Frederik Dagnaes-Hansen

Aarhus University, Aarhus, Central Jutland, Denmark

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Publications (82)323.3 Total impact

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    ABSTRACT: Bone metastasis is one of the leading causes of death in breast cancer patients. The current treatment is performed as a palliative therapy and the adverse side effects can compromise the patients' quality of life. In order to both effectively treat bone metastasis and avoid the limitation of current strategies, we have invented a drug eluting scaffold with clay matrix release doxorubicin (DESCLAYMR_DOX) to mechanically support the structure after resecting the metastatic tissue while also releasing the anticancer drug doxorubicin which supplements growth inhibition and elimination of the remaining tumor cells. We have previously demonstrated that this device has the capacity to regenerate the bone and provide sustained release of the anticancer drug in vitro. In this study, we focus on the ability of the device to inhibit cancer cell growth in vitro as well as in vivo. Drug-release kinetics was investigated and the cell viability test showed that the tumor inhibitory effect is sustained for up to 4weeks in vitro. Subcutaneous implantation of DESCLAYMR_DOX in athymic mice resulted in significant growth inhibition of human tumor xenografts of breast origin and decelerated multi-organ metastasis formation. Fluorescence images, visualizing doxorubicin, showed a sustained drug release from the DESCLAYMR device in vivo. Furthermore, local use of DESCLAYMR_DOX implantation reduced the incidence of doxorubicin's cardio-toxicity. These results suggest that DESCLAYMR_DOX can be used in reconstructive surgery to support the structure after bone tumor resection and facilitate a sustained release of anticancer drugs in order to prevent tumor recurrence. Copyright © 2015. Published by Elsevier Ltd.
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    ABSTRACT: Bacterial biofilms causing implant-associated osteomyelitis is a severe complication with limited antimicrobial therapy options. We designed an animal model, in which implant associated osteomyelitis arise from a Staphylococcus aureus biofilm on a tibia implant. Two bioluminescently engineered (luxA-E transformed), strains of S. aureus were utilized, Xen29 and Xen31. Biofilm formation was assessed with epifluorescence microscopy. Quantitative measurements were performed day 4, 6, 8, 11 and 15 post-surgery. Bacteria were extracted from the biofilm by sonication and the bacterial load quantified by culturing. Biofilm formation was evident from day 6 post-implantation. Mean bacterial load from implants was ∼1×104 CFU/implant, while mean bacterial load from infected tibias were 1×106 CFU/bone. Bioluminesence imaging revealed decreasing activity throughout the 15-day observation period, with signal intensity for both strains reaching that of the negative control by day 15 while there was no significant reduction in bacterial load. The model is suitable for testing antimicrobial treatment options for implant associated OM, as treatment efficacy on both biofilm and viable counts can be assessed.
    PLoS ONE 10/2014; 9(10):e103688. DOI:10.1371/journal.pone.0103688 · 3.53 Impact Factor
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    ABSTRACT: Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2-miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade. Cancer Res; 74(20); 1-14. ©2014 AACR.
    Cancer Research 09/2014; 74(20). DOI:10.1158/0008-5472.CAN-13-3512 · 9.28 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) play a critical role in many biological processes and are aberrantly expressed in human cancers. Particular miRNAs function either as tumor suppressors or oncogenes and appear to have diagnostic and prognostic significance. Although numerous miRNAs are dys-regulated in colorectal cancer (CRC) only a small fraction has been characterized functionally. Using high-throughput functional screening and miRNA profiling of clinical samples the present study aims at identifying miRNAs important for the control of cellular growth and/or apoptosis in CRC. The high-throughput functional screening was carried out in six CRC cell lines transfected with a pre-miR library including 319 synthetic human pre-miRs. Phenotypic alterations were evaluated by immunostaining of cleaved cPARP (apoptosis) or MKI67 (proliferation). Additionally, TaqMan Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosa and 46 microsatellite stable stage II CRC patients. Among the miRNAs that induced growth arrest and apoptosis in the CRC cell lines, and at same time were dys-regulated in the clinical samples, miR-375 was selected for further analysis. Independent in vitro analysis of transient and stable transfected CRC cell lines confirmed that miR-375 reduces cell viability through the induction of apoptotic death. We identified YAP1 as a direct miR-375 target in CRC and show that HELLS and NOLC1 are down-stream targets. Knock-down of YAP1 mimicked the phenotype induced by miR-375 over-expression indicating that miR-375 most likely exerts its pro-apoptotic role through YAP1 and its anti-apoptotic down-stream targets BIRC5 and BCL2L1. Finally, in vivo analysis of mouse xenograft tumors showed that miR-375 expression significantly reduced tumor growth. We conclude that the high-throughput screening successfully identified miRNAs that induce apoptosis and/or inhibit proliferation in CRC cells. Finally, combining the functional screening with profiling of CRC tissue samples we identified clinically relevant miRNAs and miRNA targets in CRC.
