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  • 1
    Publication Date: 2012-04-16
    Description: Alteration of DNA integrity is a potential cause of cancer and it is assumed that reduced DNA repair capacity and accumulation of DNA damage may represent intermediate markers in carcinogenesis. In this case-control study, DNA damage and nucleotide excision repair capacity (NER-DRC) were assessed in association with sporadic colorectal cancer (CRC). Both parameters were quantified by comet assay in blood cells of 70 untreated incident patients and 70 age-matched healthy controls. mRNA expression and polymorphisms in relevant NER genes were concurrently analyzed. The aim of this study was to characterize incident CRC patients for NER-DRC and to clarify possible relations between investigated variables. Comet assay and mRNA expression analysis showed that CRC patients differ in repair capacity as compared to controls. Patients had a lower NER-DRC and simultaneously they exhibited higher endogenous DNA damage (for both P 〈 0.001). Accumulation of DNA damage and decreasing NER-DRC behaved as independent modulating parameters strongly associated with CRC. Expression levels of 6 out of 9 studied genes differed between groups ( P ≤ 0.001), but none of them was related to DRC or to any of the studied NER polymorphisms. However, in patients only, XPC Ala499Val modulated expression levels of XPC , XPB and XPD gene, whereas XPC Lys939Gln was associated with XPA expression level in controls (for all P 〈 0.05). This study provides evidence on altered DRC and DNA damage levels in sporadic CRC and proposes the relevance of the NER pathway in this malignancy. Further, alterations in a complex multigene process like DNA repair may be better characterized by functional quantification of repair capacity than by quantification of individual genes transcripts or gene variants alone.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2012-06-26
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2015-03-12
    Description: ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences the expression level of specific genes; however, deposition of H3.3 at transcribed genes is currently thought to occur independently of ATRX. We focused on a set of genes, including the autism susceptibility gene Neuroligin 4 ( Nlgn4 ), that exhibit decreased expression in ATRX-null cells to investigate the mechanisms used by ATRX to promote gene transcription. Overall TERRA levels, as well as DNA methylation and histone modifications at ATRX target genes are not altered and thus cannot explain transcriptional dysregulation. We found that ATRX does not associate with the promoter of these genes, but rather binds within regions of the gene body corresponding to high H3.3 occupancy. These intragenic regions consist of guanine-rich DNA sequences predicted to form non-B DNA structures called G-quadruplexes during transcriptional elongation. We demonstrate that ATRX deficiency corresponds to reduced H3.3 incorporation and stalling of RNA polymerase II at these G-rich intragenic sites. These findings suggest that ATRX promotes the incorporation of histone H3.3 at particular transcribed genes and facilitates transcriptional elongation through G-rich sequences. The inability to transcribe genes such as Nlgn4 could cause deficits in neuronal connectivity and cognition associated with ATRX mutations in humans.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2014-06-08
    Description: DNA mismatch repair (MMR) deficiency is one of the best understood forms of genetic instability in colorectal cancer (CRC). CRC is routinely cured by 5-fluorouracil (5-FU)-based chemotherapy, with a prognostic effect and resistance to such therapy conferred by MMR status. In this study, we aimed to analyse the effect of genetic variants in classical coding regions or in less-explored predicted microRNA (miRNA)-binding sites in the 3' untranslated region (3'UTR) of MMR genes on the risk of CRC, prognosis and the efficacy of 5-FU therapy. Four single nucleotide polymorphisms (SNPs) in MMR genes were initially tested for susceptibility to CRC in a case–control study (1095 cases and 1469 healthy controls). Subsequently, the same SNPs were analysed for their role in survival on a subset of patients with complete follow-up. Two SNPs in MLH3 and MSH6 were associated with clinical outcome. Among cases with colon and sigmoideum cancer, carriers of the CC genotype of rs108621 in the 3'UTR of MLH3 showed a significantly increased survival compared to those with the CT + TT genotype (log-rank test, P = 0.05). Moreover, this polymorphism was also associated with an increased risk of relapse or metastasis in patients with heterozygous genotype (log-rank test, P = 0.03). Patients carrying the CC genotype for MSH6 rs1800935 (D180D) and not undergoing 5-FU-based chemotherapy showed a decreased number of recurrences (log-rank test, P = 0.03). No association with CRC risk was observed. We provide the first evidence that variations in potential miRNA target-binding sites in the 3'UTR of MMR genes may contribute to modulate CRC prognosis and predictivity of therapy.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2013-12-21
    Description: Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2015-07-29
    Description: The critical depth hypothesis (CDH) is a predictive criteria for the onset of phytoplankton blooms that comes from the steady-state analytical solution of a simple mathematical model for phytoplankton growth presented by Sverdrup in 1953. Sverdrup's phytoplankton-only model is very elementary compared with state-of-the-art ecosystem models whose numerical solution in a time-varying environment do not systematically conform to the CDH. To highlight which model ingredients make the bloom onset deviate from the CDH, the complexity of Sverdrup's model is incrementally increased, and the impact that each new level of complexity introduced is analysed. Complexity is added both to the ecosystem model and to the parameterization of physical forcing. In the most complete experiment, the model is a one-dimensional Nutrient-Phytoplankton-Zooplankton model that includes seasonally varying mixed layer depth and surface irradiance, light and nutrient limitation, variable grazing, self-shading, export, and remineralization. When complexity is added to the ecosystem model, it is found that the model solution only marginally deviates from the CDH. But when the physical forcing is also changed, the model solution can conform to two competing theories for the onset of phytoplankton blooms—the critical turbulence hypothesis and the disturbance recovery hypothesis. The key roles of three physical ingredients on the bloom onset are highlighted: the intensity of vertical mixing at the end of winter, the seasonal evolution of the mixed-layer depth from the previous summer, and the seasonal evolution of surface irradiance.
