20 results on '"Laye J"'
Search Results
2. Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy.
- Author
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Wilson, David, Abbotts, R, Jewell, R, Nsengimana, J, Maloney, DJ, Simeonov, A, Seedhouse, C, Elliott, F, Laye, J, Walker, C, and Jadhav, A
- Abstract
Phosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease activi
- Published
- 2014
3. Influence of processing parameters on the tool and workpiece mechanical interaction during Friction Stir Welding
- Author
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Zimmer, S., Langlois, L., Laye, J., Goussain, J.-C., Martin, P., and Bigot, R.
- Published
- 2009
- Full Text
- View/download PDF
4. High-Resolution Copy Number Patterns From Clinically Relevant FFPE Material
- Author
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Filia, A, Droop, A, Harland, M, Thygesen, H, Randerson-Moor, J, Snowden, H, Taylor, C, Diaz, JMS, Pozniak, J, Nsengimana, J, Laye, J, Newton-Bishop, JA, and Bishop, DT
- Subjects
Paraffin Embedding ,Tissue Fixation ,Science & Technology ,Molecular medicine ,DNA Copy Number Variations ,IDENTIFICATION ,MUTATIONS ,lcsh:R ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,lcsh:Medicine ,MELANOMA ,AMPLIFICATION ,Article ,VALIDATION ,Multidisciplinary Sciences ,GENOME ,Neoplasms ,Humans ,Science & Technology - Other Topics ,TOOL ,lcsh:Q ,lcsh:Science ,Melanoma ,Cancer - Abstract
Systematic tumour profiling is essential for biomarker research and clinically for assessing response to therapy. Solving the challenge of delivering informative copy number (CN) profiles from formalin-fixed paraffin embedded (FFPE) material, the only likely readily available biospecimen for most cancers, involves successful processing of small quantities of degraded DNA. To investigate the potential for analysis of such lesions, whole-genome CNVseq was applied to 300 FFPE primary tumour samples, obtained from a large-scale epidemiological study of melanoma. The quality and the discriminatory power of CNVseq was assessed. Libraries were successfully generated for 93% of blocks, with input DNA quantity being the only predictor of success (success rate dropped to 65% if
- Published
- 2019
5. β-catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas
- Author
-
Nsengimana, J, Laye, J, Filia, A, O'Shea, S, Muralidhar, S, Poźniak, J, Droop, A, Chan, M, Walker, C, Parkinson, L, Gascoyne, J, Mell, T, Polso, M, Jewell, R, Randerson-Moor, J, Cook, GP, Bishop, DT, and Newton-Bishop, J
- Abstract
Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin–mediated failure to recruit CD141+ DCs. A second subgroup displayed an equally bad prognosis when histopathological factors were adjusted for, while 4 others maintained comparable survival profiles. The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation. The survival benefit of high immune scores was strongest in patients with double-WT tumors for BRAF and NRAS, less strong in BRAF-V600 mutants, and absent in NRAS (codons 12, 13, 61) mutants. In summary, we report evidence for a β-catenin–mediated immune evasion in 42% of melanoma primaries overall and in 73% of those with the worst outcome. We further report evidence for an interaction between oncogenic mutations and host response to melanoma, suggesting that patient stratification will improve immunotherapeutic outcomes.
