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Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease

Kazachkova, Nadiya; Raposo, Mafalda; Montiel, Rafael; Cymbron, Teresa; Bettencourt, Conceição; Fernandes, Anabela Silva; Silva, Sara Carina Duarte da; Maciel, P.; Lima, Manuela
Fonte: Karger Publicador: Karger
Tipo: Artigo de Revista Científica
Publicado em //2013 ENG
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BACKGROUND: Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia caused by a CAG tract expansions in the ATXN3 gene. Patterns of mitochondrial damage associated with pathological findings of brain tissues could provide molecular biomarkers of this disorder. OBJECTIVE: The potential of mitochondrial DNA (mtDNA) damage as a biomarker of MJD progression was investigated using a transgenic mouse model. METHODS: DNA was obtained from affected (pontine nuclei) and nonaffected tissues (hippocampus and blood) of transgenic animals of three distinct age groups: 8 weeks, before onset of the phenotype; 16 weeks, at onset, and 24 weeks, at well-established phenotype. Wild-type littermate mice, serving as controls, were analyzed for the same tissues and age groups. mtDNA damage was studied by fluorescence-based quantitative PCR in 84 transgenic and 93 wild-type samples. RESULTS: A clear pattern of decrease in mtDNA copy number with age and accumulation of 3,867-bp deletions at the initial stages (both being more pronounced in transgenic mice) was observed. Pontine nuclei, the affected tissue in transgenic mice, displayed 1.5 times less copies of mtDNA than nonaffected brain tissue hippocampus (odds ratio = 1.21). Pontine nuclei displayed the highest percentage of mtDNA deletions (6.05% more in transgenic mice). CONCLUSION: These results suggest that mtDNA damage is related to the initiation of the phenotype in transgenic mice; mtDNA 3...

Differential mtDNA damage patterns in a transgenic mouse model of Machado-Joseph disease (MJD/SCA3)

Ramos, Amanda; Kazachkova, Nadiya; Silva, Francisca; Maciel, P.; Fernandes, Anabela Silva; Silva, Sara Carina Duarte da; Santos, Cristina; Lima, Manuela
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em //2014 ENG
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65.81%
Mitochondrial dysfunction has been associated with late onset neurodegenerative disorders, among which is Machado-Joseph disease (MJD/SCA3). In a previous study, using a transgenic mouse model of MJD, we reported a decrease in mitochondrial DNA (mtDNA) copy number and an accumulation of the 3876-bp deletion with age and with phenotype development. We extended this study by analyzing the pattern of mtDNA depletion and the accumulation of the 3876-bp deletion in 12 older transgenic (TG) and 4 wild-type (wt) animals, and by investigating the accumulation of somatic mutations in the D-loop region in 76 mice (42 TG and 34 wt). mtDNA damage was studied in TG and wt mice at different ages and tissues (blood, pontine nuclei, and hippocampus). Results for older mice demonstrate an accumulation of the mtDNA 3867-bp deletion with age, which was more pronounced in TG animals. Furthermore, the tendency for mtDNA copy number decrease with age, in all analyzed tissues of TG and wt animals, was also confirmed. No point mutations were detected in the D-loop, neither in TG nor wt animals, in any of the tissues analyzed. Due to the absence of mtDNA somatic mutations, we can suggest that mtDNA point mutation accumulation cannot be used to monitor the development and progression of the phenotype in this mouse model and likely in any MJD mice model. The present results further confirm not only the association between mtDNA alterations (copy number and deletions) and age...

Experimentally induced intravaginal Tritrichomonas foetus infection in a mouse model