    Print ISSN: 1054-3139
    Electronic ISSN: 1095-9289
    Topics: Biology , Geosciences , Physics
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  • 7
    Publication Date: 2015-07-29
    Description: In this study, we document the regional variations of bloom phenology in the Southern Ocean, based on a 13-year product of ocean colour measurements co-located with observation-based estimates of the mixed-layer depth. One key aspect of our work is to discriminate between mixed-layer integrated blooms and surface blooms. By segregating blooms that occur before or after the winter solstice and blooms where integrated and surface biomass increase together or display a lag, we define three dominating Southern Ocean bloom regimes. While the regime definitions are solely based on bloom timing characteristics, the three regimes organize coherently in geographical space, and are associated with distinct dynamical regions of the Southern Ocean: the subtropics, the subantarctic, and the Antarctic Circumpolar Current region. All regimes have their mixed-layer integrated onset between autumn and winter, when the daylength is short and the mixed layer actively mixes and deepens. We discuss how these autumn–winter bloom onsets are controlled by either nutrient entrainment and/or reduction in prey-grazer encounter rate. In addition to the autumn–winter biomass increase, the subantarctic regime has a significant spring biomass growth associated with the shutdown of turbulence when air–sea heat flux switches from surface cooling to surface warming.
    Print ISSN: 1054-3139
    Electronic ISSN: 1095-9289
    Topics: Biology , Geosciences , Physics
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  • 8
    Publication Date: 2015-07-29
    Description: The seasonal cycle of phytoplankton biomass in the Southern Ocean (SO) is characterized by a period of rapid accumulation, known as bloom, that is typical of high-latitude regions. Recent studies have illustrated how spatial and temporal dynamics of blooms in the SO are more complex than in other oceans. This complexity is likely related to differences in vertical mixing and the iron availability. In this work, we examine the sensitivity of bloom dynamics to changes in vertical mixing and iron availability using a biogeochemical model. Under idealized physical forcing, we produce seasonal cycles of phytoplankton for an ensemble of SO scenarios and we describe the bloom dynamics in terms of the net biomass accumulation rate. Based on this metric, we define three crucial bloom phases: the onset, the climax, and the apex. For the ensemble of modelled blooms, onsets always occur in winter and can be either bottom-up (increase in productivity) or top-down (decrease in grazing) controlled. Climaxes are mostly found in spring and their magnitudes are bottom-up controlled. Apexes are always found in late spring and strongly top-down controlled. Our results show that while a "strict" onset definition is consistent with a winter onset, the surface spring bloom is associated with the climax of the integrated bloom. Furthermore, we demonstrate that onset phase can be distinguished from climax phase using appropriate bloom detection methods based on surface satellite-based products. The ensemble of these results suggests that Sverdrup's blooming conditions are not indicative of the bloom onset but of the climax. We conclude that the recent bloom onset debate may partly be due to a confusion between what is defined here as the bloom onset and the climax, and that the SO observed complexity is due to the factors that control the climax.
    Print ISSN: 1054-3139
    Electronic ISSN: 1095-9289
    Topics: Biology , Geosciences , Physics
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  • 9
  • 10
    Publication Date: 2010-10-14
    Print ISSN: 0142-7873
    Electronic ISSN: 1464-3774
    Topics: Biology
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