| 1. |
- Johansson, David, 1979-
(författare)
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Bacterial toxins for cancer treatment
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Even though anti‐cancer chemotherapy has been continuously improved during the last decades. problems with adverse effects and drug resistance still constitutes a considerable obstacle and sets a demand for new effective treatment options. Tissue homeostasis in multi‐cellular organisms is maintained through intrinsic cell death, apoptosis, which removes unwanted or damaged cells. Disrupted apoptosis is an important factor in tumorgenesis and drug resistance, therefore induction or restoration of apoptotic pathways is also important for the treatment of cancer. Several naturally occurring bacterial toxins have the ability to induce apoptosis and could thus be candidates to complement or improve the therapeutic effect of other anticancer drugs. The bacterial toxins, adenylate cyclase (AC) toxin from Bordetella pertussis, α‐toxin from Staphylococcus aureus and verotoxin‐1 (VT‐1) from Escherichia coli were investigated for their ability to induce apoptosis in different tumor cell lines. Toxin induction of cell death was investigated by cell viability assays, end‐stage apoptosis induction by DNA‐fregmentation (TUNEL) assay. Toxin receptor expression and signal transduction pathways to apoptosis were investigated by flow cytometry, caspase enzyme activity assays and western blot. Immunohistochemistry was used for identification of toxin receptor expression in tumor tissue samples. AC‐toxin was cytotoxic and induced apoptosis in cultured malignant plural mesothelioma (MPM) and small‐cell lung cancer (SCLC) cells. Low‐toxic concentrations of AC‐toxin enhanced cisplatin cytotoxicity and apoptosis in both cell lines. MPM‐cells with acquired cisplatin resistance were more sensitive to α‐toxin than the less resistant parental MPM cell line. A low‐toxic concentration of α‐toxin re‐sensitized resistant MPM cells to cisplatin cytotoxicity by apoptosis induced through the mitochondrial pathway without detectable activation of common up‐stream apoptosis signalling proteins. VT‐1 was highly cytotoxic and induced apoptosis in globotriosylceramide (Gb3) ‐expressing glioma, breast cancer and non‐small‐cell lung cancer (NSCLC) cells but was not cytotoxic to non‐Gb3‐expressing cells. PPMP, an inhibitor of glucosylceramide synthesis which makes exposed cells unable to synthesize Gb3 rendered Gb3‐expressing cells resistant to VT‐1. MPM cells with acquired‐cisplatin resistance expressed Gb3 in contrast to the absent of expression in the less resistant parental cell line. Gb3, could however be up‐regulated by cisplatin in Gb3‐negative MPM‐cells. Presence of a low‐toxic concentration of VT‐1 potentiated cisplatin‐induced cytotoxicity and apoptosis in the cisplatin‐resistance MPM cell line. VT‐1 was a potent inducer of apoptosis, probably via stress‐induced Mitogen‐activated protein kinase (MAPK)‐signaling involving c‐Jun N‐terminal kinase (JNK) and p38, leading to disruption of the mitochondrial membrane integrety, activation of caspase‐9 and ‐3, and ultimately DNA fragmentation and cell death. Gb3 expression was demonstrated in clinical specimens of glioblastoma and breast cancer making these tumor types interesting for further VT‐1 studies. We conclude that bacterial toxins may be used to induce apoptosis in several types of cancer cells. Low concentrations of verotoxin‐1 and α‐toxin may potentially be used to overcome acquired cisplatin‐resistance in cancer patients.
