognostication or therapeutics. We have accumulated a cohort of 551 genomically characterised EACs (73% WGS and 27% WES) with clinical annotation and matched RNA-seq. Using a variety of driver gene detection methods, we discover 77 EAC driver genes (73% novel) and 21 non-coding driver elements (95% novel), and describe mutation and CNV types with specific functional impact. We identify a mean of 4.4 driver events per case derived from both copy number events and mutations. We compare driver mutation rates to the exome-wide mutational excess calculated using Non-synonymous vs Synonymous mutation rates (dNdS). We observe mutual exclusivity or co-occurrence of events within and between a number of EAC pathways (GATA factors, Core Cell cycle genes, TP53 regulators and the SWI/SNF complex) suggestive of important functional relationships. These driver variants correlate with tumour differentiation, sex and prognosis. Poor prognostic indicators (SMAD4, GATA4) are verified in independent cohorts with significant predictive value. Over 50% of EACs contain sensitising events for CDK4/6 inhibitors which are highly correlated with clinically relevant sensitivity in a panel EAC cell lines and organoids.

Published
2018

21. The PRISM Trial- First UK Experience of MRI-Guided Adaptive Radiotherapy

Author

Pathmanathan, A., primary, Bower, L., additional, Creasey, H., additional, Dunlop, A., additional, Hall, E., additional, Hanson, I., additional, Herbert, T., additional, Lawes, R., additional, Mcquaid, D., additional, McNair, H., additional, Mitchell, A., additional, Murray, J., additional, Ofuya, M., additional, Parker, C., additional, Rossan, J., additional, Smith, G., additional, Huddart, R.A., additional, Oelfke, U., additional, Nill, S., additional, and Tree, A., additional

Published
2019
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22. EP-2173 Bladder filling in patients undergoing prostate radiotherapy on the MR-linac

Author

Smith, G. Adair, primary, Herbert, T., additional, Lawes, R., additional, Creasey, H., additional, Dunlop, A., additional, Mitchell, A., additional, Pathmanathan, A., additional, Bower, L., additional, Hanson, I., additional, McQuaid, D., additional, Huddart, R., additional, Oelfke, U., additional, Nill, S., additional, Tree, A., additional, and McNair, H., additional

Published
2019
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23. EP-1566 MR-guided online adaptive radiotherapy: First experience in the UK

Author

Pathmanathan, A., primary, Bower, L., additional, Creasey, H., additional, Dunlop, A., additional, Hall, E., additional, Hanson, I., additional, Herbert, T., additional, Lawes, R., additional, McQuaid, D., additional, McNair, H., additional, Mitchell, A., additional, Smith, G., additional, Huddart, R., additional, Oelfke, U., additional, Nill, S., additional, and Tree, A., additional

Published
2019
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25. A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

Author

Noorani, A, Bornschein, J, Lynch, A, Secrier, M, Achilleos, A, Eldridge, M, Bower, L, Weaver, J, Crawte, J, Ong, C, Shannon, N, Macrae, S, Grehan, N, Nutzinger, B, O'Donovan, M, Hardwick, R, Tavaré, S, Fitzgerald, R, Consortium, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS), University of St Andrews. School of Medicine, University of St Andrews. Statistics, University of St Andrews. Cellular Medicine Division, Davies, J, Lynch, Andy [0000-0002-7876-7338], Eldridge, Matthew [0000-0002-5799-8911], Fitzgerald, Rebecca [0000-0002-3434-3568], and Apollo - University of Cambridge Repository

Subjects
Male, Time Factors, DNA Copy Number Variations, Esophageal Neoplasms, Antineoplastic Agents, Adenocarcinoma, Polymorphism, Single Nucleotide, RC0254, Esophagus, Mutation Rate, SDG 3 - Good Health and Well-being, Humans, Point Mutation, Prospective Studies, Aged, Genome, Human, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Research, Gene Expression Profiling, Computational Biology, High-Throughput Nucleotide Sequencing, DAS, Middle Aged, Neoadjuvant Therapy, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Female, Corrigendum
Abstract

The whole-genome sequencing data from this study have been submitted to the European Genome-phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) under accession number EGAD00001002241. Mutation calls can be found within the ICGC data portal (https://dcc.icgc.org/) under project ID ESADUK and library IDs listed in Supplemental Table S2. The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer. Publisher PDF

Published
2017

26. Authentication and characterisation of a new oesophageal adenocarcinoma cell line: MFD-1

Author

Garcia, E, Hayden, A, Birts, C, Britton, E, Cowie, A, Pickard, K, Mellone, M, Choh, C, Derouet, M, Duriez, P, Noble, F, White, MJ, Primrose, JN, Strefford, JC, Rose-Zerilli, M, Thomas, GJ, Ang, Y, Sharrocks, AD, Fitzgerald, RC, Underwood, TJ, MacRae, S, Grehan, N, Abdullahi, Z, De la Rue, R, Noorani, A, Elliott, RF, De Silva, N, Bornschein, J, O’Donovan, M, Contino, G, Yang, T-P, Chettouh, H, Crawte, J, Nutzinger, B, Edwards, PAW, Smith, L, Miremadi, A, Malhotra, S, Cluroe, A, Hardwick, R, Davies, J, Ford, H, Gilligan, D, Safranek, P, Hindmarsh, A, Sujendran, V, Carroll, N, Turkington, R, Hayes, SJ, Preston, SR, Oakes, S, Bagwan, I, Save, V, Skipworth, RJE, Hupp, TR, O’Neill, JR, Tucker, O, Taniere, P, Owsley, J, Crichton, C, Schusterreiter, C, Barr, H, Shepherd, N, Old, O, Lagergren, J, Gossage, J, Davies, A, Chang, F, Zylstra, J, Sanders, G, Berrisford, R, Harden, C, Bunting, D, Lewis, M, Cheong, E, Kumar, B, Parsons, SL, Soomro, I, Kaye, P, Saunders, J, Lovat, L, Haidry, R, Eneh, V, Igali, L, Welch, I, Scott, M, Sothi, S, Suortamo, S, Lishman, S, Beardsmore, D, Anderson, C, Smith, ML, Secrier, M, Eldridge, MD, Bower, L, Achilleos, A, Lynch, AG, and Tavare, S