    PLoS ONE 06/2014; 9(6):e96767. DOI:10.1371/journal.pone.0096767 · 3.53 Impact Factor
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    ABSTRACT: Atherosclerosis can be achieved in animals by germline genetic engineering leading to hypercholesterolemia, but such models are constrained to few species and strains and they are difficult to combine with other powerful techniques involving genetic manipulation or variation. To develop a method for induction of atherosclerosis without germline genetic engineering. Recombinant adeno-associated viral vectors (rAAV) were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) mutants, and mice were given a single intravenous vector injection followed by high-fat diet feeding. Plasma PCSK9 and total cholesterol increased rapidly and were maintained at high levels, and after 12 weeks, mice had atherosclerotic lesions in the aorta. Histology of the aortic root showed progression of lesions to the fibroatheromatous stage. To demonstrate the applicability of this method for rapid analysis of the atherosclerosis susceptibility of a mouse strain and for providing temporal control over disease induction, we demonstrated the accelerated atherosclerosis of mature diabetic Akita mice. Furthermore, the versatility of this approach for creating atherosclerosis models also in non-murine species was demonstrated by inducing hypercholesterolemia and early atherosclerosis in Golden Syrian hamsters. Single injections of PCSK9-encoding rAAV vectors is a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involves genetic techniques, strains, or species that do not combine well with current genetically engineered models.
    Circulation Research 03/2014; 114(11). DOI:10.1161/CIRCRESAHA.114.302937 · 11.09 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):647-647. DOI:10.1136/annrheumdis-2012-eular.170 · 9.27 Impact Factor
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    ABSTRACT: RNAi-based strategies provide a great therapeutic potential for treatment of various human diseases including kidney disorders, but face the challenge of in vivo delivery and specific targeting. The chitosan delivery system has previously been shown to target siRNA specifically to the kidneys in mice when administered intravenously. Here we confirm by 2D and 3D bioimaging that chitosan formulated siRNA is retained in the kidney for more than 48 hours where it accumulates in proximal tubule epithelial cells (PTECs), a process that was strongly dependent on the molecular weight of chitosan. Chitosan/siRNA nanoparticles, administered to chimeric mice with conditional knockout of the megalin gene, distributed almost exclusively in cells that expressed megalin, implying that the chitosan/siRNA particle uptake was mediated by a megalin-dependent endocytotic pathway. Knockdown of the water channel aquaporin 1 (AQP1) by up to 50% in PTECs was achieved utilizing the systemic i.v. delivery of chitosan/AQP1 siRNA in mice. In conclusion, specific targeting PTECs with the chitosan nanoparticle system may prove to be a useful strategy for knockdown of specific genes in PTECs, and provides a potential therapeutic strategy for treating various kidney diseases.
