| 1. |
- Assi, Nada, et al.
(författare)
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A statistical framework to model the meeting-in-the-middle principle using metabolomic data : application to hepatocellular carcinoma in the EPIC study
- 2015
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 30:6, s. 743-753
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Tidskriftsartikel (refereegranskat)abstract
- Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum H-1 nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.
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| 8. |
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| 9. |
- Di Bucchianico, S., et al.
(författare)
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Genotoxicity of TiO2 nanoparticles assessed by mini-gel comet assay and micronucleus scoring with flow cytometry
- 2017
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Ingår i: Mutagenesis. - : Oxford University Press. - 0267-8357 .- 1464-3804. ; 32:1, s. 127-137
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Tidskriftsartikel (refereegranskat)abstract
- The widespread production and use of nanoparticles calls for faster and more reliable methods to assess their safety. The main aim of this study was to investigate the genotoxicity of three reference TiO2 nanomaterials (NM) within the frame of the FP7-NANoREG project, with a particular focus on testing the applicability of mini-gel comet assay and micronucleus (MN) scoring by flow cytometry. BEAS-2B cells cultured under serum-free conditions were exposed to NM100 (anatase, 50-150 nm), NM101 (anatase, 5-8 nm) and NM103 (rutile, 20-28 nm) for 3, 24 or 48 h mainly at concentrations 1-30 μg/ml. In the mini-gel comet assay (eight gels per slide), we included analysis of (i) DNA strand breaks, (ii) oxidised bases (Fpg-sensitive sites) and (iii) light-induced DNA damage due to photocatalytic activity. Furthermore, MN assays were used and we compared the results of more high-throughput MN scoring with flow cytometry to that of cytokinesis-block MN cytome assay scored manually using a microscope. Various methods were used to assess cytotoxic effects and the results showed in general no or low effects at the doses tested. A weak genotoxic effect of the tested TiO2 materials was observed with an induction of oxidised bases for all three materials of which NM100 was the most potent. When the comet slides were briefly exposed to lab light, a clear induction of DNA strand breaks was observed for the anatase materials, but not for the rutile. This highlights the risk of false positives when testing photocatalytically active materials if light is not properly avoided. A slight increase in MN formation for NM103 was observed in the different MN assays at the lower doses tested (1 and 5 μg/ml). We conclude that mini-gel comet assay and MN scoring using flow cytometry successfully can be used to efficiently study cytotoxic and genotoxic properties of nanoparticles.
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| 10. |
- Druzhinin, VG, et al.
(författare)
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Genetic damage in lymphocytes of lung cancer patients is correlated to the composition of the respiratory tract microbiome
- 2021
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 1464-3804 .- 0267-8357. ; 36:2, s. 143-153
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings indicate that the microbiome may have significant impact on the development of lung cancer by its effects on inflammation, dysbiosis or genome damage. The aim of this study was to compare the sputum microbiome of lung cancer (LC) patients with the chromosomal aberration (CA) and micronuclei (MN) frequency in peripheral blood lymphocytes. In the study, the taxonomic composition of the sputum microbiome of 66 men with untreated LC were compared with 62 control subjects with respect to CA and MN frequency and centromere fluorescence in situ hybridisation analysis. Results showed a significant increase in CA (4.11 ± 2.48% versus 2.08 ± 1.18%) and MN (1.53 ± 0.67% versus 0.87 ± 0.49%) frequencies, respectively, in LC patients as compared to control subjects. The higher frequency of centromeric positive MN of LC patients was mainly due to aneuploidy. A significant increase in Streptococcus, Bacillus, Gemella and Haemophilus in LC patients was detected, in comparison to the control subjects while 18 bacterial genera were significantly reduced, which indicates a decrease in the beta diversity in the microbiome of LC patients. Although, the CA frequency in LC patients is significantly associated with an increased presence of the genera Bacteroides, Lachnoanaerobaculum, Porphyromonas, Mycoplasma and Fusobacterium in their sputum, and a decrease for the genus Granulicatella after application of false discovery rate correction, significance was not any more present. The decrease of MN frequency of LC patients is significantly associated with an increase in Megasphaera genera and Selenomonas bovis. In conclusion, a significant difference in beta diversity of microbiome between LC and control subjects and association between the sputum microbiome composition and genome damage of LC patients was detected, thus supporting previous studies suggesting an etiological connection between the airway microbiome and LC.
