No / Telomerase-targeted strategies have aroused recent interest in anti-cancer chemotherapy, because DNA-binding drugs can interact with high-order tetraplex rather than double-stranded (duplex) DNA targets in tumour cells. However, the protracted cell-drug exposure times necessary for clinical application require that telomerase inhibitory efficacy must be accompanied by both low inherent cytotoxicity and the absence of mutagenicity/genotoxicity. For the first time, the genotoxicity of a number of structurally diverse DNA-interactive telomerase inhibitors is examined in the Ames test using six Salmonella typhimurium bacterial strains (TA1535, TA1537, TA1538, TA98, TA100, and TA102). DNA damage induced by each agent was also assessed using the Comet assay with human lymphocytes. The two assay procedures revealed markedly different genotoxicity profiles that are likely to reflect differences in metabolism and/or DNA repair between bacterial and mammalian cells. The mutational spectrum for a biologically active fluorenone derivative, shown to be mutagenic in the TA100 strain, was characterised using a novel and rapid assay method based upon PCR amplification of a fragment of the hisG46 allele, followed by RFLP analysis. Preliminary analysis indicates that the majority (84%) of mutations induced by this compound are C→A transversions at position 2 of the missense proline codon of the hisG46 allele. However, despite its genotoxic bacterial profile, this fluorenone agent gave a negative response in the Comet assay, and demonstrates how unwanted systemic effects (e.g., cytotoxicity and genotoxicity) can be prevented or ameliorated through suitable molecular fine-tuning of a candidate drug in targeted human tumour cells. / CAEB, Balearic Islands and Yorkshire Cancer Research

Yes / Genotoxic compounds have induced DNA damage in male germ cells and have been associated with adverse clinical outcomes including enhanced risks for maternal, paternal and offspring health. DNA strand breaks represent a great threat to the genomic integrity of germ cells. Such integrity is essential to maintain spermatogenesis and prevent reproduction failure. The Comet assay results revealed that the incubation of isolated germ cells with n-ethyl-n-nitrosourea (ENU), 6-mercaptopurine (6-MP) and methyl methanesulphonate (MMS) led to increase in length of Olive tail moment and % tail DNA when compared with the untreated control cells and these effects were concentration-dependent. All compounds were significantly genotoxic in cultured germ cells. Exposure of isolated germ cells to ENU produced the highest concentration-related increase in both DNA damage and gene expression changes in spermatogonia. Spermatocytes were most sensitive to 6-MP, with DNA damage and gene expression changes while spermatids were particularly susceptible to MMS. Real-time PCR results showed that the mRNA level expression of p53 increased and bcl-2 decreased significantly with the increasing ENU, 6-MP and MMS concentrations in spermatogonia, spermatocytes and spermatids respectively for 24 hr. Both are gene targets for DNA damage response and apoptosis. These observations may help explain the cell alterations caused by ENU, 6-MP and MMS in spermatogonia, spermatocytes and spermatids. Taken together, ENU, 6-MP and MMS induced DNA damage and decreased apoptosis associated gene expression in the germ cells in vitro. / Libyan Government

Yes / Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may be protective against tumours, including breast cancer. We have studied the effects of ibuprofen and aspirin on DNA damage in lymphocytes obtained from breast cancer patients and healthy female controls. Both nanoparticle (NPs) and bulk formulations were used in the comet and micronucleus (MN) assays. Non-toxic doses (250 ng/ml ibuprofen; 500 ng/ml aspirin) were tested. Aspirin, both bulk and nano formulations, significantly reduced DNA damage measured with the comet and micronucleus assays; the nano formulation was more effective. Ibuprofen was not effective in the comet assay but showed a significant reduction in MN frequency, with the nano formulation being more effective. NPs may have better penetration through the nuclear membrane relative to the bulk formulation. NSAIDs such as aspirin and ibuprofen may have a promising role in cancer prevention and treatment. / LIBYAN GOVERNMENT

