| 1. |
- Andersson, Britta, 1979-
(författare)
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Manipulation of potassium ion fluxes to induce apoptosis in lung cancer cells
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apoptosis is a special form of cell death that if non-functional may lead to diseases such as cancer. A reduction of the intracellular potassium ion (K+) content is necessary for activating enzymes important for the execution of apoptosis. Pharmacological modulation of K+ fluxes to reduce intracellular K+ in cancer cells might therefore force the cells into apoptosis and decrease tumour cell mass. Human malignant pleural mesothelioma (MPM) is a form of cancer often caused by asbestos exposure. Although asbestos has been banned in the Western World, the incidence of MPM is expected to increase. Cisplatin is the first-line chemotherapy for MPM, but acquired resistance to the drug is a clinical problem. This thesis is mainly based on work with the human malignant pleural mesothelioma cell line (P31 wt) and a cisplatin-resistant sub-line (P31 res). The aim was to first characterize K+ fluxes in P31 wt and P31 res cells, and then manipulate them in order to reduce intracellular K+ and induce apoptosis with K+ manipulation alone or in combination with cisplatin. Characterization of K+ fluxes in P31 wt cells showed that: 1) ouabain, a digitalis-like drug, and specific blocker of the Na+, K+, ATPase pump, effectively inhibited K+ uptake, 2) bumetanide, a diuretic, and an inhibitor of the Na+, K+, 2Cl-¬-cotransporter, had a transient effect on K+ uptake, and 3) the antifungal drug amphotericin B stimulated K+ efflux. In order to determine intracellular K+ content, the potassium-binding fluorescent probe PBFI-AM was used in a 96-well plate assay. After a 3-h incubation with ouabain, with or without bumetanide, combined with amphotericin B, the intracellular K+ content was reduced in P31 wt cells but not in P31 res cells. Ouabain induced apoptosis in both P31 wt and P31 res cells. P31 res cells were sensitized to cisplatin by ouabain, since 10 mg/L cisplatin in combination with ouabain induced about the same percentage of apoptotic cells as 40 mg/L cisplatin. Apoptosis was executed via caspase-3 activation in both P31 wt and P31 res cells. Amphotericin B enhanced ouabain-induced apoptosis in P31 wt cells via caspase-9 activation, with increased caspase-3 activation and DNA fragmentation as consequences. Ouabain-induced apoptosis in P31 res cells was executed via increased expression of pro-apoptotic Bak. The combination of cisplatin with ouabain and amphotericin B was stressful to both P31 wt and P31 res cells, since SAPK/JNK a known factor in stress-induced apoptosis was activated. In conclusion, K+ flux manipulation with clinical used drugs can induce apoptosis per se and also enhance cisplatin-induced apoptosis in P31 wt and P31 res cells.
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| 2. |
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| 3. |
- Brattström, Daniel, 1966-
(författare)
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Angiogenesis Related Markers In Non-Small Cell Lung Cancer
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigated the predictive and the prognostic powers of angiogenesis related markers in both operable and inoperable non-small cell lung cancer (NSCLC) patients.In the first and second study, we investigated the serological fractions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 2 cohorts of patients with either operable or inoperable NSCLC. Regarding operable NSCLC, we demonstrated significant correlations between VEGF and tumour volume and overall survival. Regarding bFGF, significant correlations with recurrent disease and survival were demonstrated. VEGF and bFGF correlated to each other and with platelet counts. In multivariate analysis, bFGF proved to be a significantly independent prognostic factor.Regarding inoperable NSCLC, we demonstrated that patients with elevated bFGF levels before any treatment and during chemotherapy had a significantly poorer survival. During chemotherapy, each rise of one unit of bFGF (ng/L) corresponded to a 4 times increased risk of death. Regarding VEGF, elevated levels after radiotherapy corresponded with better survival. All prognostic information demonstrated in this study concerned patients with a, co-sampled, normal platelet count.In the third study, three putative markers, HER-2, EGFR and COX-2, suitable for targeted therapies in resected NSCLC were investigated in a panel of 53 tumours and further investigated for a possible correlation with microvessel