Abstract

New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33. Transposase-accessible chromatin sequencing (ATAC-seq) was performed in MFD-1, OE33, and non-neoplastic HET1A cells. Functional studies were performed. MFD-1 had a high SNP genotype concordance with matched germline/tumour. Parental tumour and MFD-1 carried four somatically acquired mutations in three recurrent mutated genes in OAC: TP53, ABCB1 and SEMA5A, not present in FLO-1 or OE33. MFD-1 displayed high expression of epithelial and glandular markers and a unique fingerprint of open chromatin. MFD-1 was tumorigenic in SCID mouse and proliferative and invasive in 3D cultures. The clinical utility of whole genome sequencing projects will be delivered using accurate model systems to develop molecular-phenotype therapeutics. We have described the first such system to arise from the oesophageal International Cancer Genome Consortium project.

Published
2016

27. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40

Author

Stearne, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, L, Truscott, E, Walravens, N, Cook, L, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, F, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, ACI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Kohner, EM, Dornhorst, A, Doddridge, MC, Dumskyj, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Rose, C, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, RW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Martin, S, Davison, HA, Hadden, DR, Kennedy, L, Atkinson, AB, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Bell, PM, McCance, DR, Rutherford, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, LM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Rice, B, Hulland, S, Barron, JL, Yudkin, JS, Gould, BJ, Singer, J, Badenock, A, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Flatman, M, Rainbow, S, Borthwick, LJ, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellington, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, J, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Dornan, TL, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Searnark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, and Grp, UKPDS

Subjects
General Engineering, HC Economic History and Conditions, General Earth and Planetary Sciences, General Medicine, R Medicine (General), General Environmental Science
Abstract

Objectives: To estimate the economic efficiency of tight blood pressure control, with angiotensin converting enzyme inhibitors or beta blockers, compared with less tight control in hypertensive patients with type 2 diabetes. Design: Cost effectiveness analysis incorporating within trial analysis and estimation of impact on life expectancy through use of the within trial hazards of reaching a defined clinical end point. Use of resources driven by trial protocol and use of resources in standard clinical practice were both considered. Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes from UK prospective diabetes study randomised to tight control of blood pressure (n=758) or less tight control (n=390). Main outcome measure: Cost effectiveness ratios based on (a) use of healthcare resources associated with tight control and less tight control and treatment of complications and (b) within trial time free from diabetes related end points, and life years gained. Results: Based on use of resources driven by trial protocol, the incremental cost effectiveness of tight control compared with less tight control was cost saving. Based on use of resources in standard clinical practice, incremental cost per extra year free from end points amounted to £1049 (costs and effects discounted at 6% per year) and £434 (costs discounted at 6% per year and effects not discounted). The incremental cost per life year gained was £720 (costs and effects discounted at 6% per year) and £291 (costs discounted at 6% per year and effects not discounted). Conclusions: Tight control of blood pressure in hypertensive patients with type 2 diabetes substantially reduced the cost of complications, increased the interval without complications and survival, and had a cost effectiveness ratio that compares favourably with many accepted healthcare programmes.