Yes / Our previous case-control study observed isolated lymphocytes from 208 individuals and determined the differences in the sensitivity to genomic damage of lymphocytes derived from cancer patients, pre/suspect cancer patients and healthy volunteers using the Comet assay (Anderson et al, 2014). We adapted the LGS technique using a slightly different method and examined 700 more blood samples from 598 patients with cancer or suspected cancer and 102 healthy individuals. To help increase the sensitivity of the test and detect cancer at the level of each individual, we joined with the IMSTAR team who analysed our cells with their fully automated Pathfinder™ cell reader-analyser system. With this reading and analysis system 4,000 to 10,000 cells were able to be read per slide. The new test which is called TumorScan is a highly sensitive test to detect any cancer at an early stage through the response of the white blood cells to UV treatment. These patient blood samples have also been collected at the stage before confirming diagnosis and treatment. There were four of these individuals with cancer who had received anti-cancer treatment. The results from these patients showed a reverse pattern compared to non-treated cancer patients and followed the pattern seen in healthy individuals. The results are consistent with the early results as reported in the above 2014 paper. Given the results from these samples were in a particularly challenging subgroup, whose cancer status was difficult to distinguish, the data suggest that the technique using the TumorScan system could exceed the area under the ROC curve >93% obtained in the earlier study on a group basis, whereas this present study was to detect cancer at an early stage in each individual. / Department of Research and Knowledge Transfer at the University of Bradford, Bradford, UK

No description available.

O objetivo deste estudo é descrever o dano de DNA através das variáveis Tail Moment e Tail Intensity e investigar a associação entre o dano do DNA, padrão alimentar e concentrações plasmáticas de vitaminas em crianças e adolescentes em Ribeirão Preto (São Paulo, Brasil). Estudantes de 9 a 13 anos foram selecionados de três escolas de Ribeirão Preto (São Paulo, Brasil), totalizando uma amostra de 120 indivíduos. A coleta de dados incluiu antropometria, composição corporal, avaliação da ingestão utilizando um questionário de frequência alimentar (QFA) e o Índice de Qualidade da Dieta Revisado (IQD-R) e coleta de sangue para a dosagem de vitaminas e determinação do dano do DNA pelo método de eletroforese em gel de célula única - comet assay. Os indivíduos foram divididos em dois grupos opostos de dano do DNA usando duas técnicas distintas: análise de k-cluster e classificação por escala de dano. Padrões de ingestão de nutrientes também foram gerados, utilizando robust sparse k-means cluster, e associados com o dano de DNA. Para análise utilizaram-se os testes T de Student, Mann-Whitney e ANCOVA. Na primeira análise, o cluster 1 (n = 73), com menor dano de DNA, apresentou maior consumo de vegetais verdes escuros e alaranjados (p = 0,047), vegetais totais (p = 0,041) e carnes, ovos e leguminosas (p = 0,022), através do IQD-R, e um escore de IQD total maior (p = 0,030), indicando melhor qualidade de dieta em comparação ao cluster 2 (n = 47), de maior dano de DNA. O cluster 2 apresentou maior consumo de laticínios, em comparação ao cluster 1 (p = 0,008). Em relação a vitaminas plasmáticas, o cluster 1 apresentou maior concentração de riboflavina (p = 0,004). No segundo método de divisão, o grupo 1 (n = 108), com menor dano de DNA, apresentou maior concentração de retinol (p = 0,010), beta-caroteno (p = 0,017) e riboflavina (p = 0,046), após teste de ANCOVA ajustado para o índice de massa corporal (IMC) em comparação ao grupo 2 (n = 12). Na divisão por padrão alimentar, o cluster 2 (n = 58), com menor consumo de aminoácidos e micronutrientes, apresentou maior consumo de energia (p = 0,001) e uma tendência de maior dano do DNA (p = 0,063) em relação ao cluster 1 (n = 27), com maior ingestão de nutrientes. Estes achados corroboram a literatura, afirmando o papel protetor de vitaminas e antioxidantes contra o dano do DNA. / The aim of this study is to describe the DNA damage using values of Tail Moment and Tail Intensity and investigate the association between DNA damage, dietary pattern and vitamin status in children and adolescents in Ribeirão Preto (São Paulo, Brazil). 9 to 13 year old students were selected from three schools in the city of Ribeirão Preto (São Paulo, Brazil), totalizing a sample of 120 subjects. Data collection included anthropometry, body composition, assessment of food intake using a food frequency questionnaire (FFQ), quality of diet through Revised Health Eating Index (HEI-R), and blood sampling for vitamins dosage and determination of DNA damage with single cell gel electrophoresis - comet assay. The subjects were divided into two opposing groups according to DNA damage using two different methods: k-cluster analysis and classification by scale of damage. Nutrients intake patterns were also generated through robust sparse k-means cluster and associated with DNA damage. The statistical analysis were performed using Student\'s T test, Mann-Whitney test and ANCOVA. In the first analysis, cluster 1 (n = 73), with less DNA damage presented higher intake of dark green and orange vegetables (p = 0,047), total vegetables (p = 0,041), meat, eggs and legumes (p = 0,022), assessed through HEI, as well as a higher total HEI-R level (p = 0,030), indicating higher quality of diet compared to cluster 2 (n = 47), with increased DNA damage. Cluster 2 presented a higher intake of milk and dairy products, compared to cluster 1 (p = 0,008). In relation to vitamins plasma levels, cluster 1 presented higher levels of riboflavin (p = 0,004). In the second method of division, group 1 (n = 108), with less DNA damage, presented higher levels of retinol (p = 0,010), beta-carotene (p = 0,017) and riboflavin (p = 0,046), after ANCOVA teste adjusted for body mass index (BMI) compared to group 2 (n = 12). In the division by dietary pattern, cluster 2 (n = 58) with a lower consumption of amino acids and micronutrients had higher energy intake (p = 0,001) and a tendency of higher DNA damage (p = 0,063) compared to cluster 1(n = 27), with higher intake of nutrients. These findings corroborate the literature, asserting protective role of vitamins and antioxidants against DNA damage.

O objetivo deste estudo é descrever o dano de DNA através das variáveis Tail Moment e Tail Intensity e investigar a associação entre o dano do DNA, padrão alimentar e concentrações plasmáticas de vitaminas em crianças e adolescentes em Ribeirão Preto (São Paulo, Brasil). Estudantes de 9 a 13 anos foram selecionados de três escolas de Ribeirão Preto (São Paulo, Brasil), totalizando uma amostra de 120 indivíduos. A coleta de dados incluiu antropometria, composição corporal, avaliação da ingestão utilizando um questionário de frequência alimentar (QFA) e o Índice de Qualidade da Dieta Revisado (IQD-R) e coleta de sangue para a dosagem de vitaminas e determinação do dano do DNA pelo método de eletroforese em gel de célula única - comet assay. Os indivíduos foram divididos em dois grupos opostos de dano do DNA usando duas técnicas distintas: análise de k-cluster e classificação por escala de dano. Padrões de ingestão de nutrientes também foram gerados, utilizando robust sparse k-means cluster, e associados com o dano de DNA. Para análise utilizaram-se os testes T de Student, Mann-Whitney e ANCOVA. Na primeira análise, o cluster 1 (n = 73), com menor dano de DNA, apresentou maior consumo de vegetais verdes escuros e alaranjados (p = 0,047), vegetais totais (p = 0,041) e carnes, ovos e leguminosas (p = 0,022), através do IQD-R, e um escore de IQD total maior (p = 0,030), indicando melhor qualidade de dieta em comparação ao cluster 2 (n = 47), de maior dano de DNA. O cluster 2 apresentou maior consumo de laticínios, em comparação ao cluster 1 (p = 0,008). Em relação a vitaminas plasmáticas, o cluster 1 apresentou maior concentração de riboflavina (p = 0,004). No segundo método de divisão, o grupo 1 (n = 108), com menor dano de DNA, apresentou maior concentração de retinol (p = 0,010), beta-caroteno (p = 0,017) e riboflavina (p = 0,046), após teste de ANCOVA ajustado para o índice de massa corporal (IMC) em comparação ao grupo 2 (n = 12). Na divisão por padrão alimentar, o cluster 2 (n = 58), com menor consumo de aminoácidos e micronutrientes, apresentou maior consumo de energia (p = 0,001) e uma tendência de maior dano do DNA (p = 0,063) em relação ao cluster 1 (n = 27), com maior ingestão de nutrientes. Estes achados corroboram a literatura, afirmando o papel protetor de vitaminas e antioxidantes contra o dano do DNA. / The aim of this study is to describe the DNA damage using values of Tail Moment and Tail Intensity and investigate the association between DNA damage, dietary pattern and vitamin status in children and adolescents in Ribeirão Preto (São Paulo, Brazil). 9 to 13 year old students were selected from three schools in the city of Ribeirão Preto (São Paulo, Brazil), totalizing a sample of 120 subjects. Data collection included anthropometry, body composition, assessment of food intake using a food frequency questionnaire (FFQ), quality of diet through Revised Health Eating Index (HEI-R), and blood sampling for vitamins dosage and determination of DNA damage with single cell gel electrophoresis - comet assay. The subjects were divided into two opposing groups according to DNA damage using two different methods: k-cluster analysis and classification by scale of damage. Nutrients intake patterns were also generated through robust sparse k-means cluster and associated with DNA damage. The statistical analysis were performed using Student\'s T test, Mann-Whitney test and ANCOVA. In the first analysis, cluster 1 (n = 73), with less DNA damage presented higher intake of dark green and orange vegetables (p = 0,047), total vegetables (p = 0,041), meat, eggs and legumes (p = 0,022), assessed through HEI, as well as a higher total HEI-R level (p = 0,030), indicating higher quality of diet compared to cluster 2 (n = 47), with increased DNA damage. Cluster 2 presented a higher intake of milk and dairy products, compared to cluster 1 (p = 0,008). In relation to vitamins plasma levels, cluster 1 presented higher levels of riboflavin (p = 0,004). In the second method of division, group 1 (n = 108), with less DNA damage, presented higher levels of retinol (p = 0,010), beta-carotene (p = 0,017) and riboflavin (p = 0,046), after ANCOVA teste adjusted for body mass index (BMI) compared to group 2 (n = 12). In the division by dietary pattern, cluster 2 (n = 58) with a lower consumption of amino acids and micronutrients had higher energy intake (p = 0,001) and a tendency of higher DNA damage (p = 0,063) compared to cluster 1(n = 27), with higher intake of nutrients. These findings corroborate the literature, asserting protective role of vitamins and antioxidants against DNA damage.