- Published
- 2018
6. Transcriptomic profiling the microenvironment in primary melanoma
- Author
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O'Shea, SJ, Merchant, W, Laye, J, Nsengimana, J, Elliott, F, Treanor, D, Bishop, T, and Newton-Bishop, J
- Published
- 2017
7. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
- Author
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Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, Jw, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Solomon, Rs, Kraft, P, Wolpin, Bm, Jansen, Pwtc, Olson, S, Mcglynn, Ka, Kanetsky, Pa, Chatterjee, N, Barrett, Jh, Dunning, Am, Taylor, Jc, Newton Bishop, Ja, Bishop, Dt, Andresson, T, Petersen, Gm, Amos, Ci, Iles, Mm, Nathanson, Kl, Landi, Mt, Vermeulen, M, Brown, Km, Amundadottir, Lt, Canzian, F, Kooperberg, C, Arslan, Aa, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Jacobs, Ej, Kamineni, A, Van Den Eeden, S, Klein, Ap, Kolonel, Ln, Li, D, Olson, Sh, Risch, Ha, Sesso, Hd, Visvanathan, K, Zheng, W, Albanes, D, Austin, Ma, Boutron Ruault, Mc, Bueno de Mesquita, Hb, Cotterchio, M, Gaziano, Jm, Giovannucci, El, Goggins, M, Gross, M, Hassan, M, Helzlsouer, Kj, Holly, Ea, Hunter, Dj, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Krogh, V, Kurtz, Rc, Lacroix, A, Le Marchand, L, Mannisto, S, Patel, Av, Peeters, Phm, Riboli, E, Shu, Xo, Sund, M, Thornquist, M, Tjønneland, A, Tobias, Gs, Trichopoulos, D, Wactawski Wende, J, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, Sj, Stevens, V, Caporaso, Ne, Brennan, P, Mckay, J, Wu, X, Hung, Rj, Mclaughlin, Jr, Bickeboller, H, Risch, A, Wichmann, E, Houlston, R, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, Pg, Iglesias Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Batille, Ja, Marti, Gt, Hayward, N, Martin, N, Montgomery, G, Duffy, D, Whiteman, D, Gregor, Sm, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Ghiorzo, Paola, Bianchi, Giovanna, Pastorino, Lorenza, Bruno, William, Andreotti, Virginia, Queirolo, P, Spagnolo, Francesco, Mackie, R, Lang, J, Gruis, N, van Nieuwpoort, Fa, Out, C, Bergman, W, Kukutsch, N, Bavinck, Jnb, Bakker, B, van der Stoep, N, Ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jonsson, G, Borg, A, Harbst, K, Nielsen, K, Zander, As, Molvern, A, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Bressac de Paillerets, B, Demenais, F, Avril, Mf, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, D, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Hoiom, V, Freidman, E, Azizi, E, Baron Epel, O, Scope, A, Pavlotsky, F, Cohen Manheim, I, Laitman, Y, Harland, M, Randerson Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, Ma, Goldstein, Am, and Yang, X. r.
- Subjects
0301 basic medicine ,Male ,Lung Neoplasms ,Skin Neoplasms ,General Physics and Astronomy ,Genome-wide association study ,VARIANTS ,Histones ,Skin cancer ,RNA, Small Interfering ,Melanoma ,Telomerase ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Pancreas cancer ,Regulation of gene expression ,Genetics ,Zinc finger ,Gene knockdown ,Multidisciplinary ,Proteomics and Chromatin Biology ,TRICL Consortium ,Chromosome Mapping ,GenoMEL Consortium ,PANCREATIC-CANCER ,Multidisciplinary Sciences ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Science & Technology - Other Topics ,Chromosomes, Human, Pair 5 ,Female ,Lung cancer ,Signal Transduction ,SUSCEPTIBILITY LOCI ,Science ,Locus (genetics) ,Single-nucleotide polymorphism ,PROMOTES GROWTH ,Biology ,Polymorphism, Single Nucleotide ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,LUNG-CANCER ,Testicular Neoplasms ,Cell Line, Tumor ,MD Multidisciplinary ,Humans ,Genetic Predisposition to Disease ,QUANTITATIVE PROTEOMICS ,GENOME-WIDE ASSOCIATION ,Gene ,PanScan Consortium ,Càncer de pell ,Càncer de pàncrees ,Alleles ,Science & Technology ,Kirurgi ,HUMAN-CELLS ,Telomere Homeostasis ,Correction ,General Chemistry ,Molecular biology ,TERT-CLPTM1L LOCUS ,Telomere ,Pancreatic Neoplasms ,030104 developmental biology ,Genetic Loci ,TELOMERE LENGTH ,Càncer de pulmó ,Surgery ,Genètica ,Genome-Wide Association Study ,Transcription Factors - Abstract
Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.
- Published
- 2017
8. Eco-certification et marchés du bois. Rapport final
- Author
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Costa, Sebastian, Ibanez, L., Laye, J., Montagné, C., Rousselle, J.M., Laboratoire d'Economie Forestière (LEF), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and AgroParisTech-Institut National de la Recherche Agronomique (INRA)
- Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences ,FENETRE ,Consommation ,distribution et transformation - Abstract
Diffusion du document : INRA Unité Mixte de Recherche LEF Laboratoire d'Economie forestière ENGREF 14 rue Girardet CS 4216 54042 Nancy Cedex (FRA); Le rapport s'intéresse tout d'abord à la différenciation des produits. Une enquête auprès des consommateurs et des prescripteurs permet de préciser quel type de différenciation existe entre le bois et les matériaux concurrents dans le marché de la construction. Un modèle théorique étudie l'impact d'une différenciation par la qualité environnementale sur ces marchés, et intègre dans un deuxième temps la certification à l'analyse. Enfin, on s'interroge sur les conséquences possibles de l'écocertification sur le partage des profits entre producteurs et distributeurs.
