9 results on '"Ulla Vogel"'
Search Results
2. Primary genotoxicity in the liver following pulmonary exposure to carbon black nanoparticles in mice
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Katrin Loeschner, Nicklas Raun Jacobsen, Gitte Ravn-Haren, Trine Berthing, Anne T. Saber, Justyna Modrzynska, Ulla Vogel, Ingrid Elise Konow Weydahl, and Alicja Mortensen
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0301 basic medicine ,DNA damage ,Intratracheal instillation ,Health, Toxicology and Mutagenesis ,lcsh:Industrial hygiene. Industrial welfare ,Pharmacology ,Toxicology ,medicine.disease_cause ,Oral gavage ,03 medical and health sciences ,Mice ,Soot ,lcsh:RA1190-1270 ,Carbon black ,DNA strand breaks ,medicine ,Animals ,Intravenous injection ,lcsh:Toxicology. Poisons ,Inhalation Exposure ,Chemistry ,030111 toxicology ,Pulmonary inflammation ,Research ,Acute-phase protein ,technology, industry, and agriculture ,General Medicine ,Cerium oxide ,Pneumonia ,Comet assay ,Mice, Inbred C57BL ,030104 developmental biology ,Liver ,Injections, Intravenous ,Titanium dioxide ,Nanoparticles ,Female ,Genotoxicity ,Bronchoalveolar Lavage Fluid ,Carbon black nanoparticles ,lcsh:HD7260-7780.8 ,DNA Damage ,Mutagens - Abstract
Background Little is known about the mechanism underlying the genotoxicity observed in the liver following pulmonary exposure to carbon black (CB) nanoparticles (NPs). The genotoxicity could be caused by the presence of translocated particles or by circulating inflammatory mediators released during pulmonary inflammation and acute-phase response. To address this, we evaluated induction of pulmonary inflammation, pulmonary and hepatic acute-phase response and genotoxicity following exposure to titanium dioxide (TiO2), cerium oxide (CeO2) or CB NPs. Female C57BL/6 mice were exposed by intratracheal instillation, intravenous injection or oral gavage to a single dose of 162 μg NPs/mouse and terminated 1, 28 or 180 days post-exposure alongside vehicle control. Results Liver DNA damage assessed by the Comet Assay was observed after intravenous injection and intratracheal instillation of CB NPs but not after exposure to TiO2 or CeO2. Intratracheal exposure to NPs resulted in pulmonary inflammation in terms of increased neutrophils influx for all NPs 1 and 28 days post-exposure. Persistent pulmonary acute phase response was detected for all NPs at all three time points while only a transient induction of hepatic acute phase response was observed. All 3 materials were detected in the liver by enhanced darkfield microscopy up to 180 days post-exposure. In contrast to TiO2 and CeO2 NPs, CB NPs generated ROS in an acellular assay. Conclusions Our results suggest that the observed hepatic DNA damage following intravenous and intratracheal dosing with CB NPs was caused by the presence of translocated, ROS-generating, particles detected in the liver rather than by the secondary effects of pulmonary inflammation or hepatic acute phase response. Electronic supplementary material The online version of this article (10.1186/s12989-017-0238-9) contains supplementary material, which is available to authorized users.