The Comet Interceptor is a joint mission by European Space Agency (ESA) and Japan Aerospace Exploration Agency (JAXA) which seeks to perform a flyby over a Long Period Comet using a multi-element spacecraft. The Comet Interceptor comprises three spacecrafts- A, B1 and B2. All three spacecrafts will observe and map the comet at three different points on the coma of the comet, thereby making this mission the first ever multipoint mission dedicated to study a Long Period Comet. Out of the eleven instruments aboard the Comet Interceptor, the work done for this thesis aims to help the team designing the instrument-Optical Periscope Imager forComets (OPIC). The team designing OPIC uses the imaging simulation software Space Imaging Simulator for Proximity Operations (SISPO) to render images of theoretically modelled dust and gas densities of the coma of a comet to obtain prerequisite knowledge of the images which is to be taken by OPIC during its flyby. Using the theoretical model of the coma, a 3D model was created as part of the thesis which shall be later implemented in SISPO. The structure of the coma was made with the help of a sparse volumetric data manipulation tool OpenVDB, which was coded and run in Python. The generated data was imported in Blender to visualise the volumetric data with the help of Blender’s rendering engine-Cycles. To visualise the 3D model with utmost physical realism as the software Blender allows, a study on the scattering properties of the dust and gas model was done. Also, a motion blur was implemented in Blender to simulate the high relative velocity between the instrument and comet. Multiple approaches of varying complexities and time consumption were considered for importing and visualising the volumetric data. The final render images were brightness-matched with reference to images from previous cometary missions. Finally, a qualitative analysis was done by visually comparing the render images to the images from previous missions. With the help of this qualitative analysis, several features and characteristics were identified which were analogous to the real life images, thus establishing the correctness of the renders produced.