Published
1998

28. Abstracts

Author

Frankenfeld John W., Schulz Wolfgang, McMurty George J., Petersen Gary W., May G. A., Hering F. S., Schwartz J. I., Heywood J. B., Chigier N. A., Grohse E. W., Walker J. D., Colwell R. R., Petrakis L., Pergament H. S., Thorpe R. D., Schoepf Richard W., Krzyczkowski Roman, Henneman Suzanne S., Hudson Charles L., Putnam Evelyn S., Thiesen Donna J., Parks G. A., McCarty Perry L., Leckie J. O., Schrumpf Barry J., Simonson G. H., Paine D. P., Lawrence R. D., Pyott W. T., Leh M., Elders W., Combs J., Caplen T., Harrison F. L., Wong K. M., Heft. R. E., Charnell Robert L., Lehmann Edward J., Mallon Lawrence G., Hatfield Cecile, Adams Gerald H., Johanning James, Talvitie Antti, Noll Kenneth E., Miller Terry, Smiarowski Joseph F., Willis Cleve E., Foster John H., Schlesinger Benjamin, Daetz Douglas, Lear Donald U., Smith Mona F., Hundemann Audrey S., Crockett Pernell W., Werner Kirk G., Carroll Thomas E., Maase David L., Genco Joseph E., Ifeadi Christopher N., Lowman F. G., Christensen S. W., Van Winkle W., Mattice J. S., Harrison Elizabeth A., Barker James C., Chesness Jerry L., Smith Ralph E., Shaheeen Donald G., Raney R. Keith, Borton T., Wezernak C. T., Raney R. K., Sherwani Jabbor K., Moreau David H., Eisenberg Norman A., Lynch Cornelius J., Breeding Roger J., Johnson J. D., Foster K. E., Mouat D. A., Clark R., Hyden John William, Owen, Wilfred, Bayfield, Neil G., Barrow, Graham C., Stolz, Stephanie B., Wienckowski, Louis A., Brown, Betram S., Keyfitz, Nathan, Wilson, W. L., Newman, Peter W. G., Bammi, Deepak, Bammi, Dalip, Goddard, James E., Chisholm, Tony, Walsh, Cliff, Brennan, Geoffrey, Thompson, K. S., Richardson, R., Jensen, Clayton E., Brown, Dail W., Mirabito, John A., Cowing, Thomas G., Binghamton, Suny, Siehl, George H., Albrecht, O. W., Alexander, Ariel, Barde, Jean -Philippe, Darby, William P., McMichael, Francis Clay, Dunlap, Robert W., Muckleston, Keith W., Frankenhoff, Charles A., Giulini, Lorenzo T., Wyatt, T., Black, Peter E., Keating, William Thomas, Leonard, M. E., Fisher, E. L., Brunelle, M. F., Dickinson, J. E., Pethig, Rudiger, Clapham, Jr., W. B., Boserup, Ester, James, Jr., Franklin J., Parenteau, Patrick A., Catz, Robert S., Seneca, Joseph J., Davis, Robert K., Sievering, H., Sinopoli, J., Gamble, Hays B., Bevins, Malcolm I., Cole, Gerald L., Donald, Donn Derr, Tobey, M., Domokos, Mikklos, Weber, Jean, Duckstein, Lucien, Knudson, Douglas M., Barron, J. C., Dickinson, T. E., Schwartz, S. I., Hansen, D. E., Myrup, L. O., Rogers, D. L., Bodege, R., Braatz, U., Heger, H., McConnell, K. E., Duff, Virginia A., Adede, A. O., Zeckhauser, Richard, Kolbye, A. C., Schussel, George, Pisano, Mark A., Bartolotta, R. J., Budnitz, Robert J., Holdren, John P., Wills, Richard H., Sen, P. K., Ghoshal, S. N., Wonders, William C., Bartolotta, Robert J., Leich, Harold H., Gwvnne, P., Miller, S. S., Picardi, Anthony C., Seifer, William W., Bowbrick, P., Hunt, S. E., Keays, J. L., Fisher, Anthony C., Peterson, Frederick M., Cesario, F. J., Knetsch, J. L., Wood, C., Lee, N., Puechl, Karl H., Robert, J., Hansen, David E., Foin, T. C., Wolpert, Julian, Moskow, Michael H., Phillips, Joseph A., Hicks, Jesse L., Nobbs, Christopher L., Pearce, David W., Schoenbau, Thomas J., Rosenberg, Ronald H., Ravenholt, R. T., Kim, K. D., Groves, David L., McCart, Gerald D., Ewald, Jr., W. R., Dando, W. A., Gebelein, C. A., Martin, W. H., Mason, S., Ostrovskii, A. A., Currie, David P., Payne, P. R., Rosentraub, Mark S., Warren, Robert, Irland, Lloyd C., Booth, A., Kolb, Kenneth H., Caldwell, Lynton K., Johnson, W. H., Brewer, Max C., Bowden, Gerald, Haney, Paul D., Logue, D. E., Sweeney, R. J., Egbuniwe, Nnamdi, Heron, N., Franssen, H. T., Wranglen, G., Fairfax, Sally K., Pinhey, Thoma K., Paterson, Karen W., Sitterlev, John H., Connaughton, Charles A., De Viedman, M. G., Leon, F., Coronado, R., Myers, John G., Nakamura, Leonard I., Madrid, Norman