Soto,Pedro; Echevarría,Hilda María; Monteavaro,Cristina Esther; Catena,María del Carmen
Fonte: Colégio Brasileiro de Patologia Animal - CBPA; Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA) Publicador: Colégio Brasileiro de Patologia Animal - CBPA; Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA)
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2005 EN
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The interest to develop research on the host-parasite relationship in bovine tritrichomonosis has accomplished the use of experimental models alternative to cattle. The BALB/c mouse became the most appropriate species susceptible to vaginal Tritrichomonas foetus infection requiring previous estrogenization. For the need of an experimental model without persistent estrogenization and with normal estrous cycles, the establishment and persistence of vaginal infection on BALB/c mouse with different concentrations of T. foetus in two experimental groups was evaluated. Group A was treated with 5mg of b-estradiol 3-benzoate to synchronize the estrous, 48 hours before the T. foetus vaginal inoculation, and Group B was inoculated in natural estrus. At 5-7 days after treatment, estrogenic effect decreased allowing all animals to cycle regularly during the experiment. From the first week post-infection, samples of vaginal mucus were taken from all animals during 34 weeks, in order to evaluate the course of infection and the stage of the estrus cycle. Group A showed 93.6% of infected animals, and Group B showed 38%. Different doses of T. foetus were assayed to establish the vaginal infection, with a persistence of 34 weeks. Although different behavior was observed in each subgroup belonging to either Group A or Group B...

Histopathological characteristics of a novel knock-in mouse prostate cancer model

Wu,G.; Wang,D.; Wang,H.; Yuan,J.; Xuan,J.W.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2006 EN
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Prostate cancer is relatively unique to man. There is no naturally occurring prostate cancer in the mouse. Pre-clinical studies involve the establishment of a genetically engineered mouse prostate cancer model with features close to those of the human situation. A new knock-in mouse adenocarcinoma prostate (KIMAP) model was established, which showed close-to-human kinetics of tumor development. In order to determine if the similar kinetics is associated with heterogeneous tumor architecture similar to the human situation, we utilized a new mouse histological grading system (Gleason analogous grading system) similar to the Gleason human grading system and flow cytometry DNA analysis to measure and compare the adenocarcinoma of the KIMAP model with human prostate cancer. Sixty KIMAP prostate cancer samples from 60 mice were measured and compared with human prostate cancer. Flow cytometry DNA analysis was performed on malignant prostate tissues obtained from KIMAP models. Mice with prostate cancer from KIMAP models showed a 53.3% compound histological score rate, which was close to the human clinical average (50%) and showed a significant correlation with age (P = 0.001). Flow cytometry analyses demonstrated that most KIMAP tumor tissues were diploid...

Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Rakoczy, Piroska Elizabeth; Zhang, Dan; Robertson, Terry; Barnett, Nigel L.; Papadimitriou, John; Constable, Ian Jeffrey; Lai, Chooi-May
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /10/2002 EN
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Age-related macular degeneration (AMD) is the major cause of blindness in the developed world. Its pathomechanism is unknown and its late onset, complex genetics and strong environmental components have all hampered investigations. Here we demonstrate the development of an animal model for AMD that reproduces features associated with geographic atrophy; a transgenic mouse line (mcd/mcd) expressing a mutated form of cathepsin D that is enzymatically inactive thus impairing processing of phagocytosed photoreceptor outer segments in the retinal pigment epithelial (RPE) cells. Pigmentary changes indicating RPE cell atrophy and a decreased response to flash electroretinograms were observed in 11- to 12-month-old mcd/mcd mice. Histological studies showed RPE cell proliferation, photoreceptor degeneration, shortening of photoreceptor outer segments, and accumulation of immunoreactive photoreceptor breakdown products in the RPE cells. An accelerated photoreceptor cell death was detected in 12-month-old mcd/mcd mice. Transmission electron microscopy demonstrated presence of basal laminar and linear deposits that are considered to be the hallmarks of AMD. Small hard drusen associated with human age-related maculopathy were absent in the mcd/mcd mouse model at the ages analyzed. In summary...

Effects of Murine Norovirus Infection on a Mouse Model of Diet-Induced Obesity and Insulin Resistance

