62 research outputs found

    Chromatin interaction neural network (ChINN): a machine learning-based method for predicting chromatin interactions from DNA sequences.

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    Chromatin interactions play important roles in regulating gene expression. However, the availability of genome-wide chromatin interaction data is limited. We develop a computational method, chromatin interaction neural network (ChINN), to predict chromatin interactions between open chromatin regions using only DNA sequences. ChINN predicts CTCF- and RNA polymerase II-associated and Hi-C chromatin interactions. ChINN shows good across-sample performances and captures various sequence features for chromatin interaction prediction. We apply ChINN to 6 chronic lymphocytic leukemia (CLL) patient samples and a published cohort of 84 CLL open chromatin samples. Our results demonstrate extensive heterogeneity in chromatin interactions among CLL patient samples

    Telomerase reverse transcriptase promoter alterations across cancer types as detected by next-generation sequencing: A clinical and molecular analysis of 423 patients.

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    BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015. RESULTS: Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in this population. TERT promoter alterations were more frequent in men (P = .031) and were associated with brain cancers (P = .001), skin cancers/melanoma (P = .001), and a higher number of aberrations (P = .0001). A co-alteration analysis found that TERT promoter alterations were significantly correlated with CDKN2A/B (P = .001) and BRAF abnormalities (P = .0003). Patients harboring TERT promoter alterations or TP53 or CDKN2A/B alterations and those with 4 or more alterations demonstrated shorter survival (hazard ratio for normal TERT promoters vs aberrant ones, 0.44; P = .017). However, only a higher number of alterations remained significant in the multivariate analysis. CONCLUSIONS: Overall, TERT promoter alterations were among the most prevalent aberrations in this population, with very high rates in brain cancers (48% of patients) and melanomas (56% of patients). These aberrations frequently coexist with a high number of other aberrations, with the latter feature also significantly associated with poorer overall survival. Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of novel approaches are under development. Cancer 2018;124:1288-96. © 2017 American Cancer Society

    Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner

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    TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.This work was supported by a generous gift from the Dabbiere family (J.F.C.), the Hana Jabsheh Research Initiative (J.F.C.), NIH grant NCI P50CA097257 (J.F.C. and J.A.D.), NCI P01CA118816-06 (J.F.C.), T32 GM008568 and T32 CA151022 (A.M.), and NCI R01CA163336 (J.S.S.), and the Sontag Foundation Distinguished Scientist Award (J.S.S.). C.F. is supported by a US NIH K99/R00 Pathway to Independence Award (K99GM118909) from the National Institute of General Medical Sciences. Additional support was provided by Fundação para a Ciência e Tecnologia SFRH/BD/88220/2012 (A.X.-M.) and IF/00601/2012 (B.M.C.). J.A.D. is an investigator of the Howard Hughes Medical Institute.info:eu-repo/semantics/publishedVersio

    Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

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    Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

    Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications

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    A specific issue on sustainability of transportation planning in an urban region: Ambulance location problem

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    In this study, ambulance location problem, which is a significant research field in transportation in healthcare, is focused on. It is assumed that travelling time of vehicles between two demand points is uncertain and this uncertainty is represented as a crisp and as well as convex set. In order to deal with this uncertainty, robust counterpart approach, which is capable of providing conservatism, is employed. According to results of the simulation process, which is designedfor the sake of benchmarking robust and nominal solutions, it can be easily claimed that conservative robustness is able to be achieved with significantly sufferable costs, even with no costs in most of the scenarios, by the proposed model. Ultimately, since robustness is one of the most important keywords for sustainability, on which discussions can be found in several parts of the text, this chapter is concluded with the claim that, by the proposed model, sustainability of transportation in healthcare is enhanced based on the adopted problem. © 2017, IGI Global. All rights reserved

    TOOLS AND TECHNIQUES FOR ECONOMIC DECISION ANALYSIS

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    Since decision on making an investment in exchange rate is one of the main problems faced by financial players acting in markets around the world, it is extensively discussed in the literature. In this study, it is investigated whether judgmental factors affect the decision in behavioral environment or not, and, if such an effect exists, its impact is whether positive or negative. In order to achieve that purpose, multi-criteria decision making approach is integrated with time series analysis approach which leads to clearly question the existence and direction of such an impact if it exists. The proposed model is applied to the Turkish market, indicating that judgmental factors prevent the financial player from misleading which is caused by considering solely profitability criterion. Thus, it is demonstrated that judgmental factors have a positive impact on the decision regarding exchange rate selection problem. Ultimately, it is demonstrated that the proposed integrated model provides accurate and reliable results

    ACTA PHYSICA POLONICA A

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    In case of considerable traffic congestion in an airport, transportation of passengers to city centre may become a challenging task, since airports are generally located far from the centre. In this study, transportation of passengers, who arrive at an airport, to the city centre has been handled. A mathematical model has been developed, which minimises total costs arising from both, the time passed, while passengers are waiting for a vehicle, and the dispatching of a significant amount of vehicles for transporting the passengers. By utilising the proposed model, in addition to matter of when to dispatch, it is also possible to specify which type of vehicles, and how many of them should be dispatched at each time interval. Ultimately, it is reported that such a plan has a great potential to enhance the productivity
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