R., Bar-Shalom, Y., Cohen, A. J., Seldman, Neil N., Hardy, Jr., William E., Grissom, Curtis L., Quarles, Jr., John R., Gee, Edwin A., Chaudhri, D. P., Infanger, Craig L., Bordeauz, Jr., A. Frank, Dougal, Merwin D., Ganotis, C. G., Hopper, R. E., Boyd, J., Woodard, Kim, Haedrich, R. L., Thompson, R. G., Lievano, R. J., Stoneburner, D. L., Smock, L. A., Eichhorn, H. C., Montalvo, J. G., Lee, C. G., von Jeszensky, T., Dunn, I. J., Wilson, M. J., Swindle, Jr., D. W., Runove, T. G., Pearson, T. H., Rosenberg, R., Sharp, Jr., John M., Greist, David A., Kinard, J. T., Tisdale, J., Alexander, E., Stone, Ralph, Willis, Robert, Anderson, Donald R., Dracup, John A., Rogers, C. J., Hunter, John M., Cassola, Fabio, Lovari, Sandro, Tew, R. W., Egdorf, S. S., Deacon, J. E., Sly, George R., Brandvold, D. K., Popp, C. J., Brierley, J. A., Zeidler, Ryszard B., Gonzalez, R. H., Lapage, S. P., Cornish, Edward S., Ryerson, Foresman, D. K., Walejko, R. N., Paulson, W. H., Pendleton, J. W., Fowler, Bruce A., Minckler, Leon S., Wallis, I. G., Nebel, C., Gottschling, R. D., Unangst, P. C., O'Neill, H. J., Zintel, G. V., Reid, F., Ricci, L. J., Odum, Eugene P., Johnson, J. H., Sturino, E. E., Bourne, S., Richerson, Jim V., Cameron, E. Alan, Brown, Elizabeth A., Stopford, W., Goldwater, L. J., Gray, John, Jorgensen, S. E., Santhirasegaram, K., Chapman, J. D., Skelton, Thomas E., Stahl, D., Herzog, Jr., Henry W., Matsunaka, S., Kuwatsuka, S., Tatsukawa, R., Wakimoto, T., Moyle, Peter B., Kornilov, B. A., Timoshkina, V. A., Johnstone, Peter A., McMinn, James W., Hewlett, John D., Cunha, T. J., Cameron, Guy N., Blais, J. R., Macgregor, Alan, Martin, G. D., Mulholland, R. J., Thornton, K. W., Spano, L. A., Medeiros, J., Ostarhild, H., Minnick, D. R., Hayden, Bruce P., Dolan, Robert, Rendel, J., Lee, J. A., Leistra, M., Frye, R. D., Ramse, David, Safferman, R. S., Morris, Mary -Ellen, Lisella, Frank S., Johnson, Wilma, Lewis, Claudia, Kutt, E. C., Martin, D. F., Prakash, A., Kunkle, S. H., Mrak, E. M., Bruce, R. R., Harper, L. A., Leonard, R. A., Snyder, W. M., Thomas, A. W., Eckholm, Erik P., Snelling, John C., Veblen, Thomas T., Buckhouse, J. C., Gifford, G. F., Fosberg, F. R., Naveh, Z., Kelcey, J. G., Scanlon, John W., Lijinsky, W., Elias, Thomas S., Philip, M. S., Kverno, Nelson B., Mitchell, G. Clay, Gysin, H., Morita, M., Mimura, S., Ohi, G., Yagyu, H., Nishizawa, T., Worcester, B. K., Brun, L. J., Doering, E. J., Hiatt, V., Huff, J. E., Pfeffer, J. T., Liebman, J. C., Ray, William, Ramamurthy, V. C., Black, A. H., Coty, A., Kassler, H., Dixon, R. L., Trout, Thomas J., Smith, James L., McWhorter, David B., Rowe, M. C., Quinlan, A. V., Paynter, H. M., Born, D., Roth, D., Wall, G., Schindler, D. W., Frost, P. G. H., Siegfried, W. R., Cooper, J., MacDonald, S., Mason, C. F., Bar, F., Moore, G., Coldrick, John, Selman, P. H., Dempster, J. P., King, M. L., Lakhani, K. H., Evans, G. Clifford, Coote, D. R., Haith, D. A., Zwerman, P. J., Herricks, Edwin E., Shanholtz, Vernon O., Smith, V. K., Johnson, D. Gale, Mitsch, W. J., Fried, Maurice, Tanji, Kenneth K., Van De Pol, Ronald M., Dawson, Allan, Smith, Malcolm, McLaren, Neil, Cooley, James L., Moran, J. W., Witter, L. D., Tomlinson, E. J., Cheremisinoff, Paul N., Holcomb, William F., Hall, J. M., Kerut, E. G., Irico, J., Bower, L. C., Duggan, J. B., Cleasby, J. L., Klein, David H., Andren, Anders W., Bolton, Newell E., Joshi, Ramesh C., Duncan, Donald M., McMaster, Howard M., Russell, George A., Hochstein, Anatoly B., Elgohary, F. A., Brooks, D. J., Brainard, F. S., Ott, W. R., Thorn, G. C., Panicker, N. N., Middleton, A. C., Lawrence, A. W., Hannigan, John T., Post, R. F., Hall, D. G., White, K. E., Shaw, E. M., Sidwick, J. M., Preston, J. R., Nichol, Janet E., Maxwell, Bruce, Watson, M. B., Kammer, W. A., Langley, N. P., Selzer, L. A., Beck, R. L., Munn, Harold C., Peirano, Lawrence E., Cooper, Charles