- Published
- 2014
9. Stratégies d'écocertification : ou comment le rêve des uns peut faire le bonheur des autres
- Author
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Ibanez, L., Laye, J., Laboratoire d'Economie Forestière (LEF), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)
- Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences ,Consommation ,distribution et transformation - Abstract
Cahiers Scientifiques du Bois ; 3; L'article s'interroge sur les motivations d'une gestion durable de la ressource forestière par l'adhésion au label d'écocertification de la part des propriétaires forestiers, et de la mise en vente de produits écocertifiés de la part des distributeurs. Il s'agit d'une analyse d'impact ex post pour la filière lorsque l'écocertification permet de renforcer le pouvoir de marché des producteurs par une coordination. Un modèle de relations verticales intégrant la possibilité pour les distributeurs de former une coalition montre que le surplus total est toujours diminué par cette coordination et que le distributeur écocertifié, à l'instigation de cette stratégie de certification, peut s'en voir lésé si les consommateurs ne perçoivent pas une différenciation suffisamment importante entre produit écocertifié et produit standard. Dans ce cas, les producteurs et le distributeur standard sont les seuls à bénéficier de l'écocertification.
- Published
- 2004
10. Ecocertification : stratégie de différenciation des distributeurs et coordination des producteurs
- Author
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Ibanez, L., Laye, J., Laboratoire d'Economie Forestière (LEF), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)
- Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences ,Consommation ,distribution et transformation - Abstract
Diffusion du document : INRA Unité Mixte de Recherche LEF Laboratoire d'Economie forestière ENGREF 14 rue Girardet CS 4216 54042 Nancy Cedex (FRA); L'article s'interroge sur les motivations d'une gestion durable de la ressource forestière par l'adhésion au label d'écocertification de la part des propriétaires forestiers, et de la mise en vente de tels produits de la part des distributeurs. Il s'agit d'une analyse d'impact ex post pour le distributeur si l'écocertification permet de renforcer le pouvoir de marché des producteurs par une coordination. La modélisation, intégrant des relations verticales avec possibilité de coalitions, montre qu'en supposant que le regroupement des producteurs permet une négociation plus favorable pour ces derniers, l'écocertification est susceptible de nuire au profit du distributeur écocertifié mais en revanche bénéficie à tous les autres acteurs de la filière, ainsi qu'aux consommateurs. Le modèle montre également que l'écocertification bénéficie toujours au bien-être social.
- Published
- 2004
11. Systemic Inflammation, the Peripheral Blood Transcriptome, and Primary Melanoma.
- Author
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Randerson-Moor J, Davies J, Harland M, Nsengimana J, Bigirumurame T, Walker C, Laye J, Appleton ES, Ball G, Cook GP, Bishop DT, Salmond RJ, and Newton-Bishop J
- Abstract
Peripheral blood transcriptomes from 383 patients with newly diagnosed melanoma were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor-infiltrating lymphocytes) and evidence of systemic inflammation (high-sensitivity CRP and fibrinogen levels). Higher fibrinogen levels were associated with thicker primary tumors. In single-gene analysis, high-sensitivity CRP levels were significantly associated with higher blood CD274 expression (coding for PD-L1), but each was independently prognostic, with high-sensitivity CRP associated with increased mortality and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signaling pathways in the blood of people with thicker tumors and notable upregulation of signal transducer and activator of transcription 1 gene STAT1 in people with brisk tumor-infiltrating lymphocytes. Transcriptomic data provided evidence for increased NF-kB signaling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274, suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer tumor-infiltrating lymphocytes at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma, suggesting that systemic inflammation contributes to that reduced immune function., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
12. Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro-tumourigenicity.