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| 11. |
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| 16. |
- Gallo, Valentina, et al.
(författare)
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STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement
- 2012
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 27:1, s. 17-29
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Tidskriftsartikel (refereegranskat)abstract
- Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and / or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.
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| 17. |
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| 18. |
- Golkar, Siv Österman, et al.
(författare)
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Intracellular deoxyribonucleotide pool imbalance and DNA damage in cells treated with hydroxyurea, an inhibitor of ribonucleotide reductase
- 2013
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 28:6, s. 653-660
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Tidskriftsartikel (refereegranskat)abstract
- Imbalance in the nucleotide pool of mammalian cells has been shown to result in genotoxic damage. The goal of this study was to devise a sensitive, reproducible and simple method for detection of nucleotide pool changes in mammalian cells that could be used for problem-solving activities in drug development, e.g. mechanistic explanation of a positive response in a mammalian in vitro genotoxicity test. The method evaluated in this study is based on ethanol extraction of the total nucleotide pool, heat treatment and filtration, treatment with calf intestine alkaline phosphatase to convert nucleotides to nucleosides and analysis of the nucleosides by high-performance liquid chromatography with ultraviolet detection. The method was applied to measure the intracellular levels of deoxyribonucleotides in mouse lymphoma (ML) L5178Y cells treated with various concentrations of a model compound, hydroxyurea (HU), a ribonucleotide reductase inhibitor. DNA strand breakage and micronuclei formation were assessed in the same experiments. Imbalance of nucleotide pool (i.e. changes in the relative ratios between individual nucleotide pools) in HU-treated ML cells has been observed already at a concentration of 0.01 mmol/l, whereas genotoxic effects became apparent only at higher concentrations of HU (i.e. 0.25 mmol/l and higher) as indicated by formation of DNA strand breaks and micronuclei.
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| 19. |
- Gottipati, Ponnari, et al.
(författare)
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Transcription-associated recombination in eukaryotes : link between transcription, replication and recombination.
- 2009
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 1464-3804 .- 0267-8357. ; 24:3, s. 203-10
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Tidskriftsartikel (refereegranskat)abstract
- Homologous recombination (HR) is an important DNA repair pathway and is essential for cellular survival. It plays a major role in repairing replication-associated lesions and is functionally connected to replication. Transcription is another cellular process, which has emerged to have a connection with HR. Transcription enhances HR, which is a ubiquitous phenomenon referred to as transcription-associated recombination (TAR). Recent evidence suggests that TAR plays a role in inducing genetic instability, for example in the THO mutants (Tho2, Hpr1, Mft1 and Thp2) in yeast or during the development of the immune system leading to genetic diversity in mammals. On the other hand, evidence also suggests that TAR may play a role in preventing genetic instability in many different ways, one of which is by rescuing replication during transcription. Hence, TAR is a double-edged sword and plays a role in both preventing and inducing genetic instability. In spite of the interesting nature of TAR, the mechanism behind TAR has remained elusive. Recent advances in the area, however, suggest a link between TAR and replication and show specific genetic requirements for TAR that differ from regular HR. In this review, we aim to present the available evidence for TAR in both lower and higher eukaryotes and discuss its possible mechanisms, with emphasis on its connection with replication.
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| 20. |
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| 21. |
- Honma, Masamitsu, et al.
(författare)
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Improvement of quantitative structure-activity relationship (QSAR) tools for predicting Ames mutagenicity : outcomes of the Ames/QSAR International Challenge Project
- 2019
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Ingår i: Mutagenesis. - Oxford : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 34:1, s. 3-16
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Tidskriftsartikel (refereegranskat)abstract
- The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models.
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| 22. |
- Huhn, Stefanie, et al.