    Theranostics 01/2014; 4(10):1039-51. DOI:10.7150/thno.7866 · 7.83 Impact Factor
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    ABSTRACT: In patients with acute kidney injury (AKI) mortality remains high, despite the fact that the patients are treated with continuous renal replacement therapy. The interaction between the kidney and the immune system might explain the high mortality observed in AKI. In order to elucidate the interaction between the kidney and immune system we developed a two-hit model of AKI and endotoxemia. Our hypothesis was that ischemia/reperfusion (I/R) of the kidney simultaneously with endotoxemia would generate a more extensive inflammatory response compared to I/R of the hind legs. Our expectation was that elevated levels of cytokines would be found in both blood and in organs distant to the kidneys. Forty mice were divided into five groups. The mice were subjected to the following operations: A: Sham only, no lipopolysaccharide (LPS); B: I/R of both kidneys + LPS; C: LPS only; D: Nephrectomy + LPS; E: I/R of both hind legs + LPS. In groups B and E, I/R times were identical. All mice were kept alive for 24 h and then sacrificed. Levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α were measured in the blood. The activity of myeloperoxidase (MPO) in lungs, kidneys, and liver was evaluated as an indirect measurement of accumulation of granulocytes. In this study, significantly higher amount of IL-6 and IL-10 in the plasma was observed following renal I/R compared to hind leg I/R. The elevated levels of cytokine in plasma were observed following nephrectomy and endotoxemia. The neutrophil infiltration of distant organs measured by the levels of MPO in the lung and liver also showed a significantly higher level in renal I/R compared to hind leg I/R. Renal I/R is associated with a more pronounced inflammatory response in blood and distant organs. The high cytokine levels measured following nephrectomy might be explained by compromised elimination of cytokines by the kidney in AKI.
    Apmis 09/2013; DOI:10.1111/apm.12157 · 1.92 Impact Factor
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    ABSTRACT: We describe a simple method for bone engineering using biodegradable scaffolds with mesenchymal stem cells derived from human induced-pluripotent stem cells (hiPS-MSCs). The hiPS-MSCs expressed mesenchymal markers (CD90, CD73, and CD105), possessed multipotency characterized by tri-lineages differentiation: osteogenic, adipogenic, and chondrogenic, and lost pluripotency - as seen with the loss of markers OCT3/4 and TRA-1-81 - and tumorigenicity. However, these iPS-MSCs are still positive for marker NANOG. We further explored the osteogenic potential of the hiPS-MSCs in synthetic polymer polycaprolactone (PCL) scaffolds or PCL scaffolds functionalized with natural polymer hyaluronan and ceramic TCP (PHT) both in vitro and in vivo. Our results showed that these iPS-MSCs are functionally compatible with the two 3D scaffolds tested and formed typically calcified structure in the scaffolds. Overall, our results suggest the iPS-MSCs derived by this simple method retain fully osteogenic function and provide a new solution towards personalized orthopedic therapy in the future.
    Scientific Reports 07/2013; 3:2243. DOI:10.1038/srep02243 · 5.08 Impact Factor
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    ABSTRACT: Background: The tyrosine kinase receptor HER4 is a member of the epidermal growth factor receptor (EGFR) family. It plays diverse roles in cancer development and cancer progression and can both exert oncogenic and tumour-suppressive activities. Alternatively spliced isoforms of HER4 are critical to the different signalling possibilities of HER4. Methods: We use a splice-switching oligonucleotide (SSO) to direct the alternative splicing of HER4 from the CYT1 to the CYT2 isoform in HER4-expressing breast cancer cells. Results: Treatment with a target-specific SSO was accompanied by a decreased growth of the cells (P<0.0001). In addition, the SSO treatment induced a decreased activity of Akt. We confirmed the SSO-dependent switching of the HER4 isoform CYT1 to CYT2 expression in a xenografted mouse tumour model driven by subcutaneously injected MCF7 cells. We hence demonstrated the feasibility of SSO-directed splice-switching activity in vivo. Furthermore, the SSO treatment efficiently decreased the growth of the xenografted tumour (P=0.0014). Conclusion: An SSO directing the splicing of HER4 towards the CYT2 isoform has an inhibitory effect of cancer cell growth in vitro and in vivo. These results may pave the way for the development of new anticancer drugs in HER4-deregulated cancers in humans.
    British Journal of Cancer 05/2013; 108(11). DOI:10.1038/bjc.2013.247 · 4.82 Impact Factor
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    ABSTRACT: Harnessing the RNA interference pathway offers a new therapeutic modality; however, solutions to overcome biological barriers to small interfering RNA (siRNA) delivery are required for clinical translation. This work demonstrates, by direct northern and quantitative PCR (qPCR) detection, stability, gastrointestinal (GI) deposition, and translocation into peripheral tissue of nonmodified siRNA after oral gavage of chitosan/siRNA nanoparticles in mice. In contrast to naked siRNA, retained structural integrity and deposition in the stomach, proximal and distal small intestine, and colon was observed at 1 and 5 hours for siRNA within nanoparticles. Furthermore, histological detection of fluorescent siRNA at the apical regions of the intestinal epithelium suggests mucoadhesion provided by chitosan. Detection of intact siRNA in the liver, spleen, and kidney was observed 1 hour after oral gavage, with an organ distribution pattern influenced by nanoparticle N:P ratio that could reflect differences in particle stability. This proof-of-concept work presents an oral delivery platform that could have the potential to treat local and systemic disorders by siRNA.Molecular Therapy - Nucleic Acids (2013) 2, e76; doi:10.1038/mtna.2013.2; published online 5 March 2013.