Paik, Jisun; Fierce, Yvette; Drivdahl, Rolf; Treuting, Piper M; Seamons, Audrey; Brabb, Thea; Maggio-Price, Lillian
Fonte: American Association for Laboratory Animal Science Publicador: American Association for Laboratory Animal Science
Tipo: Artigo de Revista Científica
EN
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Murine norovirus (MNV) is prevalent in SPF mouse facilities in the United States, and we currently lack sufficient data to determine whether it should be eliminated. It is generally accepted that the virus does not cause clinical symptoms in immunocompetent mice. However, we previously reported that MNV infection alters the phenotype of a mouse model of bacteria-induced inflammatory bowel disease in part through its effects on dendritic cells. The tropism of MNV toward macrophages and dendritic cells makes MNV a potential intercurrent variable in murine models of macrophage-driven inflammatory diseases, such as obesity, insulin resistance, and atherosclerosis. Therefore, we determined whether MNV infection altered obesity and insulin resistance phenotypes in C57BL/6 mice, a widely used model of diet-induced obesity. We found that MNV did not alter weight gain, food intake, and glucose metabolism in this model, but it did induce subtle changes in lymphoid tissue. Further studies using other models of metabolic diseases are needed to provide additional information on the potential role this ‘subclinical’ virus might have on disease progression in mouse models of inflammatory diseases.

Mouse Model of Muscle Crush Injury of the Legs

Dobek, Georgina L; Fulkerson, Nadia D; Nicholas, Jennifer; Schneider, Barbara St Pierre
Fonte: American Association for Laboratory Animal Science Publicador: American Association for Laboratory Animal Science
Tipo: Artigo de Revista Científica
EN
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55.83%
Because crush injury to skeletal muscle is an important cause of morbidity in natural disaster and battlefield settings, a reproducible and refined animal model of muscle crush injury is needed. Both open and closed small-animal models of skeletal muscle crush injury are available but are limited by their need for surgical isolation of the muscle or by the adverse effect of fibular fracture, respectively. In the current study, we developed and validated a novel, noninvasive mouse model of lower-extremity muscle crush injury. Despite the closed nature of our model, gross evidence of muscle damage was evident in all mice and was verified microscopically through hematoxylin and eosin staining. The injury elicited both neutrophil and macrophage infiltration at 24 and 48 h after injury. The area percentage and mean antigen area of F4/80-positive macrophages were higher at 48 h than at 24 h after injury, and CD68-positive macrophage area percentage and mean antigen area differed significantly between injured and uninjured muscle. In addition, the incidence of fibular fracture was one third lower than that reported for an alternative noninvasive model. In conclusion, our model is a reproducible method for muscle crush injury in the mouse pelvic limb and is a refinement of previous models because of its decreased bone fractures and reduction of animal numbers.

Hypothermic Endpoint for an Intranasal Invasive Pulmonary Aspergillosis Mouse Model

Adamson, Trinka W; Diaz-Arevalo, Diana; Gonzalez, Tracey M; Liu, Xueli; Kalkum, Markus
Fonte: American Association for Laboratory Animal Science Publicador: American Association for Laboratory Animal Science
Tipo: Artigo de Revista Científica
EN
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Immunocompromised mice were infected intranasally with Aspergillus fumigatus as part of a vaccine efficacy study. Although body temperature was measured throughout the study, a formal evaluation of its usefulness as an endpoint criterion was not performed. We retrospectively evaluated survival data and temperature records to determine whether body temperature can be used as an objective predictor of death and included in the humane endpoint criteria for this mouse model. CF1 mice were immunosuppressed with either cortisone acetate or by treatment with antiGR1 (a neutrophil-depleting antibody) and then intranasally challenged with A. fumigatus. Body temperature was measured by using an infrared noncontact thermometer a maximum of 3 times daily until death or euthanasia. A surface body temperature below 29.0 °C was correlated with a poor chance of survival, and using this cutoff point with signs of morbidity (hunched, ruffled fur, respiratory distress) reliably indicates mice for euthanasia without negatively affecting data collection. Using 2 subsequent readings of less than 31.0 °C as an endpoint would have led to premature euthanasia of only one mouse (2.2%). As a single reading, a body temperature of 28.8 °C had a sensitivity of 92.2% and specificity of 90.9%. Hypothermia proved to be a useful addition to the humane endpoint criteria for this mouse model...

Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer’s Disease

Cherry, Jonathan D.; Liu, Bin; Frost, Jeffrey L.; Lemere, Cynthia Ann; Williams, Jacqueline P.; Olschowka, John A.; O’Banion, M. Kerry
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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Galactic Cosmic Radiation consisting of high-energy, high-charged (HZE) particles poses a significant threat to future astronauts in deep space. Aside from cancer, concerns have been raised about late degenerative risks, including effects on the brain. In this study we examined the effects of (^{56})Fe particle irradiation in an APP/PS1 mouse model of Alzheimer’s disease (AD). We demonstrated 6 months after exposure to 10 and 100 cGy (^{56})Fe radiation at 1 GeV/µ, that APP/PS1 mice show decreased cognitive abilities measured by contextual fear conditioning and novel object recognition tests. Furthermore, in male mice we saw acceleration of Aβ plaque pathology using Congo red and 6E10 staining, which was further confirmed by ELISA measures of Aβ isoforms. Increases were not due to higher levels of amyloid precursor protein (APP) or increased cleavage as measured by levels of the β C-terminal fragment of APP. Additionally, we saw no change in microglial activation levels judging by CD68 and Iba-1 immunoreactivities in and around Aβ plaques or insulin degrading enzyme, which has been shown to degrade Aβ. However, immunohistochemical analysis of ICAM-1 showed evidence of endothelial activation after 100 cGy irradiation in male mice...

Acquired MET Expression Confers Resistance to EGFR Inhibition In a Mouse Model of Glioblastoma Multiforme

Jun, Hyun Jung; Acquaviva, Jaime; Chi, Dorcas; Lessard, Julie; Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T.; Pfannl, Rolf; White, Forest; Housman, David E.; Iyer, Lakshmanan; Whittaker, Charles A.; Boskovitz, Abraham; Raval, Ami; Charest, Alain
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
EN_US
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Glioblastoma Multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type EGFR and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that a key component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

Maternal thyroid hormones are transcriptionally active during embryo–foetal development: results from a novel transgenic mouse model

Nucera, Carmelo; Muzzi, Patrizia; Tiveron, Cecilia; Farsetti, Antonella; Regina, Federico La; Foglio, Benedetta; Shih, Shou-Ching; Moretti, Fabiola; Pietra, Linda Della; Mancini, Francesca; Sacchi, Ada; Trimarchi, Francesco; Vercelli, Alessandro; Pontecor
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
EN_US
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Abstract Even though several studies highlighted the role of maternal thyroid hormones (THs) during embryo–foetal development, direct evidence of their interaction with embryonic thyroid receptors (TRs) is still lacking. We generated a transgenic mouse model ubiquitously expressing a reporter gene tracing TH action during development. We engineered a construct (TRE2×) containing two TH-responsive elements controlling the expression of the LacZ reporter gene, which encodes β-galactosidase (β-gal). The specificity of the TRE2× activation by TH was evaluated in NIH3T3 cells by cotransfecting TRE2× along with TRs, retinoic or oestrogen receptors in the presence of their specific ligands. TRE2× transgene was microinjected into the zygotes, implanted in pseudopregnant BDF1 (a first-generation (F1) hybrid from a cross of C57BL/6 female and a DBA/2 male) mice and transgenic mouse models were developed. β-gal expression was assayed in tissue sections of transgenic mouse embryos at different stages of development. In vitro, TRE2× transactivation was observed only following physiological T3 stimulation, mediated exclusively by TRs. In vivo, β-gal staining, absent until embryonic day 9.5–10.5 (E9.5–E10.5), was observed as early as E11.5–E12.5 in different primordia (i.e. central nervous system...

Regulation of gene expression of the 25-Hydroxyvitamin D 1α-Hydroxylase (CYP27B1) promoter : study of a transgenic mouse model.

Hendrix, Ivanka
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2004
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The enzyme 25-hydroxyvitamin D la-hydroxylase or CYP27Bl is the key enzyme in the two-step activation process by which vitamin D is converted to its biologically active form 1,25-dihydroxyvitamin D (1,25D). The actions of a number of regulators on the renal CYP27B1 enzyme activity have been recognized for some years, although the underlying molecular mechanisms remain largely unknown and the DNA regions involved in the in vivo regulation of gene expression by these factors have not been delineated as yet. In order to identify the regulatory regions through which these factors control CYP27B1 expression in the kidney in vivo and to study the spatial and temporal expression of the CYP27B1 gene during development, a transgenic mouse model was established. This model was developed using pro-nuclear injection of a DNA construct containing the firefly luciferase reporter gene under the control of the 1541 bp region of the human CYP27B1 promoter. Following pro-nuclear injection, three transgenic founders were obtained and bred to establish three independent transgenic lines. In all three lines, a very similar expression pattern of the luciferase reporter gene was detected. High levels of luciferase activity were detected in the kidney, brain...