(författare)
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Ancestral susceptibility to colorectal cancer
- 2012
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 27:2, s. 197-204
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Tidskriftsartikel (refereegranskat)abstract
- Every year, approximately 1 million new colorectal cancer (CRC) cases are diagnosed and about half a million people worldwide die due to this cancer. Known differences in CRC incidence rates are mainly attributed to differences in diet and other environmental factors represented, among others, by nutrition-related complex diseases (e.g. obesity and diabetes mellitus type II). Within the last years, it has become evident that environmental risk factors can be complemented by a genetic component when considering the risk of CRC. For example, a number of polymorphisms are known to be associated with an increased risk of obesity and obesity is a risk factor for CRC. Several studies have shown that the 'ancestral-susceptibility model' can be reasonably applied to nutrition-related complex diseases such as obesity. The work in hand shortly discusses whether the ancestral-susceptibility model can also be applied to CRC as a nutrition-related complex disease.
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- Lebedova, Jana, et al.
(författare)
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Size-dependent genotoxicity of silver, gold and platinum nanoparticles studied using the mini-gel comet assay and micronucleus scoring with flow cytometry
- 2018
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Ingår i: Mutagenesis. - : OXFORD UNIV PRESS. - 0267-8357 .- 1464-3804. ; 33:1, s. 77-85
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Tidskriftsartikel (refereegranskat)abstract
- Metallic nanoparticles (NPs) are promising nanomaterials used in different technological solutions as well as in consumer products. Silver (Ag), gold (Au) and platinum (Pt) represent three metallic NPs with current or suggested use in different applications. Pt is also used as vehicle exhaust catalyst leading to a possible exposure via inhalation. Despite their use, there is limited data on their genotoxic potential and possible size-dependent effects, particularly for Pt NPs. The aim of this study was to explore size-dependent genotoxicity of these NPs (5 and 50 nm) following exposure of human bronchial epithelial cells. We characterised the NPs and assessed the viability (Alamar blue assay), formation of DNA strand breaks (mini-gel comet assay) and induction of micronucleus (MN) analysed using flow cytometry (in vitro microflow kit). The results confirmed the primary size (5 and 50 nm) but showed agglomeration of all NPs in the serum free medium used. Slight reduced cell viability (tested up to 50 mu g/ml) was observed following exposure to the Ag NPs of both particle sizes as well as to the smallest (5 nm) Au NPs. Similarly, at non-cytotoxic concentrations, both 5 and 50 nm-sized Ag NPs, as well as 5 nm-sized Au NPs, increased DNA strand breaks whereas for Pt NPs only the 50 nm size caused a slight increase in DNA damage. No clear induction of MN was observed in any of the doses tested (up to 20 mu g/ml). Taken together, by using the comet assay our study shows DNA strand breaks induced by Ag NPs, without any obvious differences in size, whereas effects from Au and Pt NPs were size-dependent in the sense that the 5 nm-sized Au NPs and 50 nm-sized Pt NPs particles were active. No clear induction of MN was observed for the NPs.
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| 31. |
- Liljendahl, Tove Sandberg, et al.
(författare)
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Urinary levels of thymine dimer as a biomarker of exposure to ultraviolet radiation in humans during outdoor activities in the summer
- 2013
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 28:3, s. 249-256
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of skin cancer is rising rapidly in many countries, presumably due to increased leisure time exposure to solar ultraviolet radiation (UVR). UVR causes DNA lesions, such as the thymine dimer (T=T), which have been causatively linked to the development of skin cancer. T=T is clearly detectable in urine and may, thereby, be a potentially valuable biomarker of UVR exposure. The objective of this study was to evaluate the relationship between UVR exposure and urinary levels of T=T in a field study involving outdoor workers. Daily ambient and personal exposure of 52 beach lifeguards and agricultural workers to UVR were determined (employing 656 personal polysulphone dosimeters). In 22 of these subjects, daily urinary T=T levels (120 samples) were measured, the area of skin exposed calculated and associations assessed utilizing mixed statistical models. The average daily UVR dose was approximately 600 J/m(2) (7.7 standard erythemal doses), i.e. about 20% of ambient UVR. T=T levels were correlated to UVR dose, increasing by about 6 fmol/mu mol creatinine for each 100 J/m(2) increase in dose (average of the three preceding days). This is the first demonstration of a relationship between occupational UVR exposure and urinary levels of a biomarker of DNA damage. On a population level, urinary levels of T=T can be used as a biomarker for UVR exposure in the field.