density. We demonstrated that HER-2 and COX-2 were mainly expressed in adenocarcinomas, whereas EGFR was only expressed in squamous cell carcinomas. COX-2 showed a trend towards a correlation with microvesssel density. The expression profile, HER-2+/EGFR-, was significantly correlated to poorer survival. In the fourth study, a predictive model for recurrences consisting of p53, CD34 and CD105, and circulating serum fractions of VEGF and bFGF, was investigated. The two endothelial markers correlated with each other. CD105 expression correlated with p53 expression. No other significant correlations between markers could be demonstrated. A significant correlation between p53 overexpression and recurrent disease was demonstrated. The mutational status could not confirm the immunohistochemical correlation between p53 and recurrences. In conclusion, the present thesis demonstrates that the angiogenic factors VEGF and bFGF analysed in sera have both predictive and prognostic information when measured in operable and inoperable NSCLC. Since HER-2 is overexpressed in NSCLC and linked with prognostic information, this marker might be a suitable target for therapy in NSCLC. Furthermore, in patients with operable NSCLC, p53 expression status was linked with recurrent disease and mean MVD.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Brattström, Daniel, et al.
(författare)
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Serum VEGF and bFGF adds prognostic information in patients with normal platelet counts when sampled before, during and after treatment for locally advanced non-small cell lung cancer
- 2003
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 43:1, s. 55-62
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have both been implicated to have roles in tumour angiogenesis. In the present retrospective study, serum VEGF and bFGF from patients with locally advanced non-small cell lung cancer (NSCLC) were analysed before, during and after treatment. Seventy-three patients and a total of 460 serum samples were analysed for VEGF and 443 serum samples were analysed for bFGF. Pre-treatment bFGF levels in patients with normal platelet counts, were correlated to poorer survival, P-value = 0.047. During chemotherapy, each rise of one unit bFGF corresponded to a hazard ratio of 4.06 (P=0.022). In patients with normal platelet counts, VEGF levels after radiotherapy significantly correlated to good prognosis (P=0.023), during radiotherapy VEGF levels indicated the same correlation (P=0.085). We conclude that serum VEGF and especially bFGF are of clinical interest as prognostic factors, especially in patients presenting with normal platelet counts.
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| 8. |
- Brodin, Daniel, et al.
(författare)
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Inhaled ciclesonide in adults hospitalised with COVID-19 : a randomised controlled open-label trial (HALT COVID-19)
- 2023
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19.DESIGN: Multicentre, randomised, controlled, open-label trial.SETTING: 9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021.PARTICIPANTS: Adults hospitalised with COVID-19 and receiving oxygen therapy.INTERVENTION: Inhaled ciclesonide 320 µg two times a day for 14 days versus standard care.MAIN OUTCOME MEASURES: Primary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death.RESULTS: Data from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49-67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3-9) days in the ciclesonide group and 4 (2-7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a <1 day absolute reduction in a post-hoc calculation). Three participants in each group died/received invasive mechanical ventilation (HR 0.90 (95% CI 0.15 to 5.32)). The trial was discontinued early due to slow enrolment.CONCLUSIONS: In patients hospitalised with COVID-19 receiving oxygen therapy, this trial ruled out, with 0.95 confidence, a treatment effect of ciclesonide corresponding to more than a 1 day reduction in duration of oxygen therapy. Ciclesonide is unlikely to improve this outcome meaningfully.TRIAL REGISTRATION NUMBER: NCT04381364.
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| 9. |
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| 10. |
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| 11. |
- Brodin, Ola, et al.
(författare)
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Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study
- 2015
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 7:6, s. 4978-4994
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.