F., Kruger, Paul, Zebroski, E., Levenson, M., Mason, B. J., Rehberger, Glenn W., Field, A. A., Jones, John F., Penner, S. S., Black, Francis M., High, Larry E., Sigsby, John E., Janssens, M., Darns, R., Giebel, J., Dilaj, Michael, Lenard, John F., Beran, D. W., Linden, H. R., Bodle, W. W., Lee, B. S., Vyas, K. C., Golueke, Clarence G., McCurdy, P. H., Hines, W. G., Rickert, D. A., McKenzie, S. W., Bennett, J. P., Goldstein, Elliot, Ragaini, Richard C., Pearl, Richard Howard, Turner, Norma, Miller, Terry L., Noll, Kenneth E., Etzel, James E., Bell, John M., Lindermann, Eckhart G., Lancelot, Charles J., Lane, Dennis D., Stukel, James J., Lee, G. F., Morse, Frederick H., Simmons, Melvin K., Alpert, S. B., Lundberg, R. M., Schmidt, Richard A., Hill, George R., Anspaugh, Lynn R., Harem, F. E., Bielman, K. O., Worth, J. E., Kuester, J. L., Lutes, L., Henten, M. Patricia, Tazieff, Haroun, Patrick, P. K., Baker, Ralph N., Kalhammer, Fritz R., Schneider, Thomas R., Landwehr, J. Maciunas, Deininger, R. A., Rattien, Stephen, Eaton, David, Dezeeuw, R. E., Haney, E. B., Wong, R. B., De Planque Burke, Gail, Siegrist, Robert, Witt, Michael, Boyle, William C., Rickert, David A., Hines, Walter G., McKenzie, Stuart W., Brutsaert, W., Gross, G. W., McGehee, R. M., Hyzer, William G., Mohr, Adolph W., Wildman, S. V., Goldsmith, T. J., Sargent, Frederick O., Brande, Justin H., Work, Jr., Edgar A., Gilmer, David S., Hord, B. Michael, Brooner, William, Baraby, Frank, Snodgrass, W. J., O'Melia, C. R., Rollier, M. A., Kunz, R. G., Giannelli, J. F., Stensel, H. D., Moyer, W. W., Osman, F. P., Campbell, W. J., Wilson, E. M., Freeman, H. M., Hogan, B. J., Dick, R. I., Tangborn, Wendell V., Rasmussen, Lowell A., Ruff, James F., Skinner, Morris M., Winkley, Brian R., Simons, Daryl B., Dorratcague, Dennis E., Lanterman, B. A., Staudenmire, J. H., Fritz, Norman L., Williams, Richard D., Wood, Richard, Huillet, F. D., Muzyka, Ann, Fantasia, John F., Goodman, Joseph M., Anderl, Bernhard, Attmanspacher, Walter, Singh, Vijay P., Peleg, H., Scavia, D., Park, R. A., Niemann, Jr., Bernard J., Bonilla, Xavier A., Bruno, S. Richards, Rose, Richard A., Meyer, Charles F., Tempo, G E, Klumb, D., Maddock, Jr., Thomas, Chermisinoff, Paul N., Bethea, Robert M., Hellman, Thomas M., Laren, Oscar Bud, Leenheer, J. A., Malcolm, R. L., White, W. R., McNamara, John R., Windheim, L. S., Wodder, R. R., Smith, D. D., Mallan, G. M., Titlow, E. I., Peleg, M., Greco, I. R., Gregory, D. P., Pangborn, J. B., Somers, Edward V., Berg, Daniel, Fickett, Arnold P., Larsen, R. I., Heck, W. W., Cochran, Neal P., Ulaby, Fawwaz T., Bush, Thomas F., Cunningham, Ernest R., Nakada, M., Wyndham, H. B., Schulte, Harry F., Serpa, Douglas P., Young, R. L., Spell, J. E., Slu, H. M., Philip, R. H., Jones, E. R., Sprowl, James A., Kohout, Ladislav J., Gaines, Brian R., McCoy, K., Mejer, H., Reutlinger, Shlomo, Lieberman, M. A., LaNier, R., Crampton, C. B., Sabadell, J. Eleonora, Axtmann, Robert C., Josephson, J., Gutierrez, A. P., Regev, U., Summers, C. G., Daniels, A., Bach, W., Mairs, John W., Bengtsson, L., Oleckno, William A., Wildman, W. E., Neja, R. A., Clark, J. K., Larson, Don, Wagner, Frederick W., Durabb, Edwin J., Barnes, H. M., Homolya, J. B., Jacoby, Neil H., Kispert, R. G., Sadek, S. E., Wise, D. L., Nihoul, J. C. J., Foyster, A. M., Gessaman, Paul H., Sisler, Daniel G., Pinkham, C. F. A., Pearson, J. G., MacAdam, W. K., Gribbin, John, Schwartz, Seymour I., Green, F. H. W., Viscomi, B. V., Gray, S. L., McKean, J. R., Usher, M. B., Svestka, Milan, Eckholm, E. P., Johnston, H., Mausel, Paul W., Leivo, Carl Eric, Lewellen, Michael T., Nilles, Jack M., Gray, Paul, Campbell, Thomas C., Wogman, N. A., Bockris, John M., Jenne, E. A., Avotins, Peter, Nelson, D. W., Sommers, L. E., Scott, Frank M., Benz, L. C., Sandoval, F. M., Willis, W. O., Chapman, Peter F., MacDougall, E. B., Peakall, David B., Office of Technology Assessment, and Office of Science and Technology

