Search results for "genome instability"
showing 10 items of 62 documents
Never cared for what they do. High structural stability of Guanine-quadruplexes in presence of strand-break damages
2021
AbstractDNA integrity is an important factor to assure genome stability and, more generally, cells and organisms’ viability. In presence of DNA damage, the normal cell cycle is perturbed while cells activate their repair processes. Although efficient, the repair system is not always able to ensure the complete restoration of gene integrity. In these cases, not only mutations may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold which induces apoptosis and the programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiations are the most toxic, due to their inherently difficult repair, which may lead to …
Long-Lasting Genomic Instability Following Arsenite Exposure inMammalian Cells: The Role of Reactive Oxygen Species
2011
Previously, we reported that the progeny of mammalian cells, which has been exposed to sodium arsenite for two cell cycles, exhibited chromosomal instability and concurrent DNA hypomethylation, when they were subsequently investigated after two months of subculturing (about 120 cell generations) in arsenite-free medium. In this work, we continued our investigations of the long-lasting arsenite-induced genomic instability by analyzing additional endpoints at several time points during the cell expanded growth. In addition to the progressive increase of aneuploid cells, we also noted micronucleated and multinucleated cells that continued to accumulate up to the 50th cell generation, as well a…
Tumor Hypoxia and Malignant Progression
2004
Publisher Summary This chapter discusses tumor hypoxia and malignant progression. Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen. Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels. Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors are (a) severe structural and functional abnormalities of the tumor microvessels (b) a deterioration of the diffusion geometry, …
Biological consequences of tumor hypoxia
2001
Growing evidence from experimental and clinical studies points to the fundamental, pathophysiologic role of hypoxia in solid tumors. Intratumoral hypoxia is a consequence of a structurally and functionally disturbed microcirculation, with deterioration of the diffusion geometry and of tumor-associated anemia. Hypoxia-induced changes of the proteome in the neoplastic and stroma cells may lead to neoplastic growth impairment through molecular mechanisms, resulting in cellular quiescence, differentiation, and apoptosis. Alternatively, hypoxia-induced proteome changes activating nonspecific stress response, anaerobic metabolism, angiogenesis, tissue remodeling, and change of cell contacts may p…
Physiological Mechanisms of Treatment Resistance
2009
It is generally accepted that tumor perfusion, microcirculation, characteristics of the interstitial space of tumors, oxygen (and nutrient) supply, tissue pH distribution and the bioenergetic status—factors that are usually closely linked and that define the so-called pathophysiological microenvironment—can markedly influence the therapeutic response of malignant tumors to sparsely ionizing radiation, chemotherapy, photodynamic therapy, hormonal therapy and immunotherapy. Besides more direct mechanisms involved in the development of acquired therapeutic resistance, there are in addition, obstacles in intratumor pharmacokinetics of antitumor agents due to delivery problems caused by an inade…
Genome structure reveals the diversity of mating mechanisms in Saccharomyces cerevisiae x Saccharomyces kudriavzevii hybrids, and the genomic instabi…
2020
Interspecific hybridization has played an important role in the evolution of eukaryotic organisms by favouring genetic interchange between divergent lineages to generate new phenotypic diversity involved in the adaptation to new environments. This way, hybridization between Saccharomyces species, involving the fusion between their metabolic capabilities, is a recurrent adaptive strategy in industrial environments. In the present study, whole-genome sequences of natural hybrids between Saccharomyces cerevisiae and Saccharomyces kudriavzevii were obtained to unveil the mechanisms involved in the origin and evolution of hybrids, as well as the ecological and geographic contexts in which sponta…
Patterns of genomic instability in gastric cancer: clinical implications and perspectives
2007
In gastric cancer (GC) the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It is widely accepted that GC can follow at least two major genomic instability pathways, microsatellite instability (MSI) and chromosome instability (CIN). MSI is responsible for a well-defined subset of GCs. CIN represents a more common pathway comprising heterogeneous subsets of GC. In addition to MSI and CIN, the CpG islands methylator phenotype (CIMP) plays an important role in gastric carcinogenesis. CIMP may lead to th…
Imbalance between genomic gain and loss identifies high-risk neuroblastoma patients with worse outcomes
2021
Survival in high-risk neuroblastoma (HR-NB) patients remains poor despite multimodal treatment. We aimed to identify HR-NB patients with worse outcomes by analyzing the genomic instability derived from segmental chromosomal aberrations. We calculated 3 genomic instability indexes for primary tumor SNP array profiles from 127 HR-NB patients: (1) Copy number aberration burden (%gainslength+%losseslength), (2) copy number load (CNL) (%gainslength-%losseslength) and (3) net genomic load (NGL) (%gainsamount-%lossesamount). Tumors were classified according to positive or negative CNL and NGL genomic subtypes. The impact of the genomic instability indexes on overall survival (OS) was assessed with…
Increased Oxidative Damage Associated with Unfavorable Cytogenetic Subgroups in Chronic Lymphocytic Leukemia
2014
Oxidative stress contributes to genomic instability in chronic lymphocytic leukemia (CLL), but its relationship with the acquisition of specific chromosomal abnormalities is unknown. We recruited 55 untreated CLL patients and assessed 8-oxo-2′-deoxyguanosine (8-oxo-dG), glutathione, and malondialdehyde (MDA) levels, and we compared them among the cytogenetic subgroups established using fluorescence in situ hybridization (FISH). Significant increases in 8-oxo-dG and/or MDA were observed in patients with unfavorable cytogenetic aberrations (17p and 11q deletions) compared to the 13q deletion group.TP53deletion patients exhibited a diminished DNA repair efficiency. Finally, cases with normal F…
The dual role of p53: DNA protection and antioxidant.
2011
The classical functions of p53 protein are those related to its role on DNA damage, cell growth arrest, senescence and apoptosis. For this reason it is called 'the guardian of the genome' and is considered one of the most important players in the development of cancer. However, more recently it has been show that p53 is not only involved in cancer, but also in ageing. p53 is stimulated by stress, which in turn results in the activation of a wide range of transcriptional targets. Low-intensity stress will activate p53 in a manner which results in antioxidant response, thus protecting against ageing because of its antioxidant function. On the contrary, high-intensity activation of p53 will re…