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- 2018
3. The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk
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Olga M. Sinilnikova, Rudolf Kaaks, Pilar Amiano, Anne Tjønneland, José Ramón Quirós, Eiliv Lund, Daniele Campa, Carla H. van Gils, Göran Hallmans, Kay-Tee Khaw, H. Bas Bueno-de-Mesquita, Anika Hüsing, Sabina Rinaldi, Nicholas J. Wareham, Nathalie Chabbert-Buffet, Kim Overvad, Eva Ardanaz, Sabine Rohrmann, Vittorio Krogh, Federico Canzian, Giovanna Masala, Françoise Clavel-Chapelon, María Dolores Chirlaque, Per Lenner, Carlotta Sacerdote, Esther Molina-Montes, Guy Fagherazzi, Jakob Stegger, James McKay, N. Charlotte Onland-Moret, Salvatore Panico, Rosario Tumino, Afshan Siddiq, Birgit Teucher, Timothy J. Key, Erifili Oustoglou, Ruth C. Travis, Veronique Chajes, Dimosthenis Zylis, Ulla Vogel, Antonia Trichopoulou, Elio Riboli, Nadia Slimani, Heiner Boeing, Núria Sala, Eva Fisher, Wareham, Nicholas [0000-0003-1422-2993], Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, Campa, D, Hüsing, A, Mckay, Jd, Sinilnikova, O, Vogel, U, Tjønneland, A, Overvad, K, Stegger, J, Clavel Chapelon, F, Chabbert Buffet, N, Fagherazzi, G, Trichopoulou, A, Zylis, D, Oustoglou, E, Rohrmann, S, Teucher, B, Fisher, E, Boeing, H, Masala, G, Krogh, V, Sacerdote, C, Panico, Salvatore, Tumino, R, Onland Moret, Nc, van Gils, Ch, Bueno de Mesquita, Hb, Lund, E, Chirlaque, Md, Sala, N, Quirós, Jr, Ardanaz, E, Amiano, P, Molina Montes, E, Hallmans, G, Lenner, P, Travis, Rc, Key, Tj, Wareham, N, Khaw, Kt, Rinaldi, S, Slimani, N, Chajes, V, Siddiq, A, Riboli, E, Kaaks, R, Canzian, F., and [Campa D, Hüssing A, Rohrmann S, Teucher B, Kaaks R, Canzian F] German Cancer Research Center (DKFZ), Heidelberg, Germany. [McKay JD, Slimani N, Chajes V] International Agency for Research on Cancer, Lyon, France. [Sinilnikova O] Hospices Civils de Lyon/Centre Léon Bérard, UMR5201 CNRS-Université Claude Bernard, Lyon, France. [Vogel U] National Food Institute Technical University of Denmark, Denmark. [Tjønneland A] Danish Cancer Society, Copenhagen, Denmark. [Overvad K] Aarhus University Hospital, Aalborg, Denmark. [Stegger J] Department of Cardiology, Cardiovascular Research Centre, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark. [Clavel-Chapelon F, Chabbert-Buffet N, Fagherazzi G] Institut Gustave Roussy, Villejuif, France. [Trichopoulou A, Zylis D] WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. [Trichopoulou A, Oustoglou E] Hellenic Health Foundation, Athens, Greece. [Fisher E, Boeing H] German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany. [Masala G] Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy. [Krogh V] Istituto Nazionale dei Tumori (IRCCS), Milan, Italy. [Sacerdote C] CPO Piemonte, Turin, Italy. [Panico S] Department of Clinical and Experimental Medicine Federico II University, Naples, Italy. [Tumino R] Azienda Ospedaliera 'Civile M.P.Arezzo' Ragusa, Italy. [Onland-Moret NC, van Gils CH] Julius Center, University Medical Center, Utrecht, The Netherlands. [Bueno-de-Mesquita HB] National Institute for Public Health and the Environment, Bilthoven, The Netherlands. [Lund E] Institute of Community Medicine University of Tromsø, Tromsø, Norway. [Chirlaque MD] Murcia Regional Health Council, Murcia, Spain. [Sala N] Catalan Institute of Oncology, Barcelona, Spain. [Quirós JR] Consejería de Salud y Servicios Sanitarios Principado de Asturias, Oviedo, Spain. [Ardanaz E] Public Health Institute of Navarra, Pamplona, Spain. [Amiano P] Public Health Department of Gipuzkoa, San Sebastian, Spain. [Molina-Montes E] Andalusian School of Public Health, Granada, Spain. [Chirlaque MD, Amiano P, Molina-Montes E] CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. [Hallmans G, Lenner2 P] Umeå University, Umeå, Sweden. [Travis RC, Key TJ] Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK OX3 7LF. [Wareham N, Khaw KT] University of Cambridge, Cambridge, UK. [Siddiq A, Riboli E] Imperial College, London, UK.
