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| 2. |
- Berglund, U. W., et al.
(författare)
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Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
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| 3. |
- Jonsson, Amanda, et al.
(författare)
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Therapy using implanted organic bioelectronics
- 2015
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Ingår i: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug’s spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter g-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics. 2015 © The Authors.
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| 7. |
- Cozzolino, C. A., et al.
(författare)
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Exploiting the nano-sized features of microfibrillated cellulose (MFC) for the development of controlled-release packaging
- 2013
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Ingår i: Colloids and Surfaces B. - : Elsevier BV. - 0927-7765 .- 1873-4367. ; 110, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Microfibrillated cellulose (MFC) was used in this study to prepare films containing an active molecule, lysozyme, which is a natural antimicrobial agent. The main goal of this research was to assess the potential for exploiting the nano-sized dimension of cellulose fibrils to slow the release of the antimicrobial molecule, thus avoiding a too-quick release into the surrounding medium, which is a major disadvantage of most release systems. For this purpose, the release kinetics of lysozyme over a 10-day period in two different media (pure water and water/ethanol 10. wt.%) were obtained, and the experimental data was fitted with a solution of Fick's second law to quantify the apparent diffusion coefficient (D). The results indicate that the MFC retained lysozyme, presumably due to electrostatic, hydrogen, and ion-dipole interactions, with the largest release of lysozyme-approximately 14%-occurring from the initial amount loaded on the films. As expected, ethanol as a co-solvent slightly decreased the diffusion of lysozyme from the MFC polymer network. The addition of two potential modulating release agents-glycerol and sodium chloride-was also evaluated. Findings from this work suggest that MFC-based films can be considered a suitable candidate for use in controlled-release packaging systems.
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| 8. |
- Hanson, Maj, 1939, et al.
(författare)
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Magnetic properties of epitaxial Ni(001) films and sub-micron particles
- 2001
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Ingår i: Journal of Magnetism and Magnetic Materials. - 0304-8853 .- 1873-4766. ; 236, s. 139-50
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Tidskriftsartikel (refereegranskat)abstract
- The magnetic properties of Ni particles with well-defined geometry, prepared by electron lithography from epitaxial Ni(001) films of thickness 50 and 60 nm were studied. The particles were circles with diameters 0.6 m and rectangles with sides 0.9 m and 0.3 m, that were positioned in square and rectangular lattices, having lattice constants about twice the particle dimensions. Reference samples and particles with the lattices oriented along the [100] and [110] directions were prepared. Hysteresis curves were obtained for particles and reference samples, in the field range 2T at temperatures between 50 and 300 K. The particles were further imaged by magnetic force microscopy. The coercivities of the particles are about the same as that of the reference samples, being of the order of 10 mT at room temperature and increasing with decreasing temperature. This may be explained by the temperature dependence of the magnetic anisotropy of the Ni film, estimated to K1=-12.5, -12.8 and -87.6 kJ m-3 at 295, 250 and 50 K, respectively. Whereas the hysteresis curves of the particles are governed by the intrinsic properties of the starting film in low fields, the decreased lateral size influences the behaviour in higher fields as demagnetization effects and features characteristic for annihilation and nucleation of domain walls. One of the samples, rectangles with the long axis alone the [110] direction, has a significantly higher remanence and coercivity than the others. The magnetic images show that the demagnetized state of this sample comprises both single-domain and multidomain particles. Corresponding images showed only multidomain particles in all other samples. Thus it was concluded that the actual size (0.9 m0.3 m50 nm) is close to the critical size for single domains in Ni
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| 10. |
- Lindgren, Kristina, et al.
(författare)
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Parascaris equorum in foals and in their environment on a Swedish stud farm, with notes on treatment failure of ivermectin
- 2008
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Ingår i: Veterinary parasitology. - : Elsevier BV. - 0304-4017 .- 1873-2550. ; 151:2-4, s. 337-343
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Tidskriftsartikel (refereegranskat)abstract
- Environmental contamination and the egg excretion pattern of the ascarid Parascaris equorum (Nematoda) was investigated in relation to anthelmintic treatment on a Swedish stud farm. Faecal samples from 15 foals, dewormed every 8th-week with a paste formulation of ivermectin at the standard dose rate of 0.2 mg/kg bodyweight, were collected at five sampling occasions between August and November 2006. In addition, soil samples were obtained from four paddocks used by these foals in November 2006. The number of eggs per gram (epg) was counted in both faeces and soil. Egg excretion started when the foals were 3-4 months, and reached the highest levels when they were approximately 5-month-old, and was then followed by a decline. Egg excretion seemed to be unaffected by ivermectin despite these foals were dewormed at regular intervals. In four out of five foals examined 10 days after treatment, epg actually increased. In contrast, when either fenbendazol or pyrantel embonate were used instead of ivermectin, treatments were effective. The number of eggs in soil was significantly higher in the permanent paddock compared to in the temporarily used soil paddock and in the summer paddocks. © 2007 Elsevier B.V. All rights reserved.
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