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| 2. |
- Aneheim, Emma, 1982, et al.
(författare)
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Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates
- 2016
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1520-4812 .- 1043-1802. ; 27:3, s. 688-97
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Tidskriftsartikel (refereegranskat)abstract
- Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 μm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies.
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| 3. |
- Gustafsson, Sofia, 1982-
(författare)
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Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis. In this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied. In both cell lines, the compounds examined produced a concentration- and time-dependent decrease in cell viability. In Caco-2-cells, HU 210 and the pyrimidine antagonist 5-fluorouracil produced synergistic effects upon cell viability. The mechanisms behind the cytocidal effects of cannabinoids appear to be mediated by other than solely the CB receptor, and a common mechanism in Caco-2 and P19 EC cells was oxidative stress. However, in P19 EC cells the CB receptors contribute to the cytocidal effects possibly via ceramide production. In paper II, the association between CB1 receptor immunoreactivity (CB1IR) and different histopathological variables and disease-specific survival of colorectal cancer (CRC) was investigated. In microsatellite stable (MSS) cases there was a significant positive association of the tumor grade with the CB1IR intensity. A high CB1IR is indicative of a poorer prognosis in MSS with stage II CRC patients. Paper IV focused on the cytotoxic effects of cannabinoids during neuronal differentiation. HU 210 affected the cell viability, neurite formation and produced a decreased intracellular AChE activity. The effects of cannabinoids on embryonic development and survival were examined in Paper V, by repeated injection of cannabinoids in fertilized chicken eggs. After 10 days of incubation, HU 210 and cannabidiol (without CB receptor affinity), decreased the viability of chick embryos, in a manner that could be blocked by α-tocopherol (antioxidant) and attenuated by AM251 (CB1 receptor antagonist). In conclusion, based on these studies, the cannabinoid system may provide a new target for the development of drugs to treat cancer such as CRC. However, the CBs also produce seemingly unspecific cytotoxic effects, and may have negative effects on the neuronal differentiation process. This may be responsible for, at least some of, the embryotoxic effects found in ovo, but also for the cognitive and neurotoxic effects of cannabinoids in the developing and adult nervous system.
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| 4. |
- Gustafsson, Sofia, 1982-, et al.
(författare)
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Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells
- 2013
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Ingår i: Archives of Toxicology. - : Springer Berlin/Heidelberg. - 0340-5761 .- 1432-0738. ; 87:11, s. 1939-1951
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Tidskriftsartikel (refereegranskat)abstract
- Compounds acting on the cannabinoid (CB) receptors are involved in the control of cell fate, and there is an emerging consensus that CBs have anticancer effects. However, the CB-mediated effects are contradictory since some studies suggest stimulatory effects on cancer cell proliferation, and CBs have been shown to stimulate both proliferation and differentiation of other mitotic cells such as stem and progenitor cells. In this study, the concentration-dependent effects of synthetic and endogenous CBs on the viability of mouse P19 embryonal carcinoma (EC) cells have been examined by using fluorescence assays of cell membrane integrity, cell proliferation, oxidative stress, and detection of apoptosis and necrosis. All compounds examined produced a concentration-dependent decrease in cell viability in the micromolar range, with the potent CB receptor agonist HU 210 and the enantiomer HU 211(with no CB receptor activity) being the most potent compounds examined with apparent IC50 values of 1 µM and 0.6 µM, respectively. The endogenous CB anandamide showed similar potency and efficacy as structurally related polyunsaturated fatty acids with no reported activity at the CB receptors. The rapid (within hours) decrease in cell viability induced by the examined CBs suggests cytocidal rather than antiproliferative effects, and is dependent on the plating cell population density with the highest toxicity around 100 cells/mm2. The CB-induced cytotoxicity, that appears to involve CB receptors and the sphingomyelin-ceramide pathway, is a mixture of both apoptosis and necrosis that can be blocked by the antioxidants α-tocopherol and N-acetylcysteine. In conclusion, both synthetic and endogenous CBs, produce seemingly unspecific cytotoxic effects in the P19 EC cells.