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| 2. |
- Johansson, Peter, 1962-
(författare)
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Health‐related quality of life, depression, sleep and breathing disorders in the elderly : With focus on those with impaired systolic function/heart failure
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to describe the prevalence of depressive symptoms, sleep disordered breathing (SDB) and sleep complaints, as well as to investigate the prognostic value of health-related quality of life (Hr-QoL) and depressive symptoms on mortality in an elderly community living population with a focus on those with impaired systolic function/heart failure (HF). Descriptive, prognostic and explorative study designs were used to examine if a single question about global perceived health (GPH) is associated with the domains of Hr-QoL as assessed by the SF-36 (I), as well as to evaluate whether GPH provided prognostic information concerning cardiovascular mortality (II). The aim was also to evaluate if depressive symptoms are associated with mortality (III), and to describe the prevalence of SDB and its relationship to impaired systolic function, different insomnia symptoms, as well as excessive daytime sleepiness (IV).In primary care elderly patients with HF, GPH correlated to the physical and mental aspects of Hr-QoL. Patients who rated poor GPH also scored worse physical and mental Hr-QoL compared to patients with good GPH, but the mental aspect of Hr-QoL was however not significant (p<0.07) (I). Moreover, GPH also had an independent association with cardiovascular mortality during a ten-year follow-up. Compared to patients with good GPH, those who scored poor GPH had a four times increased risk for cardiovascular mortality (II). A total of 24% of the patients with HF suffered from depressive symptoms, not significantly different compared to 19% among those without HF. Depressive symptoms were a poor prognostic sign during the six-year follow-up and HF patients with depressive symptoms had the highest risk for cardiovascular mortality compared to HF patients without depressive symptoms (III). SDB is common among elderly people living in the community, almost one quarter (23%) had moderate or severe SDB. However, people with moderate impaired systolic function had a median apnea hypopnea index that was more than twice as high compared to those with normal systolic function (10.9 vs. 5.0, p<0.001). No obvious associations between SDB and excessive daytime sleepiness or the insomnia symptoms; difficulties maintaining sleep; non-restorative sleep; or early morning awakenings were detected. Difficulties initiating sleep were however more common in those with moderate or severe SDB (IV).GPH can be used as a simple tool in clinical routine practice as an aid in identifying patients in need of additional management. SDB is a common phenomenon among elderly people and associated with impaired systolic function, but with a limited impact on subjective sleep complaints. Depressive symptoms were shown to be a poor prognostic sign and may amplify the patient’s experience of suffering. Screening for depressive symptoms could therefore be an important action in the management of patients with HF.
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| 3. |
- Johansson, Anders, 1972-
(författare)
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Biopolitics and Reflexivity : A Study of GMO Policymaking in the European Union
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The political discourse that has emerged as a consequence of establishing a European regulatory framework for GMOs has not been without problems. This dissertation addresses the political and regulatory challenges created by the development and use of genetically modified organisms (GMOs) in the EU. The underlying hypothesis in the dissertation is that the emergence of a European policy in the field of GMOs has appeared through new reflexive forms of governance. The aim of this research is to understand how these reflexive forms of regulation have emerged and operate within the EU, with a particular focus on the two GMO directives 90/220/EEC and 2001/18/EC. However, the study scrutinises the regulatory regimes from the 1970s onwards by investigating how the regulatory framework regarding GMOs has been developed and implemented in the EU. This is done through an analysis of the notion of ‘risk’ and the ‘precautionary principle’ since these concepts have been at the forefront of the GMO regulation debate. The empirical approach focuses on how the European Commission, the European Parliament and the European Council as well as other actors and institutions articulate ambivalence, interpretations and uncertainties in the decision-making processes regarding regulative measures for GMOs, with an accent on risk and the precautionary principle. The main empirical material has been documents concerning the inter-institutional process involved in the regulatory process of making the two directives. The analysis indicates that during the process of implementing GMO regulations, new steering strategies have appeared within the EU’s decision-making institutions when the objective of the regulation has taken centre stage in political and scientific controversies.
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| 4. |
- Johansson, Anders, 1976-
(författare)
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Template-Based fabrication of Nanostructured Materials
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Materials prepared on the nanoscale often exhibit many different properties compared to the same materials in their bulk-state. Interest in nanostructured materials has increased because of these properties in fields such as microelectronics, catalysis, optics and sensors. This increased interest in nanostructured materials calls for new and more precise fabrication techniques.This thesis describes how to use the porous anodic aluminium oxide as a template for the fabrication of a variety of nanostructured materials. Palladium and copper nanoparticles were deposited along the pore walls in anodic aluminum oxide using electroless deposition and atomic layer deposition. In both cases, it was possible to control the size of the nanoparticles by carefully monitoring the deposition parameters. The thesis also describes how Prussian blue nanoparticles and nanotubes can be fabricated using the anodic aluminium oxide as a template. The deposition of Prussian blue was performed by a sequential wet-chemical method. By using atomic layer deposition, it was also possible to deposit thin films of amorphous Nb2O5 on the pore walls. When the template was removed by etching, freestanding nanotubes were obtained. The anodic aluminium oxide membrane was also used as a mask for high energy (MeV) ion irradiation of an underlying substrate. The tracks produced were etched away with hydrogen fluoride. In this way, it was possible to transfer the highly ordered porous pattern from the mask onto other oxides such as SiO2 and TiO2.All fabricated structures were characterized using a variety of analysis techniques: scanning electron microscopy for evaluating sample morphology; transmission electron microscopy for better resolved investigations of the morphology; X-ray diffraction to assess crystallinity; energy dispersive spectroscopy and X-ray fluorescence spectroscopy to determine the elemental composition and identify possible contaminants.The general aim of the work described in this thesis has been to create a set of tools for use in the fabrication of a variety of nanostructured materials, whose dimensions composition can be tailored by selecting appropriate fabrication methods and parameters.
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| 5. |
- Johansson, Jonas, 1970-
(författare)
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Comparative Treatment Planning in Radiotherapy and Clinical Impact of Proton Relative Biological Effectiveness
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses.Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel.A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning.This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.
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| 6. |
- Johansson, Niclas, 1976-
(författare)
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Neonatal Exposure to Highly Brominated Diphenyl Ethers and Perfluorinated Compounds : Developmental Dependent Toxicity and Interaction
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigated the developmental neurotoxic effects of neonatal exposure to highly brominated diphenyl ethers (PBDEs) and perfluorinated compounds (PFCs), alone or in combinations, during a critical period of the brains’ rapid growth and development, in mice. The compounds investigated were the decaBDE (PBDE 209), nonaBDE (PBDE 206), octaBDE (PBDE 203), heptaBDE (PBDE 183), and three PFCs, PFOS, PFOA, and PFDA. PBDEs and PFCs have been identified as emerging classes of persistent environmental compounds, present in wildlife as well as humans, and present at higher levels in infants/children, compared to older persons. Individuals can be exposed to these compounds throughout her/his lifetime and newborn/children can be exposed to toxicants both via the mothers’ milk and directly via ingestion and inhalation. The brain growth spurt (BGS) is defined by rapid growth and developmental of the brain. For rodents (mice and rats), the BGS is postnatal spanning the first 3-4 weeks after birth. In humans this period begins during the third trimester of pregnancy and continues throughout the first two years of life. It has been shown that several environmental toxicants can induce permanent disorders in brain function when administered to the neonatal mouse, during the BGS. This thesis shows that highly brominated PBDEs, including PBDE 209, PBDE 206, and PBDE 203 can cause developmental neurotoxic effects, when given directly to the neonatal mouse. Of the investigated PFCs, PFOS and PFOA were shown to cause similar effects as the PBDEs. Furthermore, PBDE 209 and PFOA can at low doses interact and enhance the neurotoxic effects in mice. Effects in the adult animal included; deranged spontaneous behavior, reduced or lack of habituation, decreased learning and memory abilities, and increased susceptibility of the cholinergic system. Both classes of compounds were shown to affect proteins (CaMKII, GAP-43, synaptophysin, and tau) important for neuronal growth and synaptogenesis in the neonatal mouse brain.
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| 7. |
- Lesser, Alice, 1977-
(författare)
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Optimal and Hereditarily Optimal Realizations of Metric Spaces
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This PhD thesis, consisting of an introduction, four papers, and some supplementary results, studies the problem of finding an optimal realization of a given finite metric space: a weighted graph which preserves the metric's distances and has minimal total edge weight. This problem is known to be NP-hard, and solutions are not necessarily unique.It has been conjectured that extremally weighted optimal realizations may be found as subgraphs of the hereditarily optimal realization Γd, a graph which in general has a higher total edge weight than the optimal realization but has the advantages of being unique, and possible to construct explicitly via the tight span of the metric.In Paper I, we prove that the graph Γd is equivalent to the 1-skeleton of the tight span precisely when the metric considered is totally split-decomposable. For the subset of totally split-decomposable metrics known as consistent metrics this implies that Γd is isomorphic to the easily constructed Buneman graph.In Paper II, we show that for any metric on at most five points, any optimal realization can be found as a subgraph of Γd.In Paper III we provide a series of counterexamples; metrics for which there exist extremally weighted optimal realizations which are not subgraphs of Γd. However, for these examples there also exists at least one optimal realization which is a subgraph.Finally, Paper IV examines a weakened conjecture suggested by the above counterexamples: can we always find some optimal realization as a subgraph in Γd? Defining extremal optimal realizations as those having the maximum possible number of shortest paths, we prove that any embedding of the vertices of an extremal optimal realization into Γd is injective. Moreover, we prove that this weakened conjecture holds for the subset of consistent metrics which have a 2-dimensional tight span
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