Cancer-related metabolic changes lead to locus-specific recoding of epigenetic marks. Consistent with the down-regulation of these HMGA-targeting miRNAs, an increase in the HMGA1 and HMGA2-specific mRNAs was observed. Mechanistically, CTCF may function as a boundary element to stop the spread of DNA methylation. BioMAP profiling is the broadest, most physiologically relevant method to quickly and robustly determine the efficacy, safety, and mechanism of action (MOA) of candidate drug molecules to support their pipeline progression. Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH 2-CH 2-).Examples are dopamine, norepinephrine and serotonin.. All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, … Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. [61] FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,[62] prostate,[63] stomach,[64][65] neuroblastomas,[66] pancreas,[67] and lung. Several epigenetic alterations are known to play a role in the transition of melanocytes to melanoma cells. This is an excellent course that introduces you to fundamental knowledge of several hot topics in the field of epigenetics. When mutation results in loss of heterozygosity at tumor suppressor gene sites, these genes may become inactive. This also means that you will not be able to purchase a Certificate experience. Up to 15% of the MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression. This week we’ll bring together much of what we’ve learned in previous weeks of the course, to understand how the epigenome is affected, and can also affect, cancer development and progression. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. [27], The tumor suppressor gene p53 regulates DNA repair and can induce apoptosis in dysregulated cells. 34 Unlike other members of the statin group, … Gateway Drug Theory. By comparison, the mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation. [102] Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer, and have been seen in genes involved in hormonal response. Mutation rates are strongly increased in cells with mutations in DNA mismatch repair[72][73] or in homologous recombinational repair (HRR). In fact, cancer cell genomes have 20-50% less methylation at individual CpG dinucleotides across the genome. Upon completing the course, your electronic Certificate will be added to your Accomplishments page - from there, you can print your Certificate or add it to your LinkedIn profile. [31], In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes. Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. As indicated in the Wikipedia articles on RAD51 and BRCA2, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. [25][26], Some research has focused on blocking the action of BRD4 on acetylated histones, which has been shown to increase the expression of the Myc protein, implicated in several cancers. [74] Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see DNA repair defects and increased cancer risk). For those interested, additional information can be obtained in the following textbook. Transcription reshapes methylation on the repaired gene", "A DNA methylation fingerprint of 1628 human samples", "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations", "Epigenetic Alterations in Ultraviolet Radiation-Induced Skin Carcinogenesis: Interaction of Bioactive Dietary Components on Epigenetic Targets†", "Tackling malignant melanoma epigenetically: histone lysine methylation", "Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target", "Epigenetic changes in prostate cancer: implication for diagnosis and treatment", "Molecular alterations in prostate cancer as diagnostic, prognostic, and therapeutic targets", "Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention", "Methylation of HPV16 genome CpG sites is associated with cervix precancer and cancer", "Electromagnetic fields may cause leukaemia in children", "EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation", "Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer", "MGMT gene silencing and benefit from temozolomide in glioblastoma", "Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma", "Epigenetics as a mechanism driving polygenic clinical drug resistance", "Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review)", "A pilot pharmacokinetic study of oral azacitidine", "Demethylating agents in myeloid malignancies", "Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia", "Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome", "Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study", "Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)", http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205353Orig1s000MedR.pdf, "Chemopreventive Property of a Soybean Peptide (Lunasin) That Binds to Deacetylated Histones and Inhibits Acetylation", https://en.wikipedia.org/w/index.php?title=Cancer_epigenetics&oldid=999538060, Creative Commons Attribution-ShareAlike License, This page was last edited on 10 January 2021, at 18:14. In cancer cells, hypermethylation in the CpG island shores move into CpG islands, or hypomethylation of CpG islands move into CpG island shores eliminating sharp epigenetic boundaries between these genetic elements. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG sites evaluated) showed differential DNA methylation. The development process of the drug to bind to BRD4 is noteworthy for the collaborative, open approach the team is taking. Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team. Marijuana, alcohol, nicotine and other gateway drugs … Learn more. In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of histone H4 (decreased H4ac and H4me3). This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis. If you only want to read and view the course content, you can audit the course for free. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity. Two broad experimental survey articles[59][60] also document most of these epigenetic DNA repair deficiencies in cancers. These proteins have three highly positively charged regions, termed AT hooks, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Histone modification profiles of healthy and cancerous cells tend to differ. OncLive serves as a connection to everything oncology, including interviews and videos from thought leaders and cutting edge articles and resources on cancer. In 29–66%[48][49] of glioblastomas, DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT. We’ll learn about metastable epialleles, which have allowed the study of transgenerational epigenetics in mice, and provided some evidence for transgenerational epigenetics in mammals. Apply for it by clicking on the Financial Aid link beneath the "Enroll" button on the left. These milder substances, such as nicotine or alcohol, are believed to open the door to drugs such as meth, heroin and cocaine, which can lead to addiction.. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. [46] However, the majority of 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1 were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene.[47]. Additionally, increased CpG site methylation was found in low levels in most of the five host nuclear genes studied, including 5/5 TERT, 1/4 DAPK1, 2/5 RARB, MAL, and CADM1. Dr. Blewitt herself studies X inactivation, and I learned so much! [23] In mouse models, the loss of histone H4 acetylation and trimethylation increases as tumor growth continues. The "normal" CpG methylation profile is often inverted in cells that become tumorigenic. The University of Melbourne is an internationally recognised research intensive University with a strong tradition of excellence in teaching, research, and community engagement. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of CpG islands) than by mutations. This includes DNA methylation that can be inherited without making changes to the DNA sequence, as well as silencing the tumor suppressor genes in the epidermis that have been exposed to UV radiation for periods of time. [100] These alterations are the consequence of deregulation of their corresponding enzymes. started a new career after completing these courses, got a tangible career benefit from this course. We’ll learn about the chromatin modifications implicated in gene silencing and activation, the role of non-coding RNA, and higher order chromatin structures. It has also become clear in recent years that epigenetic modifications are sensitive to the environment (for example diet), which has sparked a large amount of public debate and research. BRCA1-A activity arrests the cell cycle at the G2/M checkpoint, allowing time for DNA repair, or apoptosis may be initiated. [97] In rats, endocrine differences were observed in offspring of males exposed to morphine. Cancer epigenetics can be precisely reprogramed by cellular metabolism through 1) dose-responsive modulation of cancer epigenetics by metabolites; 2) sequence-specific recruitment of metabolic enzymes; and 3) targeting of epigenetic enzymes by nutritional signals.[37]. It appears that cancers may frequently be initiated by an epigenetic reduction in expression of one or more DNA repair enzymes. Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. [101], Prostate cancer kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. [12] These agents inhibit all three types of active DNA methyltransferases, and had been thought to be highly toxic, but proved to be effective when used in low dosage, reducing progression of myelodysplastic syndrome to leukemia. [106] Furthermore, 1/3 of CpG sites in mitochondrial DNA were associated with increased methylation in CIN3+. [14][15][16][17] CpG islands found in promoter regions are usually protected from DNA methylation. [35] The epigenetic silencing of miRNA genes by aberrant DNA methylation is a frequent event in cancer cells; almost one third of miRNA promoters active in normal mammary cells were found hypermethylated in breast cancer cells - that is a several fold greater proportion than is usually observed for protein coding genes. A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to carcinogenesis. [93][94] While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence. Visit the Learner Help Center. A high level of H2A.Z expression is detected in many cancers and is significantly associated with cellular proliferation and genomic instability. We’ll discuss the molecular mechanisms for regulating gene expression in some detail, from how the DNA is packaged at a local level, right up to how the chromatin is positioned within the nucleus. These include APC, CDKN1A, CDKN2A, CDKN2B, Ezrin, FGFR1, GADD45A, MGMT, STK3, STK4, PTEN, RASSF1A, WIF1, as well as several miRNAs. [110] Sarcomas comprise a large number of rare, histogenetically heterogeneous mesenchymal tumors that, for example, include chondrosarcoma, Ewing's sarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, synovial sarcoma, and (alveolar and embryonal) rhabdomyosarcoma. The course may not offer an audit option. [43] referred to 6 DNA repair genes that are directly targeted by the miRNAs indicated in parentheses: ATM (miR-421), RAD52 (miR-210, miR-373), RAD23B (miR-373), MSH2 (miR-21), BRCA1 (miR-182) and P53 (miR-504, miR-125b). As Vogelstein et al. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. [10] Since epigenetic profiles change, scientists would like to use the different epigenomic profiles to determine the stage of development or level of aggressiveness of a particular cancer in patients. [9] However, epigenetic DNA methylation differs between normal cells and tumor cells in humans. Walter and Eliza Hall Institute of Medical Research, 1.1 Introduction to the concepts of epigenetic control, 1.2 Mitotic heritability of epigenetic marks, 1.4 Chromatin compaction - heterochromatin versus euchromatin, 1.6 DNA methylation at intergenic regions and repetitive elements, Week 1 quiz - contributes 8% towards your final grade, 2.2 Histone acetylation and histone methylation, 2.7 Noncoding RNAs - long noncoding RNAs introduction, 2.9 3D organisation of the nucleus and summary of epigenetic marks, Week 2 quiz - contributes 8% towards your final grade, 3.2 Timing of random and imprinted X chromosome inactivation, 3.3 Stages of X inactivation - counting and control of Xist expression, 3.4 Control of Xist expression by pluripotency factors, 3.5 Stages of X inactivation - choice of which X to inactivate, 3.6 Stages of X inactivation - initiation and spreading of silencing, 3.7 Stages of X inactivation - establishment of silencing, 3.8 Stages of X inactivation - maintenance of silencing e.g. ... effective, or approved for treating any patient or health condition. Canadian researchers created the fast-growing genetically engineered salmon with a growth hormone gene from Chinook salmon and a gene promoter from ocean pout.They microinjected the transgene into fertilized eggs of wild Atlantic salmon, and characterized the insertion.. [10][24], Other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (H3K4me3), and increased monomethylation of histone H3 Lysine 9 (H3K9me) and trimethylation of histone H3 Lysine 27 (H3K27me3). 355) and biological At least eight other epigenetic drugs are currently in different stages of development or human trials. [32] Some miRNAs also undergo methylation-associated silencing in cancer cells. We’ll learn about the two important periods during development for the erasure and resetting of the epigenome. [122] Drug development has focused mainly on modifying DNA methyltransferase, histone acetyltransferase (HAT) and histone deacetylase (HDAC). Such epigenetic deficiencies likely arise early in carcinogenesis, since they are also frequently found (though at somewhat lower frequency) in the field defect surrounding the cancer from which the cancer likely arose (see Table). The phase 3 BEACON CRC trial tested both a three … Epigenetic biomarkers can also be utilized as tools for molecular prognosis. I am very happy to have done this course and find it a very interesting field to take upm in my future career. [50] showed that each of the miRNAs that target HMGA genes are drastically reduced in almost all human pituitary adenomas studied, when compared with the normal pituitary gland. Epigenetic defects in DNA repair genes are frequent in cancers. two HDAC inhibitors, vorinostat and romidepsin, have been approved by the Food and Drug Administration. In patients with breast cancer, hypermethylation of CpG islands located proximal to the transcription start site was observed. [8] Typically, this methylation only occurs at cytosines that are located 5' to guanosine in the CpG dinucleotides of higher order eukaryotes. Within the HPV16L1 region, 14 tested CpG sites have significantly higher methylation in CIN3+ than in HPV16 genomes of women without CIN3. © 2021 Coursera Inc. All rights reserved. Government Agencies CDC CIA DEA EPA FBI FCC FDA FEMA IRS NSA TSA USDA X chromosome inactivation is a really well-characterised epigenetic process that is now used as a model system to study epigenetic processes that are relevant more broadly. However, in cancer cells, CpG islands preceding tumor suppressor gene promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic repeat sequences is often decreased. We’ll learn about this process and how it occurs in a mouse in great detail, which will greatly add to the mechanistic understanding gained in week two. [55], Palmieri et al. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Cancers have high levels of genome instability, associated with a high frequency of mutations. The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. [92] examined the DNA methylation profiles of 855 primary tumors. When you purchase a Certificate you get access to all course materials, including graded assignments. You’ll be prompted to complete an application and will be notified if you are approved. It is generally wrapped around special proteins called histones to form a structure called a nucleosome. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. The histone variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering chromatin structure. Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. Thanks to the support of the Lifespan Heroes and as part of our commitment to bringing you the latest news in longevity research, we have created the rejuvenation roadmap.. Replication errors past these damages (see translesion synthesis) can lead to increased mutations and, ultimately, cancer. ... Drugs.com provides … [102] Prostate cancer is the second leading cause of cancer-caused fatalities in men, and within a man's lifetime, one in six men will have the disease. [51] Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is not only associated with cancers, but that the HMGA1 gene can act as an oncogene to cause cancer. A nucleosome consists of 2 sets of 4 histones: H2A, H2B, H3, and H4. Genes commonly found to be transcriptionally silenced due to promoter hypermethylation include: Cyclin-dependent kinase inhibitor p16, a cell-cycle inhibitor; MGMT, a DNA repair gene; APC, a cell cycle regulator; MLH1, a DNA-repair gene; and BRCA1, another DNA-repair gene. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. This option lets you see all course materials, submit required assessments, and get a final grade. [106] Only 2/16 CpG sites tested in HPV16 upstream regulatory region were found to have association with increased methylation in CIN3+. Another variant, H2A.Z, plays an important role in both gene activation and repression. Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. [129], Histone deacetylase (HDAC) inhibitors show efficacy in treatment of T cell lymphoma. How are some genes activated and others are silenced? Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. Several medications which have epigenetic impact are now used in several of these diseases. [108] This is what leads to the increase in white blood cells. [38][39] If DNA repair is deficient, DNA damage tends to accumulate. Leukemia related genes are managed by the same pathways that control epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. Data sources include IBM Watson Micromedex (updated 3 … In the cells carrying both the epimutation of the DNA repair gene and the mutation with the selective advantage, further DNA damages will accumulate, and these could, in turn, give rise to further mutations with still greater selective advantages. These histone modifications can silence tumor suppressor genes despite the drop in methylation of the gene's CpG island (an event that normally activates genes). MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway. Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years. [71] Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in blue. [106], Recent studies have shown that the mixed-lineage leukemia (MLL) gene causes leukemia by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control. Therefore, they concluded that DNA methylation has a part in silencing the gene. ISBN-13: 978-0879697242 | Edition: 1. More questions? [18] In healthy cells, CpG dinucleotides of lower densities are found within coding and non-coding intergenic regions. [106] This could be a potential biomarker for future screens of cancerous and precancerous cervical disease. Epigenetics has been a hot topic for research over the past decade as it has become clear that aberrant epigenetic control contributes to disease (particularly to cancer). [103] More than 90% of prostate cancers show gene silencing by CpG island hypermethylation of the GSTP1 gene promoter, which protects prostate cells from genomic damage that is caused by different oxidants or carcinogens. DNA methylation, specifically hypermethylation, is one of the main ways that the miR-125b1 is epigenetically silenced. Many types of cancers are associated with epigenetic changes. For some patients with an aggressive form of metastatic colorectal cancer, a treatment regimen that consists of a combination of targeted cancer drugs can improve how long they live without increasing their risk of serious side effects, results from a new clinical trial show.. Deficiencies in DNA repair proteins that function in accurate DNA repair pathways increase the risk of mutation. [106] Furthermore, cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16. [120] Pharmaceuticals that reverse epigenetic changes might have a role in a variety of cancers. Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. We’ll learn about mechanisms for genomic imprinting, and study three examples in more depth. Cancer cells are deferentially methylated at CpG island shores. [100] The silencing of tumor suppressor genes leads to photocarcinogenesis which is associated to epigenetic alterations in DNA methylation, DNA methyltransferases, and histone acetylation. Yes, Coursera provides financial aid to learners who cannot afford the fee. Dasatinib is approved as a cancer medication, but recent attention has been focused on its ability to act as a senolytic; that is an agent that can remove ‘dead’ (senescent) cells within the body by inducing a process known as autophagy. Established in 1853, it is Australia's second oldest University. [115][116][117][118] Therefore, if the gene encoding MGMT in cancer cells is hypermethylated and in effect silenced or repressed, the chemotherapeutic drugs that act by methylating guanine will be more effective than in cancer cells that have a functional MGMT enzyme. For two of these, miR-15 and miR-16, the coding regions are epigenetically silenced in cancer due to histone deacetylase activity. [106] As in many cases, the causative factor for cancer does not always take a direct route from infection to the development of cancer. Several researchers in … When these genes have low or absent expression, DNA damages can accumulate. In an early study, looking at a limited set of transcriptional promoters, Fernandez et al. The DNA damage response to double strand DNA breaks (DSB) is mediated in part by histone modifications. [48] In the glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3’UTR (the three prime untranslated region of MGMT mRNA). This course will give an introduction to the fundamentals of epigenetic control. A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). IMPORTANT: Listing a study does not mean it has been evaluated by the U.S. Federal Government.Read our disclaimer for details.. Before participating in a study, talk to your health care provider and learn about the risks and potential benefits. [36], Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Methylated cytosines make hydrolysis of the amine group and spontaneous conversion to thymine more favorable. It was indicated that infections, electromagnetic fields and increased birth weight can contribute to being the causes of leukemia.[109]. HMGA2 protein specifically targets the promoter of ERCC1, thus reducing expression of this DNA repair gene. Allis, Jenuwein, Reinberg and Caparros. A look at the mechanisms underlying some of the observations we discussed in week 5, through the study of model organisms. Some of these epigenetic alterations may contribute to cancer progression. [75] Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 protein was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).
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