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| 32. |
- Mandle, Hannah B., et al.
(författare)
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Inflammation and gut barrier function-related genes and colorectal cancer risk in western European populations
- 2024
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Ingår i: Mutagenesis. - : Oxford University Press. - 0267-8357 .- 1464-3804.
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Tidskriftsartikel (refereegranskat)abstract
- Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases = 1001; Ncontrols = 667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted <= 0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted <= 0.04) and at the gene level (Punadjusted <= 0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at an SNP and gene level (both Punadjusted <= 0.01), but not colon cancer. Genes and SNPs were selected a priori; therefore, we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia, and CRC development.
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| 33. |
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| 34. |
- Naccarati, A., et al.
(författare)
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Mutations and polymorphisms in TP53 gene-an overview on the role in colorectal cancer
- 2012
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 27:2, s. 211-218
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Tidskriftsartikel (refereegranskat)abstract
- A functionally normal TP53 is essential to protect organisms from developing cancer. Somatic mutations in the gene represent one of the highest recurring perturbations in human tumours, including colorectal cancer (CRC). However, the variegated phenotype of wide spectrum of somatic mutations in TP53 and the complexity of the disease prevent a straight interpretation of the mutational analysis in tumours. In addition to the presence of somatic mutations, polymorphic features of the gene may also contribute to alteration of the normal TP53 functioning and variants, mainly in the form of single nucleotide polymorphisms, can be expected to impact susceptibility to sporadic CRC. In the present study, we reviewed the potential role of alterations in the TP53 gene, both somatic mutations and inherited sequence variations, in predisposition to CRC and in the prognosis and response to therapy. The available data from association studies have mostly shown contradictory outcomes. The majority of the studies were based on limited sample sizes and focussed on a limited number of polymorphisms, with main being the rs1042522 (Arg72Pro). Thus far, there is no possible generalisation of the role of TP53 as also a predictor of therapeutic response and prognosis. The effects of TP53, and its abnormalities, on the response of tumours to cytotoxic drugs, radiation and chemoradiation are complex. However, from studies it is emerging that the inherited genetics of TP53 pathway components could be utilised to further define patient populations in their abilities to induce p53 activity in response to either DNA damaging or p53-targeted therapies.
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| 35. |
- Nagy, E, et al.
(författare)
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Accelerated 32P-HPLC for bulky DNA adducts
- 2009
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Ingår i: MUTAGENESIS. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 24:6, s. 541-541
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Norinder, Ulf, 1956-, et al.
(författare)
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Predicting Ames Mutagenicity Using Conformal Prediction in the Ames/QSAR International Challenge Project
- 2019
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Ingår i: Mutagenesis. - : Oxford University Press. - 0267-8357 .- 1464-3804. ; 34:1, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- Valid and predictive models for classifying Ames mutagenicity have been developed using conformal prediction. The models are Random Forest models using signature molecular descriptors. The investigation indicates, on excluding not-strongly mutagenic compounds (class B), that the validity for mutagenic compounds is increased for the predictions based on both public and the Division of Genetics and Mutagenesis, National Institute of Health Sciences of Japan (DGM/NIHS) data while less so when using only the latter data source. The former models only result in valid predictions for the majority, non-mutagenic, class whereas the latter models are valid for both classes, i.e. mutagenic and non-mutagenic compounds. These results demonstrate the importance of data consistency manifested through the superior predictive quality and validity of the models based only on DGM/NIHS generated data compared to a combination of this data with public data sources.
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| 40. |
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| 41. |
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| 42. |
- Savolainen, Linda, et al.
(författare)
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The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells
- 2010
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 25:6, s. 623-629
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of XPD in nucleotide excision repair explains the increased risk of skin cancer in XP patients, but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD defective cells, suggesting that transcription underlie a portion of spontaneous HR events. We also report that transcription-coupled repair (TCR) defective CSB cells, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB deficient cells. In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR.