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| 5. |
- Gustafsson, Sofia, 1982-, et al.
(författare)
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Effects of cannabinoids on the development of chick embryos in ovo
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- We have examined the effects of the synthetic cannabinoids HU 210 and HU 211, the plant-derived cannabidiol and the endogenous cannabinoid anandamide on the viability and development of chick embryos. Fertilized White Leghorn chicken eggs were injected with the test compounds or carrier vehicle, via a drilled small hole in the egg, directly into the egg yolk. After nine days of exposure, the embryonal viability, length and wet weight of embryos, and wet weight of brains were measured, and the development stages were assessed according to the Hamburger and Hamilton (HH) scale. The potent synthetic cannabinoid receptor agonist HU 210 and the non-psychotropic cannabidiol were embryotoxic at the highest concentrations examined (10µM and 50µM, respectively), with no viable embryos after the HU 210 injection, and 20% viability after the cannabidiol injections. The efects of HU 210 on the chick embryo were attenuated by α-tocopherol and the cannabinoid receptor antagonist AM251, whereas only α-tocopherol gave a statistically signifcant protection against the embryotoxic efects of cannabidiol. This study shows that exposure to plant-derived or synthetic cannabinoids during early embryonal development decreases embryonal viability. Extrapolation of data across species is of course difcult, but the data would argue against the use of cannabinoids, be it recreationally or therapeutically, during pregnancy
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| 6. |
- Gustafsson, Sofia, 1982-, et al.
(författare)
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The effects of cannabinoids on the viability and differentiation of neurons derived from retinoic acid-induced P19 embryonal carcinoma cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cannabinoids and cannabinoid receptors play an important role in development and differentiation of the nervous system, but the mechanisms behind that role have not been fully elucidated. We have examined the effects of synthetic and endogenous cannabinoids and related polyunsaturated fatty acids upon mouse embryonal carcinoma P19 stem cell viability - before, during and after retinoic acid (RA)-induced neural differentiation. Experiments were also performed to investigate whether the cannabinoids affect the differentiation of P19-derived neurons by measuring the development and growth of neurites and intracellular acetylcholinesterase activity. Both synthetic and endogenous cannabinoids as well as related fatty acids produced a concentration-dependent decrease in undifferentiated P19 cell viability, but induction of the neural pathway reduced the sensitivity to the cytotoxic effects, and in differentiated neurons anandamide and related fatty acids showed no cytotoxicity. However, synthetic cannabinoids such as HU 210, HU 211 and WIN 55,212-2 produced cytotoxicity in both undifferentiated and differentiated cells, but there was a right-shifted concentration-effect curve in RA-induced cells and differentiated neurons compared with the undifferentiated cells. HU 210 produced a time- and concentration-dependent decrease in cell number, percentage of cells expressing neurites, number of neurites per cell and neurite length. Statistically significant inhibition was seen at a concentration of 1 µM to 3 µM, and this was confirmed by the measurement of intracellular acetylcholinesterase activity, an enzyme that is dramatically increased during the differentiation process, where HU 210 significantly decreased the activity after six and nine days of exposure. However, these effects of HU 210 could only be observed in the same concentration range as those affecting neuronal viability. Anandamide, on the other hand, had modest effect on measured markers of neuronal differentiation but decreased the fraction of neurite expressing cells and neurite length after nine days of exposure at a concentration ≥ 10 µM. No effect on the acetylcholinesterase activity was observed. It is concluded that cannabinoids and related fatty acids have cytotoxic effects in undifferentiated P19 embryonal carcinoma cells, but induction of the neuronal pathway reduces the sensitivity to the cytotoxic effects. The synthetic cannabinoids are more potent than the endogenous cannabinoids and fatty acids in causing cytotoxicity in differentiated neurons, but the CB-induced decrease in neurite formation and acetylcholinesterase activity in RA-induced P19-derived neurons occurs only at concentrations that cause measurable neuronal cell death.