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| 12. |
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| 13. |
- Frånberg, Oskar, 1976-
(författare)
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Oxygen content in semi-closed rebreathing apparatuses for underwater use : Measurements and modeling
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present series of unmanned hyperbaric tests were conducted in order to investigate the oxygen fraction variability in semi-closed underwater rebreathing apparatuses. The tested rebreathers were RB80 (Halcyon dive systems, High springs, FL, USA), IS-Mix (Interspiro AB, Stockholm, Sweden), CRABE (Aqua Lung, Carros Cedex, France), and Viper+ (Cobham plc, Davenport, IA, USA). The tests were conducted using a catalytically based propene combusting metabolic simulator. The metabolic simulator connected to a breathing simulator, both placed inside a hyperbaric pressure chamber, was first tested to demonstrate its usefulness to simulate human respiration in a hyperbaric situation. Following this the metabolic simulator was shown to be a useful tool in accident investigations as well as to assess the impact of different engineering designs and physiological variables on the oxygen content in the gas delivered to the diver by the rebreathing apparatuses. A multi-compartment model of the oxygen fractions was developed and compared to the previously published single-compartment models. The root mean squared error (RMSE) of the multi-compartment model was smaller than the RMSE for the single-compartment model, showing its usefulness to estimate the impact of different designs and physiological variables on the inspired oxygen fraction.
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| 14. |
- Hedman, Mattias, et al.
(författare)
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Comparison of predicted and clinical response to radiotherapy: a radiobiology modelling study.
- 2009
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Ingår i: Acta oncologica (Stockholm, Sweden). - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 48:4, s. 584-90
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A model to predict clinical outcome after radiation therapy would be a valuable aid in the effort of developing more tailored treatment regimes for different patients. In this work we evaluate the clinical utility of a model that incorporates the following individually measured radiobiology parameters: intrinsic radiosensitivity, proliferation and number of clonogenic cells. The hypothesis underlying the study was that the incorporation of individually measured tumour parameters in a model would increase its reliability in predicting treatment outcome compared with the use of average population derived data. MATERIAL AND METHODS: Forty-six patients with head and neck tumours were analyzed, the majority of whom received both external beam radiotherapy and brachytherapy. Eighteen patients received external beam treatment alone and statistical analyses were carried out on this subgroup. RESULTS: Four of the 18 patients had a >95% calculated probability of cure and none developed a local recurrence resulting in a negative predictive value of 100% (compared with 67% for population-derived data). The sensitivity of the model in predicting local recurrence was 75% (compared with 38% for population-derived data). Using a model that incorporated individually measured radiobiology data, there was a statistically significant difference in local control levels for patients with >95% and <5% predicted probability of local control (chi(2), p = 0.04). DISCUSSION: This study suggests, therefore, that incorporation of measured biological data within a radiobiological model improves its ability to predict radiation therapy outcome compared with the use of population-derived data.
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| 15. |
- Hedman, Mattias, et al.
(författare)
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Fractionated Irradiation of Five Human Lung Cancer Cell Lines and Prediction of Survival According to a Radiobiology Model
- 2011
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 31:4, s. 1125-1130
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study evaluates a predictive radiobiology model by measurements of surviving fraction (SF) by the clonogenic assay or the extrapolation method and the proliferation rate in vitro. It is hypothesized that incorporating proliferation to intrinsic radiosensitivity, measured by SF, to predict radiation responsiveness after fractionated irradiation adds to the model's accuracy. Materials and Methods. Five lung cancer cell lines with known SF after 1 Gy (SF1), and also SF2 and SF5, were irradiated with three different fractionation regimes; 10x1 Gy, 5x2 Gy or 2x5 Gy during the same total time to achieve empirical SF. In addition, the SF1, SF2 and SF5 after fractionated irradiation was calculated for each cell line based on the already known single fraction SF and with or without a proliferation factor. The results were compared to the empirical data. Results and Discussion: By using the clonogenic assay to measure radiosensitivity, prediction of radiosensitivity was improved after fractionated radiotherapy when proliferation was used in the radiobiology model. However, this was not the case in the cell lines where the extrapolation method was used to calculate SF. Thus, a radiobiology model including intrinsic radiosensitivity, measured by the clonogenic assay, as well as proliferation, is better at predicting survival after fractionated radiotherapy, compared to the use of intrinsic radiosensitivity alone.
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| 16. |
- Hedman, Mattias, et al.
(författare)
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Predictive value of modelled tumour control probability based on individual measurements of in vitro radiosensitivity and potential doubling time
- 2013
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Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 0007-1285 .- 1748-880X. ; 86:1025
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to compare patient-specific radiobiological parameters to population averages in predicting clinical outcome after radiotherapy using a tumor control probability (TCP) model based on BED.Methods: A previously published material of forty-six head and neck carcinomas with individually identified radiobiological parameters; SF2 and Tpot, and known tumor size was investigated. These patients had all been treated with external beam radiotherapy and the majority had also received brachytherapy. TCP for each individual based on BED using patient-specific radiobiological parameters was compared to TCP based on BED using average radiobiological parameters (α = 0.3 Gy-1 and Tpot = 3 days).Results: Forty-three patients remained in the final analysis. There was only a weak trend for increasing local tumor control with increasing BED in both groups. However, when TCP was calculated the use of patient-specific parameters was better to identify local control correctly. Sensitivity and specificity for tumor-specific parameters were 63% and 80%, respectively. The corresponding values for population-based averages were 0% and 91%, respectively. Positive predictive value was 92% when tumor-specific parameters were used compared to 0 % for population-based. A receiver operating characteristic (ROC) curve confirmed the superiority of patient-specific parameters over population averages in predicting local control.Conclusions: Individual radiobiological parameters are better than population derived averages when used in a mathematical model to predict tumor control probability after curative radiotherapy in head and neck carcinomas.Advances in knowledge: TCP based on individual radiobiological parameters are better than TCP based on population based averages.
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| 17. |
- Holgersson, Georg, et al.
(författare)
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The value of induction chemotherapy for survival in patients with non-small cell lung cancer treated with radiotherapy.
- 2012
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Ingår i: Anticancer research. - : The International Institute of Anticancer Research. - 1791-7530 .- 0250-7005. ; 32:4, s. 1339-46
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of the present study was to retrospectively investigate the impact of induction chemotherapy on treatment outcome in patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with a diagnosed NSCLC that have been subjected to curatively intended irradiation (≥50 Gy) and treated in an oncology department in Sweden during the years 1990-2000 were included in the study. Operated patients and patients having received concomitant chemotherapy were excluded. The included patients were localised by a manual search of all the oncology departments' medical records and radiation charts. RESULTS: Patients treated with induction chemotherapy (n=79) had a significantly better overall survival compared with patients treated with radiotherapy alone (p=0.0097) in a univariate Cox regression analysis. A platinum/taxane combination produced the greatest survival benefit; hazard ratio=0.49 (95% confidence interval=0.31 to 0.75). CONCLUSION: We found that patients treated with induction chemotherapy in addition to radiotherapy for NSCLC have a better overall survival than patients treated with radiotherapy alone and that the best results are achieved using a platinum/taxane combination.
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| 18. |
- Lampic, Claudia, et al.
(författare)
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Coping, psychosocial well-being and anxiety in cancer patients at follow-up visits
- 1994
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 33:8, s. 887-894
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Tidskriftsartikel (refereegranskat)abstract
- Coping, psychosocial well-being, situation-specific anxiety and cancer-related worry were assessed in 197 consecutive cancer patients attending follow-up visits. Participants completed questionnaire on three occasions: at the follow-up visit, some days later (n = 175) and three weeks later (n = 125). High levels of coping styles 'Anxious Preoccupation' and 'Helplessness/Hopelessness' were associated with low levels of psychosocial well-being, more situation-specific anxiety and more cancer-related worry. High levels of 'Fighting Spirit' and 'Fatalistic' were found to be associated with high psychosocial well-being and, for 'Fighting Spirit', also with less cancer-related worry. Patients with a 'dismal' prognosis were found to have higher levels of 'Helplessness/Hopelessness' than patients with a more 'favorable' prognosis. Clinical implications of these findings are discussed.
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| 19. |
- Mellin, Pelle, et al.