    03/2013; 2(3):e76. DOI:10.1038/mtna.2013.2
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    ABSTRACT: Some of the main concerns with application of naked small interfering RNA are rapid degradation and urinary excretion resulting in a short plasma half-life. In this study we investigated how conjugation of polyethylene glycol (PEG) with variable chain length affects siRNA pharmacokinetics and biodistribution. The PEG chains were conjugated to chemically stabilized siRNA at the 5' terminal end of the passenger strand using click chemistry. The siRNA conjugate remained functionally active and showed significantly prolonged circulation in the blood stream after intravenous injection. siRNA conjugated with 20kDa PEG (PEG20k-siRNA) was most persistent, approximately 50% PEG20k-siRNA remained 1h post-injection, while the uncoupled siRNA was rapidly removed >90% at 15min. fluorescent imaging of the living animal showed increased concentration of siRNA in peripheral tissue and delayed urine excretion when coupled to PEG 20k. Biodistribution studies by northern blotting revealed equal distribution of conjugated siRNA in liver, kidney, spleen and lung without significant degradation 24 h post-injection. Our study demonstrates that PEG conjugated siRNA can be applied as a delivery system to improve siRNA bioavailability and may potentially increase the efficiency of siRNA in therapeutic applications.
    Theranostics 02/2013; 3(3):201-9. DOI:10.7150/thno.5743 · 7.83 Impact Factor
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    ABSTRACT: Mitochondria, the powerhouses of our cells, are remnants of a eubacterial endosymbiont. Notwithstanding the evolutionary time that has passed since the initial endosymbiotic event, mitochondria have retained many hallmarks of their eubacterial origin. Recent studies have indicated that during perturbations of normal homeostasis, such as following acute trauma leading to massive necrosis and release of mitochondria, the immune system might mistake symbiont for enemy and initiate an inappropriate immune response. The innate immune system is the first line of defense against invading microbial pathogens, and as such is the primary suspect in the recognition of mitochondria-derived danger-associated molecular patterns (DAMPs) and initiation of an aberrant response. Conversely, innate immune mechanisms are also central to non-inflammatory clearance of innocuous agents. Here we investigated the role of a central humoral component of innate immunity, the lectin pathway of complement, in recognition of mitochondria in vitro and in vivo. We found that the soluble pattern-recognition molecules (PRMs), mannan-binding lectin (MBL), L-ficolin and M-ficolin were able to recognize mitochondria. Furthermore, MBL in complex with MBL-associated serine protease 2 (MASP-2) was able to activate the lectin pathway and deposit C4 onto mitochondria, suggesting that these molecules are either involved in homeostatic clearance of mitochondria or induction of untoward inflammatory reactions. We found that following mitochondrial challenge, C3 was consumed in vivo in the absence of overt inflammation, indicating a potential role of complement in non-inflammatory clearance of mitochondria. Thus, we report here the first indication of involvement of the lectin pathway in mitochondrial immune handling.
    Journal of Biological Chemistry 02/2013; DOI:10.1074/jbc.M112.430249 · 4.60 Impact Factor
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    ABSTRACT: Circulating mannan-binding lectin (MBL) levels are elevated in type 1 diabetes. Further, high MBL levels are associated with the development of diabetic nephropathy. In animals, a direct effect of MBL on diabetic kidney changes is observed. We hypothesized that MBL levels and detrimental complement activation increase as a consequence of diabetes. We measured plasma MBL before and seven weeks after inducing diabetes by streptozotocin. Mice have two MBLs, MBL-A and MBL-C. Diabetes-induction led to an increase in MBL-C concentration whereas no change during the study was found in the control group. The increase in MBL-C was associated with the increasing plasma glucose levels. In accordance with the observed changes in circulating MBL levels, liver expression of Mbl2 mRNA (encoding MBL-C) was increased in diabetes. Mbl1 expression (encoding MBL-A) did not differ between diabetic and control animals. The estimated half-life of recombinant human MBL was significantly prolonged in mice with diabetes compared with control mice. Complement activation in plasma and glomeruli did not differ between groups. We demonstrate for the first time that MBL levels increase after induction of diabetes and in parallel with increasing plasma glucose. Our findings support the previous clinical observations of increased MBL in type 1 diabetes. This change may be explained by alternations both in MBL production and turnover.