Le sélénium est reconnu comme un micronutriment important pour l'homme et les animaux. Plusieurs études ont montré qu'une supplementation en sélénium dans le régime alimentaire pourrait être bénéfique contre les cancers du foie, du colon, du pancréas et de la prostate. Le mécanisme anti-carcinogène du sélénium se produit au niveau systémique, cellulaire et nucléaire. Ces processus peuvent également impliquer le système immunitaire et ne doivent pas être interprétés par un seul mécanisme. Jusqu'à présent son mécanisme d'action est encore inconnu. L'objectif de cette étude était d'étudier l'effet des composés du sélénium, à faibles concentrations, sur la capacité de réparation de l'ADN dans les cellules du cancer de la prostate LNCaP (p53 compétentes). Ce travail est divisé en trois parties. La première partie du travail a été consacrée à étudier l'effet des deux composés du sélénium (SS et SM) sur les propriétés cytotoxiques et génotoxiques de différents stress oxydatifs et non oxydatifs. Les résultats ont montré qu'un prétraitement avec une faible dose en Se stimulait la synthèse des sélénoprotéines, et protègait contre la toxicité et les dommages oxydatifs à l'ADN induites par les UVA ou H2O2, mais pas par MMS ou UVC. La deuxième partie a été consacrée à l'influence de la supplementation en sélénium sur la capacité de réparation de l'ADN. Notre travail a clairement montré l'augmentation de l'efficacité d'excision de certaines glycosylases que n'est pas nécessairement corrélée à une augmentation de l'expression génique et /ou protéiques. Enfin, la troisième partie de notre travail a été dédiée à l'optimisation de la technique Host Cell Reactivation (HCR) qui nous a permis d'étudier la capacité de réparation de l'ADN in cellulo, afin de cibler les partenaires impliqués dans la voie de signalisation affectées par la supplémentation en sélénium. En conclusion, nous pourront penser que le mécanisme d'action du sélénium est représenté par un délicat équilibre entre l'activation et la répression de l'activité de certaines protéines qui induit des changements conformationnels plus ou moins directement impliqués dans la réparation de l'ADN et la progression de la croissance cellulaire. / Selenium was recognized as an important micronutrient for both humans and animals. Several studies showed that increased selenium in the diet might be beneficial against liver, colon, pancreas and prostate cancer. The anticarcinogenic actions of Se occur at the systemic, cellular and nuclear level. These actions may also involve the immune system and thus cannot be interpreted by a single mechanism. Until now its mechanisms of action are not well understood. The objective of this study was to investigate the effect of selenocompounds at low doses on DNA repair capacity in the p53-proficient LNCaP prostate cancer cells. This work is divided into three parts. The first part of the work was devoted to study the effect of two selenocompounds (SS and SM) on the cytotoxic and genotoxic properties of various oxidative and non oxidative stresses. The results showed that low doses of Se pre-treatment stimulates selenoprotein synthesis, protects against toxicity and oxidative DNA damage induced by UVA or H2O2 but not by MMS or UVC. The second part of our investigation was devoted to the influence of selenium supplementation on DNA repair capacity. Our work clearly showed an increase in excision efficiency of the glycosylases activity that was not necessarily correlated with an increase of gene expression and/or protein levels. Finally, the third part of our work was devoted to the optimization of Host Cell Reactivation assay (HCR) to study the DNA repair capacity in cellulo, in order to target the partners involved in the signalling pathway affected by selenium supplementation. In conclusion, we could image that the mechanism of action of selenium is represented by a delicate balance between activation and repression of protein activity that induces conformational changes of several proteins more or less directly involved in DNA repair and progression of cell growth.

Dissertationsschrift zur Erlangung eines doctor medicinae (Dr.med.) der Medizinischen Fakultät Carl Gustav Carus der Technischen Universität Dresden