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Oncology ,Aging ,Cancer Research ,Genome-wide association study ,32 Biomedical and Clinical Sciences ,Body Mass Index ,Cohort Studies ,Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings] ,0302 clinical medicine ,2.1 Biological and endogenous factors ,membrane protein ,POPULATION ,Cancer ,2. Zero hunger ,2 Aetiology ,0303 health sciences ,education.field_of_study ,Intracellular Signaling Peptides and Proteins ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,4203 Health Services and Systems ,3. Good health ,Índice de masa muscular ,INSIG2 protein ,Adipose Tissue ,Neoplasias de la mama ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins [Medical Subject Headings] ,Female ,Life Sciences & Biomedicine ,Cohort study ,Research Article ,Adult ,Risk ,medicine.medical_specialty ,VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 ,Genotype ,Estudios de cohortes ,Population ,Polimorfismo Genético ,COMMON GENETIC VARIANT ,PHENOTYPES ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,Breast Neoplasms ,VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714 ,lcsh:RC254-282 ,Estudio de Asociación del Genoma Completo ,03 medical and health sciences ,Breast cancer ,Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings] ,SDG 3 - Good Health and Well-being ,Clinical Research ,Internal medicine ,Breast Cancer ,POLYGENIC CONTRIBUTION ,medicine ,Genetics ,Humans ,signal peptide ,Neoplasm Invasiveness ,Obesity ,human ,education ,Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings] ,030304 developmental biology ,Nutrition ,Aged ,Science & Technology ,Polymorphism, Genetic ,Models, Genetic ,business.industry ,VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762 ,Prevention ,Case-control study ,42 Health Sciences ,Membrane Proteins ,DNA ,Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings] ,medicine.disease ,3211 Oncology and Carcinogenesis ,Health Care::Environment and Public Health::Public Health::Epidemiologic Measurements::Biometry::Anthropometry::Body Mass Index [Medical Subject Headings] ,VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762 ,Case-Control Studies ,Immunology ,INSIG2 protein, human ,business ,Body mass index ,Genome-Wide Association Study - Abstract
Background The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC). Methods we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk. Results and Conclusions In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.
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- 2016
4. Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes
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Sarah Labib, Andrew Williams, Håkan Wallin, Sabina Halappanavar, Carole L. Yauk, Jake K. Nikota, and Ulla Vogel
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0301 basic medicine ,Adverse outcome pathways ,Male ,Time Factors ,Transcription, Genetic ,Health, Toxicology and Mutagenesis ,Pulmonary Fibrosis ,Engineered nanomaterials ,Gene regulatory network ,Gene Expression Regulation/drug effects ,02 engineering and technology ,Pharmacology ,Toxicology ,Toxicogenetics ,Transcription, Genetic/drug effects ,Mice ,Adverse Outcome Pathway ,Databases, Genetic ,Nanotechnology ,Gene Regulatory Networks ,Lung ,Oligonucleotide Array Sequence Analysis ,Lung fibrosis ,General Medicine ,Nano ,021001 nanoscience & nanotechnology ,Toxicogenomics ,Benchmarking ,Nanotubes, Carbon/toxicity ,0210 nano-technology ,Risk assessment ,Case study ,Computational biology ,Biology ,Risk Assessment ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Gene Regulatory Networks/drug effects ,Animals ,Humans ,Benchmark dose ,Lung/drug effects ,Dose-Response Relationship, Drug ,Nanotubes, Carbon ,Research ,Gene Expression Profiling ,Pulmonary Fibrosis/chemically induced ,Computational Biology ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,Gene Expression Profiling/methods - Abstract
Background A diverse class of engineered nanomaterials (ENMs) exhibiting a wide array of physical-chemical properties that are associated with toxicological effects in experimental animals is in commercial use. However, an integrated framework for human health risk assessment (HHRA) of ENMs has yet to be established. Rodent 2-year cancer bioassays, clinical chemistry, and histopathological endpoints are still considered the ‘gold standard’ for detecting substance-induced toxicity in animal models. However, the use of data derived from alternative toxicological tools, such as genome-wide expression profiling and in vitro high-throughput assays, are gaining acceptance by the regulatory community for hazard identification and for understanding the underlying mode-of-action. Here, we conducted a case study to evaluate the application of global gene expression data in deriving pathway-based points of departure (PODs) for multi-walled carbon nanotube (MWCNT)-induced lung fibrosis, a non-cancer endpoint of regulatory importance. Methods Gene expression profiles from the lungs of mice exposed to three individual MWCNTs with different physical-chemical properties were used within the framework of an adverse outcome pathway (AOP) for lung fibrosis to identify key biological events linking MWCNT exposure to lung fibrosis. Significantly perturbed pathways were categorized along the key events described in the AOP. Benchmark doses (BMDs) were calculated for each perturbed pathway and were used to derive transcriptional BMDs for each MWCNT. Results Similar biological pathways were perturbed by the different MWCNT types across the doses and post-exposure time points studied. The pathway BMD values showed a time-dependent trend, with lower BMDs for pathways perturbed at the earlier post-exposure time points (24 h, 3d). The transcriptional BMDs were compared to the apical BMDs derived by the National Institute for Occupational Safety and Health (NIOSH) using alveolar septal thickness and fibrotic lesions endpoints. We found that regardless of the type of MWCNT, the BMD values for pathways associated with fibrosis were 14.0–30.4 μg/mouse, which are comparable to the BMDs derived by NIOSH for MWCNT-induced lung fibrotic lesions (21.0–27.1 μg/mouse). Conclusions The results demonstrate that transcriptomic data can be used to as an effective mechanism-based method to derive acceptable levels of exposure to nanomaterials in product development when epidemiological data are unavailable. Electronic supplementary material The online version of this article (doi:10.1186/s12989-016-0125-9) contains supplementary material, which is available to authorized users.
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- 2016
5. The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals
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Mona Sæbø, Elin H. Kure, Camilla Furu Skjelbred, Lotte K. Vogel, Esben D. K. Pedersen, Kathrine Abell, and Ulla Vogel
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Male ,Adenoma ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Proteinase Inhibitory Proteins, Secretory ,medicine.disease_cause ,lcsh:RC254-282 ,Serine endopeptidases ,Colorectal neoplasms ,Internal medicine ,Genetics ,medicine ,Carcinoma ,Humans ,Matriptase ,RNA, Messenger ,Moderate Dysplasia ,Membrane Glycoproteins ,biology ,Membrane glycoproteins ,Gene Expression Profiling ,Serine Endopeptidases ,Case-control study ,virus diseases ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Endocrinology ,Cell Transformation, Neoplastic ,Oncology ,Dysplasia ,Case-Control Studies ,biology.protein ,Female ,Carcinogenesis ,Colorectal Neoplasms ,Research Article - Abstract
BACKGROUND: It has recently been shown that overexpression of the serine protease, matriptase, in transgenic mice causes a dramatically increased frequency of carcinoma formation. Overexpression of HAI-1 and matriptase together changed the frequency of carcinoma formation to normal. This suggests that the ratio of matriptase to HAI-1 influences the malignant progression. The aim of this study has been to determine the ratio of matriptase to HAI-1 mRNA expression in affected and normal tissue from individuals with colorectal cancer adenomas and carcinomas as well as in healthy individuals, in order to determine at which stages a dysregulated ratio of matriptase/HAI-1 mRNA is present during carcinogenesis. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for matriptase and HAI-1 in colorectal cancer tissue (n = 9), severe dysplasia (n = 15), mild/moderate dysplasia (n = 21) and in normal tissue from the same individuals. In addition, corresponding tissue was examined from healthy volunteers (n = 10). Matriptase and HAI-1 mRNA levels were normalized to beta-actin. RESULTS: Matriptase mRNA level was lower in carcinomas compared to normal tissue from healthy individuals (p < 0.01). In accordance with this, the matriptase mRNA level was also lower in adenomas/carcinomas combined as compared to their adjacent normal tissue (p < 0.01). HAI-1 mRNA levels in both normal and affected tissue from individuals with severe dysplasia or carcinomas and in affected tissue with mild/moderate dysplasia were all significantly lower than mRNA levels observed in corresponding tissue from healthy control individuals. HAI-1 mRNA was lower in carcinomas as compared to normal tissue from healthy individuals (p < 0.001). HAI-1 mRNA levels were significantly lower in tissue displaying mild/moderate (p < 0.001) and severe (p < 0.01) dysplasia compared to normal tissue from the same patients. Both adenomas and carcinomas displayed a significantly different matriptase/HAI-1 mRNA ratio than corresponding normal tissue from healthy control individuals (p < 0.05). In addition statistically significant difference (p < 0.001) could be observed between mild/moderate and severe adenomas and their adjacent normal tissue. CONCLUSION: Our results show that dysregulation of the matriptase/HAI-1 mRNA ratio occurs early during carcinogenesis. Future studies are required to clarify whether the dysregulated matriptase/HAI-1 ratio was causing the malignant progression or is a consequence of the same. Dyreeksperimenter har vist at matripase (en serine protease) øker risikoen for kreftutvikling mens hepatocyte growth factor activator inhibitor (HAI-1) normaliserte risikoen. I denne delstudier har en derfor sett på ratio matripase/HAI-1 i vev fra adenomer og cancer og normalslimhinne fra de samme pasientene. Både adenomer og cancer viste et signifikant forskjellig ratio enn normalsimhinne. Dette kan tyde på at en dysregulating av dette ratio kan opptre tidlig i carcinogeneseprosessen, men studien kan ikke avdekke om dette er en årsak til eller en følge av malignitetsutviklingen.
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- 2006
6. Biodistribution of gold nanoparticles in mouse lung following intratracheal instillation
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Håkan Wallin, Ulla Vogel, Gorm Danscher, Nicklas Raun Jacobsen, Evaldas Sadauskas, Agnete Larsen, Wolfgang G. Kreyling, and Meredin Stoltenberg
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Biodistribution ,Lung ,Adult female ,Chemistry(all) ,Chemistry ,Intratracheal instillation ,Nanoparticle ,General Chemistry ,Systemic circulation ,Molecular biology ,Toxicology ,medicine.anatomical_structure ,Colloidal gold ,Research article ,medicine ,Mouse Lung ,QD1-999 - Abstract
BACKGROUND: The fate of gold nanoparticles, 2, 40 and 100 nm, administered intratracheally to adult female mice was examined. The nanoparticles were traced by autometallography (AMG) at both ultrastructural and light microscopic levels. Also, the gold content was quantified by inductively coupled plasma mass spectrometry (ICP-MS) and neutron activation analysis (NAA). The liver is the major site of deposition of circulating gold nanoparticles. Therefore the degree of translocation was determined by the hepatic deposition of gold. Mice were instilled with 5 intratracheal doses of gold nanoparticles distributed over a period of 3 weeks and were killed 24 h after the last dose. One group of mice were given a single intratracheal dose and were killed after 1 h. RESULTS: The instilled nanoparticles were found in lung macrophages already 1 h after a single instillation. In mice instilled treated repeatedly during 3 weeks, the load was substantial. Ultrastructurally, AMG silver enhanced gold nanoparticles were found in lysosome-/endosome-like organelles of the macrophages and analysis with AMG, ICP-MS and NAA of the liver revealed an almost total lack of translocation of nanoparticles. In mice given repeated instillations of 2 nm gold nanoparticles, 1.4 per thousand (by ICP-MS) to 1.9 per thousand (by NAA) of the instilled gold was detected in the liver. With the 40 nm gold, no gold was detected in the liver (detection level 2 ng, 0.1 per thousand) except for one mouse in which 3 per thousand of the instilled gold was found in the liver. No gold was detected in any liver of mice instilled with 100 nm gold (detection level 2 ng, 0.1 per thousand) except in a single animal with 0.39 per thousand of the dose in the liver. CONCLUSION: We found that that: (1) inert gold nanoparticles, administered intratracheally are phagocytosed by lung macrophages; (2) only a tiny fraction of the gold particles is translocated into systemic circulation. (3) The translocation rate was greatest with the 2 nm gold particles.
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- 2009
7. The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study
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Lene Agerstjerne, Dorte Jensen, Ulla Vogel, Mette Østergaard, Mona Sæbø, Elin H. Kure, Julian Hamfjord, and Vibeke Andersen
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Oncology ,Adenoma ,Male ,medicine.medical_specialty ,lcsh:Internal medicine ,ATP Binding Cassette Transporter, Subfamily B ,lcsh:QH426-470 ,Colorectal cancer ,Population ,Colorectal adenoma ,Biology ,Polymorphism, Single Nucleotide ,SDG 3 - Good Health and Well-being ,Internal medicine ,Genotype ,medicine ,Genetics ,Confidence Intervals ,Odds Ratio ,Humans ,Genetics(clinical) ,Genetic Predisposition to Disease ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,education ,lcsh:RC31-1245 ,Genetics (clinical) ,Aged ,Aged, 80 and over ,education.field_of_study ,Norway ,Case-control study ,ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ,P-Glycoprotein ,Odds ratio ,Middle Aged ,medicine.disease ,Adenoma/genetics ,Colorectal Neoplasms/genetics ,Introns ,lcsh:Genetics ,Endocrinology ,Logistic Models ,Case-Control Studies ,Population study ,Female ,Colorectal Neoplasms ,Research Article - Abstract
Background Smoking, dietary factors, and alcohol consumption are known life style factors contributing to gastrointestinal carcinogenesis. Genetic variations in carcinogen handling may affect cancer risk. The multidrug resistance 1(MDR1/ABCB1) gene encodes the transport protein P-glycoprotein (a phase III xenobiotic transporter). P-glycoprotein is present in the intestinal mucosal lining and restricts absorption of certain carcinogens, among these polycyclic aromatic hydrocarbons. Moreover, P-glycoprotein transports various endogenous substrates such as cytokines and chemokines involved in inflammation, and may thereby affect the risk of malignity. Hence, genetic variations that modify the function of P-glycoprotein may be associated with the risk of colorectal cancer (CRC). We have previously found an association between the MDR1 intron 3 G-rs3789243-A polymorphism and the risk of CRC in a Danish study population. The aim of this study was to investigate if this MDR1 polymorphism was associated with risk of colorectal adenoma (CA) and CRC in the Norwegian population. Methods Using a case-control design, the association between the MDR1 intron 3 G-rs3789243-A polymorphism and the risk of colorectal carcinomas and adenomas in the Norwegian population was assessed in 167 carcinomas, 990 adenomas, and 400 controls. Genotypes were determined by allelic discrimination. Odds ratio (OR) and 95 confidence interval (95% CI) were estimated by binary logistic regression. Results No association was found between the MDR1 polymorphism (G-rs3789243-A) and colorectal adenomas or cancer. Carriers of the variant allele of MDR1 intron 3 had odds ratios (95% CI) of 0.97 (0.72–1.29) for developing adenomas, and 0.70 (0.41–1.21) for colorectal cancer, respectively, compared to homozygous wild type carriers. Conclusion The MDR1 intron 3 (G-rs3789243-A) polymorphism was not associated with a risk of colorectal adenomas or carcinomas in the present Norwegian study group. Thus, this MDR1 polymorphism does not seem to play an important role in colorectal carcinogenesis in this population.
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- 2009
8. A haplotype of polymorphisms in ASE-1, RAI and ERCC1 and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a danish prospective case-cohort study
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Mette Sørensen, Rikke Dalgaard Hansen, Ulla Vogel, Kim Overvad, Håkan Wallin, Ole Raaschou-Nielsen, and Anne Tjønneland
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Oncology ,Male ,medicine.medical_specialty ,Cancer Research ,Alcohol Drinking ,Colorectal cancer ,Denmark ,Single-nucleotide polymorphism ,Rate ratio ,lcsh:RC254-282 ,Polymorphism, Single Nucleotide ,Cohort Studies ,Breast cancer ,RNA Polymerase I ,Risk Factors ,Internal medicine ,medicine ,Genetics ,Humans ,Prospective Studies ,Prospective cohort study ,business.industry ,Proportional hazards model ,Haplotype ,Smoking ,Case-control study ,Intracellular Signaling Peptides and Proteins ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Endonucleases ,DNA-Binding Proteins ,Repressor Proteins ,Haplotypes ,Case-Control Studies ,Female ,business ,Colorectal Neoplasms ,Research Article - Abstract