- Author
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Davies J, Muralidhar S, Randerson-Moor J, Harland M, O'Shea S, Diaz J, Walker C, Nsengimana J, Laye J, Mell T, Chan M, Appleton L, Birkeälv S, Adams DJ, Cook GP, Ball G, Bishop DT, and Newton-Bishop JA
- Subjects
- Humans, Inflammation genetics, Systems Biology, Ulcer pathology, Melanoma metabolism, Skin Neoplasms genetics, Skin Neoplasms metabolism
- Abstract
Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort. Ulcerated melanomas were thicker and more mitotically active (with corresponding transcriptomic upregulated cell cycle pathways). Sequencing identified tumoural p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumours had perturbed expression of cytokine genes, consistent with protumourigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multiomic data using neural networks highlighted a role for the β-catenin pathway in the ulceration, linking genomic changes in the tumour to immunosuppression and cell proliferation. In summary, the data suggest that ulceration is in part associated with genomic changes but that host factors also predict melanoma death with evidence of reduced immune responses to the tumour., (© 2021 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
13. High-Resolution Copy Number Patterns From Clinically Relevant FFPE Material.
- Author
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Filia A, Droop A, Harland M, Thygesen H, Randerson-Moor J, Snowden H, Taylor C, Diaz JMS, Pozniak J, Nsengimana J, Laye J, Newton-Bishop JA, and Bishop DT
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Neoplasms pathology, Reproducibility of Results, Tissue Fixation, DNA Copy Number Variations, Neoplasms genetics, Paraffin Embedding
- Abstract
Systematic tumour profiling is essential for biomarker research and clinically for assessing response to therapy. Solving the challenge of delivering informative copy number (CN) profiles from formalin-fixed paraffin embedded (FFPE) material, the only likely readily available biospecimen for most cancers, involves successful processing of small quantities of degraded DNA. To investigate the potential for analysis of such lesions, whole-genome CNVseq was applied to 300 FFPE primary tumour samples, obtained from a large-scale epidemiological study of melanoma. The quality and the discriminatory power of CNVseq was assessed. Libraries were successfully generated for 93% of blocks, with input DNA quantity being the only predictor of success (success rate dropped to 65% if <20 ng available); 3% of libraries were dropped because of low sequence alignment rates. Technical replicates showed high reproducibility. Comparison with targeted CN assessment showed consistency with the Next Generation Sequencing (NGS) analysis. We were able to detect and distinguish CN changes with a resolution of ≤10 kb. To demonstrate performance, we report the spectrum of genomic CN alterations (CNAs) detected at 9p21, the major site of CN change in melanoma. This successful analysis of CN in FFPE material using NGS provides proof of principle for intensive examination of population-based samples.
- Published
- 2019
- Full Text
- View/download PDF
14. β-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas.
- Author
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Nsengimana J, Laye J, Filia A, O'Shea S, Muralidhar S, Poźniak J, Droop A, Chan M, Walker C, Parkinson L, Gascoyne J, Mell T, Polso M, Jewell R, Randerson-Moor J, Cook GP, Bishop DT, and Newton-Bishop J
- Subjects
- Female, GTP Phosphohydrolases genetics, Humans, Male, Melanoma genetics, Melanoma pathology, Membrane Proteins genetics, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Tumor Microenvironment genetics, beta Catenin genetics, GTP Phosphohydrolases immunology, Melanoma immunology, Membrane Proteins immunology, Mutation, Proto-Oncogene Proteins B-raf immunology, Skin Neoplasms immunology, Tumor Microenvironment immunology, beta Catenin immunology
- Abstract
Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin-mediated failure to recruit CD141+ DCs. A second subgroup displayed an equally bad prognosis when histopathological factors were adjusted for, while 4 others maintained comparable survival profiles. The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation. The survival benefit of high immune scores was strongest in patients with double-WT tumors for BRAF and NRAS, less strong in BRAF-V600 mutants, and absent in NRAS (codons 12, 13, 61) mutants. In summary, we report evidence for a β-catenin-mediated immune evasion in 42% of melanoma primaries overall and in 73% of those with the worst outcome. We further report evidence for an interaction between oncogenic mutations and host response to melanoma, suggesting that patient stratification will improve immunotherapeutic outcomes.
- Published
- 2018
- Full Text
- View/download PDF
15. Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.
- Author
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Nsengimana J, Laye J, Filia A, Walker C, Jewell R, Van den Oord JJ, Wolter P, Patel P, Sucker A, Schadendorf D, Jönsson GB, Bishop DT, and Newton-Bishop J
- Subjects
- Adult, Aged, Area Under Curve, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Melanoma classification, Melanoma diagnosis, Melanoma mortality, Middle Aged, Neoplasm Grading, Neoplasm Staging, Phenotype, Predictive Value of Tests, ROC Curve, Reproducibility of Results, Risk Factors, Seasons, Skin Neoplasms classification, Skin Neoplasms diagnosis, Skin Neoplasms mortality, Telomere genetics, Telomere Shortening, Time Factors, Vitamin D blood, Vitamin D Deficiency blood, Vitamin D Deficiency mortality, Young Adult, Biomarkers, Tumor genetics, Gene Expression Profiling methods, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3 x 10(-4)), Breslow thickness (P=5 x 10(-10)), ulceration (P=9.x10-8) and mitotic rate (P=3 x 10(-7)), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.