Published
1977
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30. Characterization of Porcine Epidemic Diarrhea Virus Isolate US/Iowa/18984/2013 Infection in 1-Day-Old Cesarean-Derived Colostrum-Deprived Piglets

Author

Madson, D. M., primary, Arruda, P. H. E., additional, Magstadt, D. R., additional, Burrough, E. R., additional, Hoang, H., additional, Sun, D., additional, Bower, L. P., additional, Bhandari, M., additional, Gauger, P. C., additional, Stevenson, G. W., additional, Wilberts, B. L., additional, Wang, C., additional, Zhang, J., additional, and Yoon, K. J., additional

Published
2015
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31. The importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice

Author

David Mark Pritchard, Bower L, Cs, Potten, Al, Jackman, and Ja, Hickman

Subjects
Male, Antimetabolites, Antineoplastic, Mice, Inbred BALB C, Mitosis, Apoptosis, Thiophenes, Intestines, Mice, Species Specificity, Mice, Inbred DBA, Quinazolines, Animals, Fluorouracil, Tumor Suppressor Protein p53
Abstract

The thymidylate synthase inhibitor raltitrexed (ZD1694, Tomudex) induces greater intestinal toxicity, manifested as diarrhea and weight loss, in BALB/c than in DBA/2 mice. No convincing pharmacokinetic or pharmacodynamic reason for this strain difference has been established. We have investigated whether this strain difference in response to raltitrexed is related to differential susceptibilities of intestinal mucosae to undergo apoptosis and also whether p53 expression, a critical factor in 5-fluorouracil-induced intestinal apoptosis and toxicity, modulates this response. Ten mg/kg or 100 mg/kg raltitrexed were administered as single or double i.p. injections 24 h apart to BALB/c, DBA/2, and p53-/- mice. Apoptosis, mitosis, and tissue damage were assessed in intestinal epithelium, and animal weight was recorded. BALB/c mice developed diarrhea and weight loss following 100 mg/kg x2 raltitrexed, whereas DBA/2 mice did not. BALB/c mice were more sensitive than DBA/2 to induction of small-intestinal and colonic apoptosis 24 h following 100 mg/kg raltitrexed. Inhibition of mitosis was equivalent in both strains. Both strains showed histopathological damage to the small intestine after 100 mg/kg x2 raltitrexed, but only BALB/c mice demonstrated colonic damage. p53-null mice showed the same level of small intestinal apoptosis as their wild-type counterparts 24 h after 100 mg/kg x1 raltitrexed and also the same levels of intestinal toxicity 3, 5, and 7 days after 100 mg/kg x2 raltitrexed. Thus, BALB/c mice were more susceptible to induction of intestinal apoptosis by raltitrexed than DBA/2 mice and also demonstrated more histopathological damage in the colon correlating with the induction of diarrhea and weight loss. In contrast to 5-fluorouracil, the intestinal apoptosis and toxicity induced by raltitrexed were p53-independent.

Published
2000

32. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Author

Turner, RC, Holman, RR, Cull, CA, Stratton, IM, Matthews, DR, Frighi, V, Manley, SE, Neil, A, McElroy, K, Wright, D, Kohner, E, Fox, C, Hadden, D, Mehta, Z, Smith, A, Nugent, Z, Peto, R, Adlel, AI, Mann, JI, Bassett, PA, Oakes, SF, Dornan, TL, Aldington, S, Lipinski, H, Collum, R, Harrison, K, MacIntyre, C, Skinner, S, Mortemore, A, Nelson, D, Cockley, S, Levien, S, Bodsworth, L, Willox, R, Biggs, T, Dove, S, Beattie, E, Gradwell, M, Staples, S, Lam, R, Taylor, F, Leung, L, Carter, RD, Brownlee, SM, Fisher, KE, Islam, K, Jelfs, R, Williams, PA, Williams, FA, Sutton, PJ, Ayres, A, Logie, LJ, Lovatt, C, Evans, MA, Stowell, LA, Ross, I, Kennedy, IA, Croft, D, Keen, AH, Rose, C, Raikou, M, Fletcher, AE, Bulpitt, C, Battersby, C, Yudkin, JS, Stevens, R, Stearn, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, L, Truscott, E, Walravens, N, Cook, L, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, F, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, ACI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Oakley, NW, Whitehead, MA, Hollier, GP, Pilkington, T, Simpson, J, Anderson, M, Martin, S, Kean, J, Rice, B, Rolland, A, Nisbet, J, Kohner, EM, Dornhorst, A, Doddridge, MC, Dumskyij, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, RW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Davison, HA, Alexander, L, Scarpello, JHB, Shiers, DE, Tucker, RJ, Worthington, JRH, Angris, S, Bates, A, Walton, J, Teasdale, M, Browne, J, Stanley, S, Davis, BA, Strange, RC, Hadden, DR, Kennedy, L, Atkinson, AB, Bell, PM, McCance, DR, Rutherford, J, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, LM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Hulland, S, Barron, JL, Gould, BC, Singer, J, Badenoch, A, McGregor, M, Isenberg, L, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, Lankester, JA, Howard, E, Waite, A, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Fatman, M, Rainbow, S, Borthwick, L, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Day, JL, Doshi, MJ, Wilson, JG, Howard-Williams, JR, Humphreys, H, Graham, A, Hicks, K, Hexman, S, Bayliss, P, Pledger, D, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellingford, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, H, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Mansingh, S, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Seamark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, Neil, HAW, Butterfield, WJH, Doll, WRS, Eastman, R, Ferris, FR, Kurinij, N, McPherson, K, Mahler, RF, Meade, TW, Shafer, G, Watkins, PJ, Keen, H, Siegel, D, Betteridge, DJ, Cohen, RD, Currie, D, Darbyshire, J, Forrester, JV, Guppy, T, Johnston, DG, McGuire, A, Murphy, M, el-Nahas, AM, Pentecost, B, Spiegelhalter, D, Alberti, KGMM, Denton, R, Home, PD, Howell, S, Jarrett, JR, Marks, V, Marmot, M, Ward, JD, and Grp, UKPDS

Subjects
General Medicine
Published
1998

33. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group

Author

Stearne, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, J, Truscott, E, Walravens, N, Cook, L, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, MJ, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, ACI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Kohner, EM, Dornhurst, A, Doddridge, MC, Dumskyj, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Rose, C, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, RW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Martin, S, Davison, HA, Hadden, DR, Kennedy, L, Atkinson, AB, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Bell, PM, McCance, DR, Rutherford, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, LM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Rice, B, Hulland, S, Barron, JL, Yudkin, JS, Gould, BJ, Singer, J, Badenock, A, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Flatman, M, Rainbow, S, Borthwick, LJ, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellingford, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, H, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Dornan, TL, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Searnark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, and Grp, USPDS

Abstract

OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of

Published
1998

34. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group

Author

Stearne, MR, Palmer, SL, Hammersley, MS, Franklin, SL, Spivey, RS, Levy, JC, Tidy, CR, Bell, NJ, Steemson, J, Barrow, BA, Coster, R, Waring, K, Nolan, L, Truscott, E, Walravens, N, Cook, BL, Lampard, H, Merle, C, Parker, P, McVittie, J, Draisey, I, Murchison, LE, Brunt, AHE, Williams, MJ, Pearson, DW, Petrie, XMP, Lean, MEJ, Walmsley, D, Lyall, F, Christie, E, Church, J, Thomson, E, Farrow, A, Stowers, JM, Stowers, M, McHardy, K, Patterson, N, Wright, AD, Levi, NA, Shearer, AGI, Thompson, RJW, Taylor, G, Rayton, S, Bradbury, M, Glover, A, Smyth-Osbourne, A, Parkes, C, Graham, J, England, P, Gyde, S, Eagle, C, Chakrabarti, B, Smith, J, Sherwell, J, Kohner, EM, Dornhorst, A, Doddridge, MC, Dumskyj, M, Walji, S, Sharp, P, Sleightholm, M, Vanterpool, G, Rose, C, Frost, G, Roseblade, M, Elliott, S, Forrester, S, Foster, M, Myers, K, Chapman, R, Hayes, JR, Henry, TW, Featherston, MS, Archbold, GPR, Copeland, M, Harper, R, Richardson, I, Martin, S, Davison, HA, Hadden, DR, Kennedy, L, Atkinson, AB, Culbert, AM, Hegan, C, Tennet, H, Webb, N, Robinson, I, Holmes, J, Bell, PM, McCance, DR, Rutherford, J, Nesbitt, S, Spathis, AS, Hyer, S, Nanson, ME, James, JM, Tyrell, JM, Davis, C, Strugnell, P, Booth, M, Petrie, H, Clark, D, Rice, B, Hulland, S, Barron, JL, Yudkin, JS, Gould, BJ, Singer, J, Badenock, A, Eckert, M, Alibhai, K, Marriot, E, Cox, C, Price, R, Fernandez, M, Ryle, A, Clarke, S, Wallace, G, Mehmed, E, MacFarlane, S, Greenwood, RH, Wilson, J, Denholm, MJ, Temple, RC, Whitfield, K, Johnson, F, Munroe, C, Gorick, S, Duckworth, E, Flatman, M, Rainbow, S, Borthwick, LJ, Wheatcroft, DJ, Seaman, RJ, Christie, RA, Wheatcroft, W, Musk, P, White, J, McDougal, S, Bond, M, Raniga, P, Newton, RW, Jung, RT, Roxburgh, C, Kilgallon, B, Dick, L, Waugh, N, Kilby, S, Ellingford, A, Burns, J, Fox, CV, Holloway, MC, Coghill, HM, Hein, N, Fox, A, Cowan, W, Richard, M, Quested, K, Evans, SJ, Paisey, RB, Brown, NPR, Tucker, AJ, Paisey, R, Garrett, F, Hogg, J, Park, P, Williams, K, Harvey, P, Wilcocks, R, Mason, S, Frost, J, Warren, C, Rocket, P, Bower, L, Roland, JM, Brown, DJ, Youens, J, Stanton-King, K, Mungall, H, Ball, V, Maddison, W, Donnelly, D, King, S, Griffin, P, Smith, S, Church, S, Dunn, G, Wilson, A, Palmer, K, Brown, PM, Humphriss, D, Davidson, AJM, Rose, R, Armistead, L, Townsend, S, Poon, P, Peacock, IDA, Culverwell, NJC, Charlton, MH, Connolly, BPS, Peacock, J, Barrett, J, Wain, J, Beeston, W, King, G, Hill, PG, Boulton, AJM, Robertson, AM, Katoulis, V, Olukoga, A, McDonald, H, Kumar, S, Abouaesha, F, Abuaisha, B, Knowles, EA, Higgins, S, Booker, J, Sunter, J, Breislin, K, Parker, R, Raval, P, Curwell, J, Davenport, H, Shawcross, G, Prest, A, Grey, J, Cole, H, Sereviratne, C, Young, RJ, Dornan, TL, Clyne, JR, Gibson, M, O'Connell, I, Wong, LM, Wilson, SJ, Wright, KL, Wallace, C, McDowell, D, Burden, AC, Sellen, EM, Gregory, R, Roshan, M, Vaghela, N, Burden, M, Sherriff, C, Clarke, J, Grenfell, J, Tooke, JE, MacLeod, K, Searnark, C, Rammell, M, Pym, C, Stockman, J, Yeo, C, Piper, J, Leighton, L, Green, E, Hoyle, M, Jones, K, Hudson, A, James, AJ, Shore, A, Higham, A, Martin, B, and Grp, USPDS

Subjects
cardiovascular diseases, circulatory and respiratory physiology
Abstract

OBJECTIVE: To determine whether tight control of blood pressure with either a beta blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes. DESIGN: Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a beta blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of =300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg). CONCLUSION: Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.

Published
1998

35. Characterization of Porcine Epidemic Diarrhea Virus Isolate US/Iowa/18984/2013 Infection in 1-Day-Old Cesarean-Derived Colostrum-Deprived Piglets.

Author

Madson, D. M., Arruda, P. H. E., Magstadt, D. R., Burrough, E. R., Hoang, H., Sun, D., Bower, L. P., Bhandari, M., Gauger, P. C., Stevenson, G. W., Wilberts, B. L., Wang, C., Zhang, J., and Yoon, K. J.

Subjects
PORCINE epidemic diarrhea virus, VIRUS diseases in swine, DIARRHEA, IMMUNOHISTOCHEMISTRY, VIREMIA, SWINE
Abstract

Porcine epidemic diarrhea virus (PEDV) was first recognized in North America in April 2013 and has since caused devastating disease. The objective of this study was to characterize disease and viral detection associated with an original North American PEDV isolate inoculated in neonatal piglets. Thirty-six 1-day-old cesarean-derived and colostrum-deprived piglets were randomly assigned to the control (n = 16) or challenged group (n = 20); the latter were orogastrically inoculated with 1 ml of US/Iowa/18984/2013 PEDV isolate titered at 1 × 103 plaque-forming units per milliliter. Rectal swabs were collected from all piglets prior to inoculation and every 12 hours postinoculation (hpi) thereafter, with 4 control and 5 challenged piglets euthanized at 12, 24, 48, and 72 hpi. One piglet had a positive real-time quantitative polymerase chain reaction test on rectal swab at 12 hpi, and all remaining piglets were positive thereafter, with highest viral quantities detected at 24 and 36 hpi. Diarrhea was evident in 30% and 100% of challenged piglets at 18 and 24 hpi, respectively. Viral antigen was detected in enterocytes by immunohistochemistry in the duodenum and ileum of piglets euthanized at 12 hpi and was apparent throughout the small intestine of all piglets thereafter, with villus height:crypt depth ratios consistently below 4:1. Viremia was confirmed in 18 of 20 pigs at euthanasia. Clinical disease was severe and developed rapidly following infection with an original North American PEDV isolate, with lesions, viremia, and antigen detection possible by 12 hpi. [ABSTRACT FROM AUTHOR]

Published
2016
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36. Major submissions tool developments at the European nucleotide archive

Author

Amid, C., primary, Birney, E., additional, Bower, L., additional, Cerdeno-Tarraga, A., additional, Cheng, Y., additional, Cleland, I., additional, Faruque, N., additional, Gibson, R., additional, Goodgame, N., additional, Hunter, C., additional, Jang, M., additional, Leinonen, R., additional, Liu, X., additional, Oisel, A., additional, Pakseresht, N., additional, Plaister, S., additional, Radhakrishnan, R., additional, Reddy, K., additional, Riviere, S., additional, Rossello, M., additional, Senf, A., additional, Smirnov, D., additional, Ten Hoopen, P., additional, Vaughan, D., additional, Vaughan, R., additional, Zalunin, V., additional, and Cochrane, G., additional

Published
2011
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37. The European Nucleotide Archive

Author

Leinonen, R., primary, Akhtar, R., additional, Birney, E., additional, Bower, L., additional, Cerdeno-Tarraga, A., additional, Cheng, Y., additional, Cleland, I., additional, Faruque, N., additional, Goodgame, N., additional, Gibson, R., additional, Hoad, G., additional, Jang, M., additional, Pakseresht, N., additional, Plaister, S., additional, Radhakrishnan, R., additional, Reddy, K., additional, Sobhany, S., additional, Ten Hoopen, P., additional, Vaughan, R., additional, Zalunin, V., additional, and Cochrane, G., additional

Published
2010
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39. Petabyte-scale innovations at the European Nucleotide Archive

Author

Cochrane, G., primary, Akhtar, R., additional, Bonfield, J., additional, Bower, L., additional, Demiralp, F., additional, Faruque, N., additional, Gibson, R., additional, Hoad, G., additional, Hubbard, T., additional, Hunter, C., additional, Jang, M., additional, Juhos, S., additional, Leinonen, R., additional, Leonard, S., additional, Lin, Q., additional, Lopez, R., additional, Lorenc, D., additional, McWilliam, H., additional, Mukherjee, G., additional, Plaister, S., additional, Radhakrishnan, R., additional, Robinson, S., additional, Sobhany, S., additional, Hoopen, P. T., additional, Vaughan, R., additional, Zalunin, V., additional, and Birney, E., additional

Published
2009
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40. Priorities for nucleotide trace, sequence and annotation data capture at the Ensembl Trace Archive and the EMBL Nucleotide Sequence Database

Author

Cochrane, G., primary, Akhtar, R., additional, Aldebert, P., additional, Althorpe, N., additional, Baldwin, A., additional, Bates, K., additional, Bhattacharyya, S., additional, Bonfield, J., additional, Bower, L., additional, Browne, P., additional, Castro, M., additional, Cox, T., additional, Demiralp, F., additional, Eberhardt, R., additional, Faruque, N., additional, Hoad, G., additional, Jang, M., additional, Kulikova, T., additional, Labarga, A., additional, Leinonen, R., additional, Leonard, S., additional, Lin, Q., additional, Lopez, R., additional, Lorenc, D., additional, McWilliam, H., additional, Mukherjee, G., additional, Nardone, F., additional, Plaister, S., additional, Robinson, S., additional, Sobhany, S., additional, Vaughan, R., additional, Wu, D., additional, Zhu, W., additional, Apweiler, R., additional, Hubbard, T., additional, and Birney, E., additional

Published
2007
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41. EMBL Nucleotide Sequence Database in 2006

Author

Kulikova, T., primary, Akhtar, R., additional, Aldebert, P., additional, Althorpe, N., additional, Andersson, M., additional, Baldwin, A., additional, Bates, K., additional, Bhattacharyya, S., additional, Bower, L., additional, Browne, P., additional, Castro, M., additional, Cochrane, G., additional, Duggan, K., additional, Eberhardt, R., additional, Faruque, N., additional, Hoad, G., additional, Kanz, C., additional, Lee, C., additional, Leinonen, R., additional, Lin, Q., additional, Lombard, V., additional, Lopez, R., additional, Lorenc, D., additional, McWilliam, H., additional, Mukherjee, G., additional, Nardone, F., additional, Pastor, M. P. G., additional, Plaister, S., additional, Sobhany, S., additional, Stoehr, P., additional, Vaughan, R., additional, Wu, D., additional, Zhu, W., additional, and Apweiler, R., additional

Published
2007
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