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| 7. |
- Lund, Olov, 1982-
(författare)
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Nätverksstaten : Statsbildningsprocesser och rumsliga praktiker i senmedeltidens Sverige ca 1440–1520
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Previous research has examined the late medieval Swedish state from a constitutional and ideological perspective and in terms of the juridical, fiscal, and military organizations. This thesis focuses on the much less known informal and practical-spatial side of the political system. The main questions of this dissertation are: How did the Swedish late medieval state function? How integrated was the state into the local community? Who and how many took part in the activities of the state, and why? The departure for any inquiry into these questions is the Council of the Realm, who reigned during the 15th Century. This thesis study two of its members as case studies: The lawmen Arvid Trolle (c. 1440–1505) and Svarte Åke Jönsson (c. 1420–1494), who both were involved in the state's activities and the local community for as long as 40 years. I use the concept of anthrospace, which denotes the necessity and interplay between social networks, material resources, and movement in space, as the driving force of history. The purpose of this thesis is mapping out the social networks of these two figures and their material resources in form of estates, land, and fiefs. It also means studying how these two lawmen moved through space in relation to their human and material resources.The results show that Svarte Åke Jönsson and Arvid Trolle had extensive networks both among the aristocratic elite in the Council of the Realm at the national level and in the local community. Their respective households and networks amounted to 100–120 families. Svarte Åke Jönsson´s and Arvid Trolle´s respective family businesses managed between 2 and 9 percent of the state's total revenues from ordinary taxes. Most of the revenues from the castle districts went to maintenance as well as food and salaries for castle crews and other staff. Finally, the results point to a geographical correlation between Arvid Trolle´s and Svarte Åke Jönsson's land, estates, fiefs, official jurisdictions, residences, the extent of their networks, and how they moved through space.Taken together, the results lead to several important conclusions regarding both the aristocratic household and how the state functioned. Their rather distinctly demarcated geographical life indicates that the state and the execution of state functions were formed as a patchwork of aristocratic family businesses, local bailiffs, county judges, and others who exercised, negotiated, contested, and took advantage of state resources. The results also conclude that the number of people who directly participated in the activities of the state and in the exercise of state functions was a minimum of 7,500–8,000 individuals. This overlapping system of aristocratic households, family businesses, and networks that exercised state functions meant both continuity and stability. The many thousands of people involved in state activities should be considered as a central force in the state-building process.
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| 8. |
- Olsson, Max, et al.
(författare)
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A pilot study of a deliberate practice intervention for therapist trainees
- 2024
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Ingår i: Nordic Psychology. - : Taylor & Francis. - 1901-2276 .- 1904-0016.
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Tidskriftsartikel (refereegranskat)abstract
- Deliberate practice (DP) is well established and widely accepted in expert performance research within a variety of fields. Recently, researchers have started to examine if the same training principles can be applied to psychotherapists. The aim of this study was to examine the impact on intrapersonal skills and the experiences of a six-week DP intervention on seven therapist trainees (n = 7). To do this, a single-case research design was used, combining weekly repeated measurements and pre- and post-intervention measurements as well as a qualitative study analyzed by inductive thematic analysis. The results from our measurements indicate mixed results, where three out of seven participants achieved a significant positive intervention effect and we can see that most participants change in the hypothesized direction on mindful attention (MAAS), experiential avoidance (MEAQ), emotional processing (EPI), and self-compassion (SCS). The participants described gains on increased self-awareness, more compassionate treatment of oneself, increased tolerance of unpleasant feelings as well as a sense of being able to use their own experiences to understand their relationship to other people. The intervention also gave the participants an ability to hold contrasting thoughts and emotions and provided an increased sense of hope for their own future development. The findings of our study should be interpreted in light of its pilot nature and the limited extent of our design. However, it indicates that it seems possible to achieve positive results on intrapersonal skills from a relatively short period of training.
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