    Scandinavian Journal of Immunology 01/2013; 77(3). DOI:10.1111/sji.12027 · 1.88 Impact Factor
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    ABSTRACT: Arthritic bone loss in the joints of patients with rheumatoid arthritis is the result of a combination of osteoclastic bone resorption and osteoblastic bone formation. This process is not completely understood, and especially the importance of local inflammation needs further investigation. We evaluated how bone formation and bone resorption are altered in experimental autoimmune arthritis. Twenty-one female SKG mice were randomized to either an arthritis group or a control group. Tetracycline was used to identify mineralizing surfaces. After six weeks the right hind paws were embedded undecalcified in methylmethacrylate. The paws were cut exhaustively according to the principles of vertical sectioning and systematic sampling. 3D design-based methods were used to estimate the total number of osteoclasts, mineralizing surfaces, eroded surfaces, and osteoclast-covered bone surfaces. In addition the presence of adjacent inflammation was ascertained. The total number of osteoclasts, mineralizing surfaces, eroded surfaces, and osteoclast covered surfaces were elevated in arthritic paws compared to normal paws. Mineralizing surfaces were elevated adjacent to as well as not adjacent to inflammation in arthritic mice compared to normal mice. In arthritic mice, eroded surfaces and osteoclast covered surfaces were larger on bone surfaces adjacent to inflammation than on bone surfaces without adjacent inflammation. However, we found no difference between mineralizing surfaces at bone surfaces with or without inflammation in arthritic mice. Inflammation induced an increase in resorptive bone surfaces as well as formative bone surfaces. The bone formative response may be more general, since formative bone surfaces were also increased when not associated with inflammation. Thus, the bone loss may be the result of a substantial local bone resorption, which cannot be compensated by the increased local bone formation. These findings may be valuable for the development of new osteoblast targeting drugs in RA.
    PLoS ONE 12/2012; 7(12):e53034. DOI:10.1371/journal.pone.0053034 · 3.53 Impact Factor
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    ABSTRACT: Gene electrotransfer is an effective non-viral technique for delivery of plasmid DNA into tissues. From a clinical perspective muscle is an attractive target tissue as long-term high-level transgenic expression can be achieved. Spatial distribution of the transgenic protein following gene electrotransfer to muscle in a large animal model has not yet been investigated. In this study 17 different doses of plasmid DNA (1-1500 µg firefly luciferase pCMV-Luc) were delivered in vivo to porcine gluteal muscle using electroporation. Forty-eight hours post treatment several biopsies were obtained from each transfection site in order to examine the spatial distribution of the transgenic product. We found a significantly higher luciferase activity in biopsies from the center of the transfection site compared to biopsies taken adjacent to the center 1 and 2 cm along muscle fibre orientation (p<0.05 and p<0.0001, respectively). On average, 43 % of the total luciferase activity was localized in the center biopsy. In conclusion, we found that gene electrotransfer to muscle in a large animal model led to localized gene expression corresponding to the area delineated by the electrodes. High doses of plasmid DNA did not lead to a larger area of the muscle expressing the transgenic protein.