Novel combination therapy for the eradication of Helicobacter pylori infection in a mouse model

Tran, C.; Kritas, S.; Campbell, M.; Huynh, H.; Lee, S.S.; Butler, R.
Fonte: Taylor & Francis As Publicador: Taylor & Francis As
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
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65.74%
Objective. To investigate the combination therapy, consisting of hyperimmune bovine colostrum, N-acetyl cysteine, zinc and amoxicillin on the eradication of Helicobacter pylori in a mouse model. Material and methods. C57BL/6 female mice (6 weeks of age) were inoculated with 0.1 ml of 1 _ 109 H. pylori via a single oro-gastric gavage and were left infected for 4 weeks. Mice (n = 9/group) were randomly allocated to receive by oral gavage (0.1 ml) HNZ (hyperimmune bovine colostrum + N-acetyl cysteine + zinc), HNZA (HNZ + amoxicillin; A), HNZA2 (2_ amoxicillin; A2), HNZA5 (5_ amoxicillin; A5), triple therapy (TT) or saline twice daily for 10 days. Bacterial load was assessed by culture. Gastric emptying was assessed by 13C-octanoic acid breath test. Results. Mice receiving HNZ, HNZA, and HNZA2 have a 22%, 44% and 67% eradication rate, respectively. Eradication rate was 100% with HNZA5, TT and those animals receiving A5 alone. In H. pylori infected mice there was an increased gastric emptying time by 7.9, 3.7, 10.1 and 7.7 min for the TT, HNZ, HNZA2, and HNZA5, respectively, compared to saline. Conclusions. HNZ with the addition of a high dose of amoxicillin is effective at eradicating H. pylori in vivo as HNZA1 and HNZA2 did not give raise to eradication. The potency of the novel anti-H. pylori combination therapy may be due to the delayed gastric emptying.; Cuong D. Tran...

Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis

Hull, M.; Prentice, A.; Wang, D.; Butt, R.; Phillips, S.; Smith, S.; Charnock-Jones, D.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em //2005 EN
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65.83%
BACKGROUND: Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. METHODS: The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. RESULTS: There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. CONCLUSION: The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.; M.L.Hull...

A gene signature identified using a mouse model of androgen receptor-dependent prostate cancer predicts biochemical relapse in human disease

Thompson, V.; Day, T.; Bianco-Miotto, T.; Selth, L.; Han, G.; Thomas, M.; Buchanan, G.; Scher, H.; Nelson, C.; Greenberg, N.; Butler, L.; Tilley, W.
Fonte: Wiley-liss Publicador: Wiley-liss
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
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Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes...

Identification of prostate cancer-associated microRNAs in circulation using a mouse model of disease

Selth, L.; Townley, S.; Gillis, J.; Tilley, W.; Butler, L.
Fonte: Springer; UK Publicador: Springer; UK
Tipo: Parte de Livro
Publicado em //2013 EN
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MicroRNAs (miRNAs) derived from the cell-free fractions of blood are emerging as useful noninvasive markers of cancer. However, many tumors display significant molecular heterogeneity, which is likely to be reflected in the circulating miRNA fingerprints associated with that pathology. One strategy to minimize such heterogeneity is to employ genetically engineered mouse models of human cancer. Here, we describe a method to profile miRNAs in the serum of a mouse model of prostate cancer, TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP), and discuss practical considerations for translating these potential biomarkers into a clinical setting.; Luke A. Selth, Scott L. Townley, Joanna L. Gillis, Wayne D. Tilley, and Lisa M. Butler

Charakterisierung leukämischer Progenitorzellen im NOD/SCID-Mausmodell mittels Hoechst 33342; Characterization of leukemic progenitor cells in the NOD/SCID mouse model using Hoechst 33342