Background Single nucleotide polymorphisms (SNPs) are the most frequent type of genetic variation in the human genome, and are of interest for the study of susceptibility to and protection from diseases. The haplotype at chromosome 19q13.2-3 encompassing the three SNPs ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn have been associated with risk of breast cancer and lung cancer. Haplotype carriers are defined as the homozygous carriers of RAI IVS1 A4364GA, ERCC1 Asn118AsnT and ASE-1 G-21AG. We aimed to evaluate whether the three polymorphisms and the haplotype are associated to risk of colorectal cancer, and investigated gene-environment associations between the polymorphisms and the haplotype and smoking status at enrolment, smoking duration, average smoking intensity and alcohol consumption, respectively, in relation to risk of colorectal cancer. Methods Associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were examined, as well as gene-environment interaction, in a Danish case-cohort study including 405 cases and a comparison group of 810 persons. Incidence rate ratio (IRR) were estimated by the Cox proportional hazards model stratified according to gender, and two-sided 95% confidence intervals (CI) and p-values were calculated based on robust estimates of the variance-covariance matrix and Wald's test of the Cox regression parameter. Results No consistent associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were found. No statistically significant interactions between the genotypes and the lifestyle exposures smoking or alcohol consumption were observed. Conclusion Our results suggest that the ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn polymorphisms and the previously identified haplotype are not associated with risk of colorectal cancer. We found no evidence of gene-environment interaction between the three polymorphisms and the haplotype and smoking intensity and alcohol consumption, respectively, in relation to the risk of colorectal cancer.
- Published
- 2008
9. Kupffer cells are central in the removal of nanoparticles from the organism
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Agnete Larsen, Gorm Danscher, Evaldas Sadauskas, P. Doering, Håkan Wallin, Ulla Vogel, and Meredin Stoltenberg
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Pathology ,medicine.medical_specialty ,genetic structures ,Health, Toxicology and Mutagenesis ,Research ,Kupffer cell ,lcsh:Industrial hygiene. Industrial welfare ,Spleen ,General Medicine ,Biology ,Endocytosis ,Toxicology ,Molecular biology ,Small intestine ,eye diseases ,Staining ,medicine.anatomical_structure ,Colloidal gold ,lcsh:RA1190-1270 ,medicine ,Ultrastructure ,Mesenteric lymph nodes ,sense organs ,lcsh:HD7260-7780.8 ,lcsh:Toxicology. Poisons - Abstract
Background The study aims at revealing the fate of nanoparticles administered intravenously and intraperitoneally to adult female mice, some of which were pregnant. Gold nanoparticles were chosen as a model because these particles have been found to be chemically inert and at the same time are easily traced by autometallography (AMG) at both ultrastructural and light microscopic levels. Results Gold nanoparticles were injected intravenously (IV) or intraperitoneally (IP) and traced after 1, 4 or 24 hours. For IV injections 2 and 40 nm particles were used; for IP injections 40 nm particles only. The injected nanoparticles were found in macrophages only, and at moderate exposure primarily in the Kupffer cells in the liver. IV injections resulted in a rapid accumulation/clustering of nanoparticles in these liver macrophages, while the uptake in spleen macrophages was moderate. IP injections were followed by a delayed uptake in the liver and included a moderate uptake in macrophages located in mesenteric lymph nodes, spleen and small intestine. Ultrastructurally, the AMG silver enhanced nanocrystals were found in lysosome-like organelles of the Kupffer cells and other macrophages wherever located. Accumulations of gold nanoparticles were not found in any other organs analysed, i.e. kidneys, brain, lungs, adrenals, ovaries, placenta, and fetal liver, and the control animals were all void of AMG staining. Conclusion Our results suggest that: (1) inert gold nanoparticles do not penetrate cell membranes by non-endocytotic mechanisms, but are rather taken up by endocytosis; (2) gold nanoparticles, independent of size, are taken up primarily by Kupffer cells in the liver and secondarily by macrophages in other places; (3) gold nanoparticles do not seem to penetrate the placenta barrier; (4) the blood-brain barrier seems to protect the central nervous system from gold nanoparticles; (5) 2 nanometer gold particles seem to be removed not only by endocytosis by macrophages, and we hypothesize that part of these tiny nanoparticles are released into the urine as a result of simple filtration in the renal glomeruli.
- Published
- 2007
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