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| 43. |
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| 44. |
- Shakeri Manesh, Sara, et al.
(författare)
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MTH1, an 8-oxo-2'-deoxyguanosine triphosphatase, and MYH, a DNA glycosylase, cooperate to inhibit mutations induced by chronic exposure to oxidative stress of ionising radiation
- 2017
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 32:3, s. 389-396
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Tidskriftsartikel (refereegranskat)abstract
- Our previous results showed that in addition to the immediate interaction of ionising radiation with DNA (direct and indirect effect), low-dose and chronic low-dose rate of irradiation induce endogenous oxidative stress. During oxidative stress, free radicals react with DNA, nucleoside triphosphates (dNTPs), proteins and lipids, and modify their structures. The MYH and MTH1 genes play important roles in preventing mutations induced by 8-hydroxy-guanine, which is an oxidised product of guanine. In this study, we used short-hairpin RNA to permanently knockdown MYH and MTH1 proteins in human lymphoblastoid TK6 cells. Knockdown and wild-type cells were chronically exposed to low dose rates of gamma-radiation (between 1.4 and 30 mGy/h). The cells were also subjected to acute doses delivered at a high-dose rate. Growth rate, extracellular 8-hydroxy-2'-deoxyguanosine, clonogenic cell survival and mutant frequencies were analysed in all cell types. A reduced level of cell growth and survival as well as increased mutant frequencies were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild-type cells. To sum up, our results suggest that low-dose rates elevate oxidative stress. MTH1 together with MYH plays an important role in protection against mutations induced by modified dNTPs during chronic oxidative stress. In addition, we found no dose-rate effect at the level of mutations in the wild-type TK6 and MYH-KD cells. Our data interestingly indicate a dose-rate threshold for mutation induction in MTH1/MYH double knockdown cells.
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| 45. |
- Shaposhnikov, Sergey, et al.
(författare)
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Detection of Alu sequences and mtDNA in comets using padlock probes
- 2006
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 21:4, s. 243-247
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Tidskriftsartikel (refereegranskat)abstract
- Single cell gel electrophoresis, or the comet assay, is widely used to measure DNA damage and repair. However, the behaviour of the DNA under the conditions used for the comet assay is not fully understood. In developing a method for studying specific gene sequences within comets, using 'padlock probes' (circularizable oligonucleotide probes), we have first applied probes that hybridize to Alu repetitive elements and to mitochondrial DNA (mtDNA). During the sequence of stages in the comet assay, mtDNA progressively disperses into the surrounding agarose gel, showing no tendency to remain with nuclear DNA in the comets. In contrast, Alu probes remain associated with both tail and head DNA.
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| 46. |
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| 47. |
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| 48. |
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| 49. |
- Tornqvist, M, et al.
(författare)
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Lars!Ehrenberg (1921-2005) -: Obituary
- 2006
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Ingår i: MUTAGENESIS. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 21:1, s. 1-2
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 50. |
- Vineis, Paolo, et al.
(författare)
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Expectations and challenges stemming from genome-wide association studies
- 2008
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Ingår i: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 23:6, s. 439-444
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- There are considerable expectations about the ability of genome-wide association (GWA) studies to make exciting discoveries about the role of genes in common diseases. GWA studies may allow researchers to identify causal pathways that have not been unveiled before, thus opening new avenues to disease understanding, prevention and therapy. However, there are still many open challenges. One is how to analyse these studies. The problem of false positives and false negatives provides an interesting methodological stimulus to find optimal solutions. Once main genetic effects have been concretely documented, the next question is how to proceed with the investigation of gene-gene and gene-environment interactions. It is possible that what really counts is not the main effect of genes but complex interactions. Finding and interpreting such interactions is not straightforward. Finally, continuous updated integration of all evidence, from both old studies, current GWA investigations and future replication studies, and careful interpretation of the strength of the evidence are crucial to maximize transparency and lead to informative selection of the next steps of research in this field. The present Commentary is a report of an Environmental Cancer Risk, Nutrition and Individual Susceptibility network Workshop held in Venice in October 2007 and discusses some of the problems outlined above, with examples.
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