Hörrmann, Reinhard
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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Zusammenfassung der Dissertation von Reinhard Hörrmann Titel: Charakterisierung leukämischer Progenitorzellen im NOD/SCID-Mausmodell mittels Hoechst 33342 Man geht davon aus, dass Leukämien auf genetisch veränderte HSC oder auf Zellen, welche Eigenschaften von HSC wiedererlangen, zurückzuführen sind. In vielen Fällen ist nur eine kleine Population von leukämischen Stammzellen zur Selbsterneuerung, Proliferation und Differenzierung fähig. Das heißt, nur diese Zellen sind fähig, alle Zellen einer Leukämie zu generieren und spielen somit eine entscheidende Rolle bei der Entstehung und Erhaltung einer Leukämie. Diese unreifen leukämischen Progenitorzellen haben bestimmte Eigenschaften, wie dem Verharren in einem Art Ruhezustand (G0-Phase des Zellzyklus) und dem Besitz von membranständigen Transporterproteinen (Effluxpumpen), mit welchen sie toxische Substanzen aktiv aus der Zelle transportieren können und dadurch besonders widerstandsfähig gegen Chemotherapeutika sind. Somit scheinen die leukämischen Progenitorzellen einen entscheidenden Beitrag bei der Initiierung eines Rezidivs zu spielen. Daher ist es von besonderem Interesse und Bestandteil dieser Arbeit, die leukämischen Progenitorzellen nachzuweisen und dadurch mögliche Targets zu finden...

Lack of Effect of Murine Norovirus Infection on a Mouse Model of Bacteria‑Induced Colon Cancer

Lencioni, Karen C; Drivdahl, Rolf; Seamons, Audrey; Treuting, Piper M; Brabb, Thea; Maggio-Price, Lillian
Fonte: American Association for Laboratory Animal Science Publicador: American Association for Laboratory Animal Science
Tipo: Artigo de Revista Científica
EN
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Murine norovirus (MNV) is endemic in mouse research facilities in the United States and Europe, with a prevalence as high as 58% to 64%. Because of MNV's orofecal route of infection, clinically silent persistent infections in some mouse strains, and proclivity for macrophage and dendritic cells, its presence in mouse colonies has potential to alter phenotypes in experimental mouse models, particularly those involving inflammation and immunologic responses. Although MNV is subclinical, not causing overt disease in immunocompetent mice, we found that MNV infection can accelerate bacteria-induced inflammatory bowel disease (IBD) progression in Mdr1a−/− mice. The studies presented here examined whether MNV infection also affects the phenotype of a bacterially driven mouse model of inflammation-associated colon cancer in genetically susceptible Smad3−/− mice. In vitro culture of bone-marrow–derived macrophages (BMDM) was used to determine whether MNV4 influenced macrophage cytokine production. For in vivo studies, Smad3−/− mice were infected with MNV4 one week prior to infection with Helicobacter. Mice were monitored for 17 to 32 wk for development of IBD and colon cancer, and tissues were analyzed histopathologically. Although in vitro infection of BMDM with MNV4 led to increased inflammatory cytokine production...

Oncogenic Actions of the Nuclear Receptor Corepressor (NCOR1) in a Mouse Model of Thyroid Cancer

Fozzatti, Laura; Park, Jeong Won; Li, Zhao; Willingham, Mark C.; Cheng, Sheue-yann
Fonte: PUBLIC LIBRARY SCIENCE Publicador: PUBLIC LIBRARY SCIENCE
Tipo: info:eu-repo/semantics/article; info:ar-repo/semantics/artículo; info:eu-repo/semantics/publishedVersion Formato: application/pdf
ENG
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Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (ThrbPV/PV mice) that spontaneously develops thyroid cancer. ThrbPV/PV mice harbor a dominantly negative thyroid hormone receptor b (TRb) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing ThrbPV mice with mice that globally express an NCOR1 mutant protein (NCOR1DID) in which the receptor interaction domains have been modified so that it cannot interact with the TRb, or PV, in mice. Remarkably, expression of NCOR1DID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of ThrbPV/PVNcor1DID/DID mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21waf1/cip1; Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53- binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3)...

A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumour angiogenesis and invasion in a mouse model of multistage cancer

Joyce, Johanna A; Freeman, Craig; Meyer-Morse, Nicole; Parish, Christopher; Hanahan, Douglas
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1 + /Mac1 + innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis...