| 1. |
- Handin, Niklas
(författare)
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Proteomics informed investigation of human hepatocytes and liver tissue
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A successful drug needs to display beneficial absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile. It is therefore important to investigate these properties during the drug discovery process. The liver is of particular interest in ADME-Tox studies, as it is highly metabolically active and oral administrated drugs needs to pass the liver before reaching the systemic circulation. However, a dose of a drug that is efficacious and safe for one individual may be inefficacious or toxic, because of inter-individual variability. Therefore, it is important to investigate the ADME-Tox properties in a sufficiently large population. Investigations on ADME-Tox is usually done in in vitro cell models. Therefore, a variety of models to simulate liver functions have been developed and ranging from subcellular microsomes to complex 3D organoid cultures. This thesis investigates variability of ADME proteins in human liver tissue and in liver cell models.First, mass spectrometry based targeted proteomics was used to quantify ADME relevant proteins from 149 human liver samples. The observed inter-individual protein variability could not solely be explained by genotype. Therefore, a single transporter protein, the bile and drug transporting protein, NTCP, was investigate in detail. Non-genetic factors, e.g. smoking and alcohol consumption, and epigenetic factors such as DNA methylation, were found to contribute to the observed inter-individual variability of NTCP. Next, hepatocytes (PHH) were isolated from 54 human livers tissues and after which the hepatocytes where cryopreserved. The variable attachment efficiency of cryopreserved hepatocytes where investigated and an apoptosis inhibition protocol for restoration of attachment properties was developed. This protocol was also successfully applied to 3D cultured PHH spheroids resulting in increased ability to form 3D spheroids. The effect of culture conditions on the quality of the 3D cultures was also investigated. 3D PHH spheroids were formed and maintained in different, commonly used culture media. The spheroids were characterized by a variety of functional assays including global proteomics. The proteome analysis showed that while no epithelial to mesenchymal transitions was observed, 3D cultures maintained in fasting glucose and insulin levels resembling the in vivo situation showed a more liver-like phenotype with a high expression of ADME proteins and functional cytochrome P450 metabolism. Transporter kinetics were also investigated in the 3D cultured PHH. Finally, we investigated if global proteomics data from 56 human liver tissues could be deconvoluted to give information about the liver composition. The cell type proportions generated by deconvolution where similar to literature values. Liver samples that displayed deviating cell composition were identified. The deviating liver compositions were in agreement with clinical markers of inflammation in the patient´s blood samples and with altered extracellular matrix protein composition, comparable to that found in liver steatosis. In conclusion, this thesis have investigated variability in ADME proteins in human liver and in in vitro cultures of human hepatocytes, characterized cofounding factors for in vitro cultured hepatocytes and further extended drug disposition studies in 3D cultured hepatocytes.
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| 2. |
- Österlund, Emerik, 1995-
(författare)
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Prognostic and Predictive Factors in Metastatic Colorectal Cancer
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The outcome for metastatic colorectal cancer (mCRC) patients has improved substantially in recent decades. This has chiefly been observed in study populations, and predominantly in left-sided primary tumours, which is why we wanted to study if and how survival has improved in the background population. It has also been seen that certain molecular subtypes are more common in population-based materials, and, thus, we studied the prevalence and effects of different molecular alterations.Paper I is a national population-based material of all 19 566 Swedish patients with a diagnosis of mCRC 2007-2016, 55% were male and 70% had synchronous metastases. Median overall survival (OS) for all patients was 14.0 months. An improvement could be seen over time, also in stratified analyses. OS was influenced by presentation of metastases, age, primary tumour location, and sex. All except sex remained statistically significant in a multivariable analysis. Differences of about one month in median OS were seen between healthcare regions, but these diminished over time.Paper II included all 765 patients from the Uppsala Region with a mCRC diagnosis 2010-2020. Right colon primary tumours were seen in 38%, left colon in 27% and rectum in 34%. BRAF-V600E mutations (mt) and deficient mismatch repair (dMMR) had a poor OS and were more common in right colon primary tumours. Primary tumour location did not affect OS in subgroups according to mutations in RAS or BRAF, nor in a multivariable analysis. Molecular alterations seem to be more important than primary tumour location for prognosis.Paper III studied KRAS-G12Cmt in three population-based and one real-world material. KRAS-G12C was seen in 2-4% of all tested and in 4-8% of all KRASmt. No differences in patient characteristics were observed between KRAS-G12C and other KRASmt. No differences in OS were seen between KRAS-G12C and other KRASmt, neither for all patients, nor in different treatment groups.Paper IV studied atypical BRAFmt (aBRAFmt) in two population-based and one real-world cohort. aBRAFmt was seen in 1-4% of the adequately tested patients in the different cohorts. aBRAFmt patients were predominantly male, had dMMR less often, more rectal primary tumours, and less peritoneal metastases compared with BRAF-V600Emt. Serrated adenocarcinomas were seen in about half of the aBRAFmt. OS was significantly better for aBRAFmt than in BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt patients. Nine aBRAFmt received epidermal growth factor receptor inhibitors without responses.
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| 3. |
- Bengtsson, Mattias
(författare)
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Att lämna en placering i samhällsvård : En studie om ungas övergång från samhällsvård till vuxenliv
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The focus in this thesis is young peoples’ (aged 17–20) experiences of leaving out-of-home care (OHC) and making the transition into adulthood. Prior research shows care leavers as a vulnerable group making the transition to adulthood at younger age, in shorter duration and with less support than their peers. The overarching aim is to gain knowledge of how young care leavers experience and handle their transition from OHC to adulthood, and how their experiences and strategies change over time. The study design is longitudinal with three waves of interviews: when still in care (T1), 6–11 months later when most of them had left care (T2) and another 10–19 months later (T3). Article I focuses the informants’ (n=15) expectations for their future and how these are changing over time (T1–T2). The participants’ short term expectations are characterized by worries (T1) and ambivalence (T2) – their long-term expectations are more optimistic (both T1 and T2) and tend to be guided by normative developmental patterns. The aim of article II is to study care leavers’ (n=20) strategies for handling adversities during their OHC transition. The results show that the participants over time (T1–T2) develop externally oriented strategies by navigating towards available resources, and internally oriented reflexive strategies for re-negotiating the meaning of their earlier experiences. Departing from an agency perspective article III focuses care leavers’ (n=14) transitional patterns of leaving care (T1–T3). Three patterns are identified: one stable long-term future oriented, one unstable short-term future oriented and one ambivalent pattern shuttling between long- and short-term future orientations. The aim in article IV is to study occupational trajectories, i.e. care leavers’ (n=14) paths into education and employment from a theoretical framework of agency vs. structure. The results show three ideal types of trajectories where agency is: (1) facilitated by structure, (2) perceived as free from structural constraints, and (3) hindered by structural constraints. The longitudinal design provides an original contribution the field of study by uncovering how care leavers’ expectations for their future is changing during the process of transition, how increasingly successful strategies are developed over time, and how transitional OHC patterns are influenced by the agents’ time horizons as well as by structural forces. A conclusion from the study is that societal support targeting young care leavers is deficient and needs to be developed and strengthened. Furthermore, the transition could be facilitated by extending the duration of the transition process, by including care leavers as active participating agents in the planning process of their passage out from OHC, and by strengthening the maintenance of care leavers’ relationships to supportive members in their formal and informal network. ”Independence” as the ultimate goal for young people leaving OHC is criticized based on the results showing that interdependent relationships to significant others is an integrated part of care leavers’ perception of adult life.
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| 4. |
- Forslund, Marina
(författare)
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A nutrition intervention in men with prostate cancer : Exploring effects on bowel symptoms from radiotherapy, patient experience, and nutrient intake
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective The main objective of this thesis was to explore the effects of a nutrition intervention on acute and late bowel symptoms in men with localised prostate cancer treated with pelvic radiotherapy (study I), participants’ experiences from receiving the nutrition intervention (study II), and associations with nutrient intakes (study III).Methods A total of 180 men with localised prostate cancer referred to curative radiotherapy targeting the prostate gland and pelvic lymph nodes were recruited to the trial. The participants were randomised to standard care plus a nutrition intervention aiming to modify fibre and lactose intakes (NIG; n=92) or standard care alone (SCG; n=88). Data on bowel symptoms and dietary intake were collected pre-treatment and at seven time points during a 26-month study period. Analyses of the effects of the nutrition intervention on bowel symptoms were conducted for the acute phase (up to 2 months post radiotherapy), and the late phase (7 to 24 months post radiotherapy). Semi-structured interviews were conducted with 15 participants from the NIG to explore experiences of the nutrition intervention.Results The nutrition intervention was associated with statistically significantly, but not clinically significantly, less bother from blood in stools and flatulence during the acute phase. The nutrition intervention was also associated with more bloated abdomen during the late phase (Study I). Social support, contributing to the greater good, prior knowledge, dietary information, and a small need for change facilitated adherence. While feeling limited, wanting to decide for themselves, the timing of the intervention, unmet expectations, and loss of motivation were described as barriers for adherence (Study II). A greater reduction of lactose was associated with decreased intake of calcium at the end of the radiotherapy period. A more modified fibre intake during the radiotherapy period was associated with increased vitamin C, but decreased selenium intake (Study III).Conclusions The effects from the nutrition intervention were small and inconclusive and do not support routine dietary advice aiming to modify fibre and lactose intakes as a mean to substantially reduce adverse effects from pelvic radiotherapy. Tailored nutritional interventions based on individual preferences, prior knowledge, and context, could enhance adherence. There were few associations between modified fibre and lactose intakes and nutrient intakes, thus, no recommendations can be made on whether such dietary advice should continue to be provided to men with prostate cancer undergoing pelvic radiotherapy.
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| 5. |
- Hauffman, Anna
(författare)
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Internet-based Psychosocial Support : Design, Effects and User Experience in the Cancer Setting
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aim Being diagnosed with cancer is often described as a major loss of control leading to severe psychological distress and symptoms of anxiety and depression can continue to affect the individual in the long term. The cancer and its treatment may influence all dimensions of health, thus the psychosocial support provided needs to be multifaceted and easy accessed. Internet-based interventions may be one way to provide such support, but evidence is limited. This thesis aimed to investigate the design, effects, and experiences of internet-based psychosocial support in cancer.Methods and Results Study 1 encompassed a co-creation development process resulting in the interactive support provided as the first step in an internet-based stepped care intervention (iCAN-DO). The effects of iCAN-DO were investigated in a randomised controlled trial, targeting individuals newly diagnosed with cancer and concurrent self-reported symptoms of anxiety and depression (according to the Hospital Anxiety and Depression Scale). Step 1 had a psycho-educative content involving self-care strategies and was available to the intervention group during the ten-month study period. Step 2 comprised a guided internet-based cognitive behavior therapy (iCBT) program and was offered those without improvement in anxiety and depression after using Step 1. The results showed that iCAN-DO improved symptoms of depression compared with standard care, while symptoms of anxiety were largely unaffected. Most participants used Step 1, while only a few used Step 2.In Study 2, aspects of usefulness, relevance, and usability in iCAN-DO were explored through qualitative interviews, analysed using content analysis. Results showed that standard healthcare did not meet the individuals' needs and iCAN-DO was used as complement, providing access to relevant, trustworthy information and support. Usability was affected by the perceived usefulness and ease of use of the intervention, as well as by the user´s circumstances in life and consequences of the cancer. The co-creation process in the development of Step 1 added relevance, but both steps 1 and 2 would have gained from being provided earlier, integrated into standard healthcare and more adaptable to the individual.Conclusion The thesis concluded that the internet-based intervention had positive effects on symptoms of depression in individuals newly diagnosed with cancer. Individuals with cancer experience several unmet needs in standard healthcare and since psycho-educative support including self-care advice seems feasible in this group, efforts are needed to incorporate internet-based support in regular oncology care. Since the intervention did not target all symptoms (i.e. anxiety) further research is needed on how to enhance efficacy and how to make iCBT more feasible for this group.
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