- Published
- 2015
- Full Text
- View/download PDF
16. The clinicopathological and gene expression patterns associated with ulceration of primary melanoma.
- Author
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Jewell R, Elliott F, Laye J, Nsengimana J, Davies J, Walker C, Conway C, Mitra A, Harland M, Cook MG, Boon A, Storr S, Safuan S, Martin SG, Jirström K, Olsson H, Ingvar C, Lauss M, Bishop T, Jönsson G, and Newton-Bishop J
- Subjects
- Adolescent, Adult, Aged, Cell Count, Databases, Genetic, Female, Humans, Immunohistochemistry, Male, Middle Aged, Multivariate Analysis, Signal Transduction genetics, Ulcer genetics, Young Adult, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Melanoma genetics, Melanoma pathology, Skin Neoplasms genetics, Skin Neoplasms pathology, Ulcer pathology
- Abstract
Ulceration of primary melanomas is associated with poor prognosis yet is reported to predict benefit from adjuvant interferon. To better understand the biological processes involved, clinicopathological factors associated with ulceration were determined in 1804 patients. From this cohort, 348 primary tumor blocks were sampled to generate gene expression data using a 502-gene cancer panel and 195 blocks were used for immunohistochemistry to detect macrophage infiltration and vessel density. Gene expression results were validated using a whole genome array in two independent sample sets. Ulceration of primary melanomas was associated with more proliferative tumors, tumor vessel invasion, and increased microvessel density. Infiltration of tumors with greater number of macrophages and gene expression pathways associated with wound healing and up-regulation of pro-inflammatory cytokines suggests that ulceration is associated with tumor-related inflammation. The relative benefit from interferon reported in patients with ulcerated tumors may reflect modification of signaling pathways involved in inflammation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
17. Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy.
- Author
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Abbotts R, Jewell R, Nsengimana J, Maloney DJ, Simeonov A, Seedhouse C, Elliott F, Laye J, Walker C, Jadhav A, Grabowska A, Ball G, Patel PM, Newton-Bishop J, Wilson DM 3rd, and Madhusudan S
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis, Blotting, Western, Cell Line, Tumor, Comet Assay, Flow Cytometry, Gene Knockdown Techniques, Genome-Wide Association Study, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Melanoma mortality, Melanoma pathology, Molecular Targeted Therapy, RNA, Messenger analysis, Real-Time Polymerase Chain Reaction, Transfection, DNA-(Apurinic or Apyrimidinic Site) Lyase antagonists & inhibitors, Melanoma genetics, PTEN Phosphohydrolase deficiency
- Abstract
Phosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease activity. In the current study we explored a synthetic lethal relationship between PTEN and APE1 in melanoma. Clinicopathological significance of PTEN mRNA and APE1 mRNA expression was investigated in 191 human melanomas. Preclinically, PTEN-deficient BRAF-mutated (UACC62, HT144, and SKMel28), PTEN-proficient BRAF-wildtype (MeWo), and doxycycline-inducible PTEN-knockout BRAF-wildtype MeWo melanoma cells were DNA repair expression profiled and investigated for synthetic lethality using a panel of four prototypical APE1 inhibitors. In human tumours, low PTEN mRNA and high APE1 mRNA was significantly associated with reduced relapse free and overall survival. Pre-clinically, compared to PTEN-proficient cells, PTEN-deficient cells displayed impaired expression of genes involved in DNA double strand break (DSB) repair. Synthetic lethality in PTEN-deficient cells was evidenced by increased sensitivity, accumulation of DSBs and induction of apoptosis following treatment with APE1 inhibitors. We conclude that PTEN deficiency is not only a promising biomarker in melanoma, but can also be targeted by a synthetic lethality strategy using inhibitors of BER, such as those targeting APE1.
