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2 MicroRNA profiling and cisplatin–DNA interactions in an isogenic model of cisplatin resistant NSCLC cell lines

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  • St James's Hospital & Trinity College Dublin
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Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related deaths among men and women worldwide. Despite the development of molecular targeted therapies, platinum-based combination chemotherapy remains the most effective systemic chemotherapy for NSCLC patients. Unfortunately, the outcomes of platinum-based therapies, in particular those containing cisplatin, have reached a plateau due to the development of both intrinsic and acquired resistance. While significant variations in response to platinum-based chemotherapeutic regimens exist, defining molecular features that may determine resistance or response to chemotherapy is critical. This review will focus on some of the emerging biomarkers that are predictive of response to such treatments that may offer potential in the future management of NSCLC patients. „ The current management of lung cancer patients remains a major challenge. „ While treatment may be potentially curative in the early stage of the disease, the majority of patients require intensive treatment with platinum-based chemotherapy. „ Resistance to platinum chemotherapy remains one of the most significant obstacles in the management of lung cancer patients and in improving long-term outcomes. „ Future management of patients may ultimately lie in personalized therapy through the selection of appropriate agents based on the likelihood of a response. „ A number of biomarkers that are predictive for response to platinum-based chemotherapeutic agents are emerging. „ Further studies are warranted in larger patient cohorts in order to validate such markers, both alone and in combination, and to develop appropriate algorithms based on these markers in order to guide treatment selection for lung cancer patients in the clinical setting.
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The double-stranded conformation of cellular DNA is a central aspect of DNA stabilisation and protection. The helix preserves the genetic code against chemical and enzymatic degradation, metabolic activation, and formation of secondary structures. However, there are various instances where single-stranded DNA is exposed, such as during replication or transcription, in the synthesis of chromosome ends, and following DNA damage. In these instances, single-stranded DNA binding proteins are essential for the sequestration and processing of single-stranded DNA. In order to bind single-stranded DNA, these proteins utilise a characteristic and evolutionary conserved single-stranded DNA-binding domain, the oligonucleotide/oligosaccharide-binding (OB)-fold. In the current review we discuss a subset of these proteins involved in the direct maintenance of genomic stability, an important cellular process in the conservation of cellular viability and prevention of malignant transformation. We discuss the central roles of single-stranded DNA binding proteins from the OB-fold domain family in DNA replication, the restart of stalled replication forks, DNA damage repair, cell cycle-checkpoint activation, and telomere maintenance.
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