    Human Gene Therapy Methods 11/2012; 23(6). DOI:10.1089/hgtb.2012.173 · 1.64 Impact Factor
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    ABSTRACT: Targeted transgenesis using site-specific recombinases is an attractive method to create genetically modified animals as it allows for integration of the transgene in a pre-selected transcriptionally active genomic site. Here we describe the application of recombinase-mediated cassette exchange (RMCE) in cells from a Göttingen minipig with four RMCE acceptor loci, each containing a green fluorescence protein (GFP) marker gene driven by a human UbiC promoter. The four RMCE acceptor loci segregated independent of each other, and expression profiles could be determined in various tissues. Using minicircles in RMCE in fibroblasts with all four acceptor loci and followed by SCNT, we produced piglets with a single copy of a transgene incorporated into one of the transcriptionally active acceptor loci. The transgene, consisting of a cDNA of the Alzheimer's disease-causing gene PSEN1M146I driven by an enhanced human UbiC promoter, had an expression profile in various tissues similar to that of the GFP marker gene. The results show that RMCE can be done in a pre-selected transcriptionally active acceptor locus for targeted transgenesis in pigs.
    Transgenic Research 10/2012; 22(4). DOI:10.1007/s11248-012-9671-6 · 2.28 Impact Factor
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    Acta Oncologica 10/2012; · 3.71 Impact Factor
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    ABSTRACT: The number of animals used in research should be limited as much as possible. Among cloned animals, genetic variation is minimal and to the extent that behaviour is genetically determined inter-individual variability is expected to be higher among naturally bred animals. However, the cloning procedure per se might affect the resultant phenotype leading to phenotypic variations independent of the genetic background. Recently, cloned Göttingen minipigs carrying a mutation for Alzheimer's disease have been produced. In order to document the development of Alzheimer's disease symptoms, these pigs were subjected to a behavioural test of memory, the spontaneous object recognition test, from an early age. At ages 1 and 2 years no evidence of memory decline was found, yet the data showed striking behavioural variability among the cloned groups. The aim of the present study was to investigate effects of genetic homogeneity on variability of cloned minipigs compared with non-cloned controls regarding behavioural variables in a cognitive test, namely the spontaneous object recognition test.Significant differences in the variability between the cloned and control pigs were found in five out of 24 behavioural variables. The clones showed lower variability for four of the measures, whereas the variability was increased for one variable. No significant difference between the cloned and the control group was found for the remaining 19 variables (79%). In 14 of these, the standard deviation was numerically greater for the control group compared to the cloned group, indicating that variation may be less in cloned animals, but not demonstrable with the small group size of the present study (n = 6 for each of the two groups tested).Overall, this study failed to show unambiguously that variability in these behavioural variables in cloned minipigs is less than in naturally bred control subjects and therefore does not directly support the hypothesis that cloning may be used to replicate animals in order to reduce group size in experimentation animals.
    Applied Animal Behaviour Science 10/2012; 141(1-2):20-24. DOI:10.1016/j.applanim.2012.07.006 · 1.63 Impact Factor
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    ABSTRACT: Background. Radiation-induced fibrosis (RIF) is a dose-limiting complication of cancer radiotherapy and causes serious problems, i.e. restricted tissue flexibility, pain, ulceration or necrosis. Recently, we have successfully treated RIF in a mouse model by intraperitoneal administration of chitosan/siRNA nanoparticles directed towards silencing TNF alpha in local macrophage populations, but the mechanism for the therapeutic effect at the lesion site remains unclear. Methods. Using the same murine RIF model we utilized an optical imaging technique and fluorescence microscopy to investigate the uptake of chitosan/fluorescently labeled siRNA nanoparticles by peritoneal macrophages and their subsequent migration to the inflamed tissue in the RIF model. Results. We observed strong accumulation of the fluorescent signal in the lesion site of the irradiated leg up to 24 hours using the optical imaging system. We further confirm by immunohistochemical staining that Cy3 labeled siRNA resides in macrophages of the irradiated leg. Conclusion. We provide a proof-of-concept for host macrophage trafficking towards the inflamed region in a murine RIF model, which thereby suggests that the chitosan/siRNA nanoparticle may constitute a general treatment for inflammatory diseases using the natural homing potential of macrophages to inflammatory sites.
    Acta oncologica (Stockholm, Sweden) 10/2012; 52(8). DOI:10.3109/0284186X.2012.726373 · 3.71 Impact Factor

Publication Stats

2k Citations
323.30 Total Impact Points

Institutions

  • 1998–2015
    • Aarhus University
      • • Department of Biomedicine
      • • Department of Medical Microbiology and Immunology
      Aarhus, Central Jutland, Denmark
  • 2002
    • Aarhus University Hospital
      Aarhus, Central Jutland, Denmark