- Published
- 2014
- Full Text
- View/download PDF
18. Clinicopathologic features of V600E and V600K melanoma--letter.
- Author
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Jewell R, Chambers P, Harland M, Laye J, Conway C, Mitra A, Elliott F, Cook MG, Boon A, and Newton-Bishop J
- Subjects
- Female, Humans, Male, Melanoma diagnosis, Melanoma genetics, Proto-Oncogene Proteins B-raf genetics
- Published
- 2012
- Full Text
- View/download PDF
19. High-resolution deletion mapping of 15q13.2-q21.1 in transitional cell carcinoma of the bladder.
- Author
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Natrajan R, Louhelainen J, Williams S, Laye J, and Knowles MA
- Subjects
- Carcinoma, Transitional Cell metabolism, Carcinoma, Transitional Cell pathology, Cell Line, Tumor, Chromosome Deletion, Chromosome Mapping, DNA, Neoplasm genetics, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins genetics, Disease Progression, Gene Dosage, Humans, In Situ Hybridization, Fluorescence, Loss of Heterozygosity, Microsatellite Repeats genetics, Rad51 Recombinase, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell genetics, Chromosomes, Human, Pair 15 genetics, Urinary Bladder Neoplasms genetics
- Abstract
Deletions found in several types of human tumor, including carcinomas of the colorectum, breast, and lung, suggest the presence of a potential tumor suppressor gene(s) on chromosome 15. Common regions of deletion in these tumors are at 15q15 and 15q21. Here, we have analyzed loss of heterozygosity (LOH) on chromosome 15 to ascertain its potential involvement in the development and progression of transitional cell carcinoma (TCC) of the bladder. A panel of 26 polymorphic markers, spanning 15q12-15q22, were used to map regions of LOH in 51 TCCs. LOH was found for at least one marker in the region 15q14-15q15.3 in 20 of 51 (39%) tumors. Deletion mapping defined two minimum regions of deletion: a distal region between the markers D15S514 and D15S537 at 15q15.1-15q15.3 (estimated as 3 Mb) and a more proximal region between the markers D15S971 and D15S1042 at 15q14 (estimated as 1.1 Mb). Analysis of a panel of 33 bladder tumor cell lines revealed regions of contiguous homozygosity for markers in 15q15, indicating likely LOH. Fluorescence in situ hybridization analysis demonstrated that mitotic recombination is the predicted mechanism of LOH in two of these. These regions of LOH on 15q may contain tumor suppressor genes the loss or inactivation of which is associated with TCC development. The DNA repair gene RAD51 at 15q15.1 represents a candidate 15q tumor suppressor gene. Expression analysis of rad51 protein in tumor cell lines revealed variable levels of expression but no significant loss of expression in cell lines with likely 15q LOH.
- Published
- 2003
20. [Infectious endocarditis induced by Actinobacillus actinomycetemcomitans. 8 new cases].
- Author
-
Grand A, Laye JM, Etienne J, Pernot F, Durand de Gevigney G, Delahaye F, Touboul P, and Froment A
- Subjects
- Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Mouth Mucosa microbiology, Prognosis, Retrospective Studies, Time Factors, Tooth Diseases complications, Tooth Diseases microbiology, Actinobacillus Infections complications, Actinobacillus Infections diagnosis, Actinobacillus Infections therapy, Aggregatibacter actinomycetemcomitans, Endocarditis, Bacterial diagnosis, Endocarditis, Bacterial etiology, Endocarditis, Bacterial microbiology, Endocarditis, Bacterial therapy
- Abstract
A commensal organism of the buccal cavity, Actinobacillus actinomycetemcomitans (AAC) has been responsible for at least four new cases of infectious endocarditis by year in France. This retrospective study was based on 90 new cases of infectious endocarditis by AAC, including 8 personal observations. One third of patients had no known cardiac disease before their infectious endocarditis, the portal of entry of which was usually dental. In cases of suspected infectious endocarditis, rapid and severe weight loss (43% of cases) and, less commonly, anicteric cholestasis (8%) should alert the physician for the possible pathological role of AAC. The echocardiographic appearances are non-specific. The diagnosis is confirmed on blood cultures but the organism grows slowly in CO2 enriched atmosphere. Initially, the course of the disease was favourable in one third of patients but, in two thirds of cases, complications were observed almost renal (26%), cardiac (24%) and neurological (18%). Two thirds of patients were cured by the time they were discharged whereas the remainder had sequellae, mainly valvular and neurological. The hospital mortality was 9%; late mortality was 6%. Therefore, the prognosis of AAC endocarditis, seems to be better than that of other bacteriological forms. A combination of cephalosporin and aminoside, or even a simple third generation cephalosporin antibiotic therapy for at least 4 weeks are usually effective. The complementary surgical indications are the same as for other forms of infectious endocarditis. Prophylaxis depends on strict prophylactic amoxicillin therapy for all cardiac patients at risk of infectious endocarditis before dental treatment and on good bucco-dental hygiene.
- Published
- 1994
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