(författare)
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Evaluating flowability of additive manufacturing powders, using the gustavsson flow meter
- 2016
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Ingår i: World PM 2016 Congress and Exhibition. - : European Powder Metallurgy Association (EPMA). - 9781899072484
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Konferensbidrag (refereegranskat)abstract
- The Gustavsson flow meter (including standard ISO-13517) is in this paper used to measure flow rate of fine AM powders. In the current paper, the results are compared to the Hall flow meter and a Freeman FT4 powder rheometer in terms of success of measuring these AM powders. The robustness is clearly superior to the Hall flow meter. Compared to using the rheometer, the Gustavsson flow meter is faster and simpler to use; however, other powder-aspects are evaluated since little correlation was found. All methods of characterizing the flowability could distinguish between (1) two alloys, and (2) if the alloys were new or used (in SLM), and (3) if they were dried or non-dried.
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| 20. |
- Mellin, Pelle, et al.
(författare)
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Evaluating flowability of additive manufacturing powders, using the Gustavsson flow meter
- 2017
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Ingår i: Metal Powder Report. - : Elsevier Ltd. - 0026-0657 .- 1873-4065. ; 72:5, s. 322-326
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Tidskriftsartikel (refereegranskat)abstract
- The Gustavsson flow meter (including standard ISO-13517) is in this paper used to measure flow rate of fine AM powders. In the current paper, the results are compared to the Hall flow meter and a Freeman FT4 powder rheometer in terms of success of measuring these AM powders. The range of possible powders to measure is smaller with Gustavsson flow meter; but in this range, the difference in flow time is greater compared to the Hall flow meter. Compared to using the rheometer, the Gustavsson flow meter is faster and simpler to use; however, other powder-aspects are evaluated since little correlation was found. For the powders in this paper, all methods of characterizing the flowability could distinguish between (1) two alloys, and (2) if the alloys were new or used (in SLM), and (3) if they were dried or non-dried.
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| 21. |
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| 23. |
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| 24. |
- Stockeld, Dag, et al.
(författare)
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A Swedish study of chemoradiation in squamous cell carcinoma of the esophagus
- 2001
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 40, s. 566-
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Tidskriftsartikel (refereegranskat)abstract
- This multicenter study describes the development of a chemoradiation protocol for the treatment of non-metastatic squamous cell carcinoma of the esophagus. Eighty patients were treated with three courses of chemotherapy (cisplatinum and 5-fluorouracil) with concomitant radiotherapy (40 Gy) during the last two courses of chemotherapy. Esophagectomy was performed, when feasible. If no operation was performed, patients were planned to receive a target dose of 64 Gy. Toxicity was mainly attributable to hematological impairment and led to two adjustments of the treatment protocol (addition of filgrastim and lowering of the 5-fluorouracil dose). These changes made it possible to administer the planned treatment in a gradually higher proportion of patients (13/23 [57%] before changes of treatment compared with 30/36 [83%] after changes). Treatment-related mortality was 3.75% (3 patients, associated with leucopenic septicemia after chemotherapy). Fifty-four patients were resected. No per- or postoperative mortality was encountered. The complete response (pathological CR) rate in operated patients was 46% (27/59 patients) after chemoradiation. In the whole series the CR rate (including clinical CR for non-resected patients) was 44%. With a minimum follow-up of 37 months, the 3-year survival for the whole group was 31% compared with 57% for the CR patients. Total 5-year survival thus far (July 1999) is 26%.
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| 25. |
- Strondl, Annika, et al.
(författare)
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Characterisation and control of powder properties for additive manufacturing
- 2014
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Powder characterization and handling in PM are important issues and required powder properties will vary between different component manufacturing processes. By understanding and controlling these, the final material properties for different applications can be improved and become more reliable. In this study, metal powders used in additive manufacturing have been investigated regarding particle size and shape using dynamic image analysis. In parallel, powder flow characteristics have been evaluated with a powder rheometer. Correlations within the results have been found between particle shape and powder flow characteristic that could explain certain effects of the powder processing in the additive manufacturing processes.
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| 26. |
- Strondl, Annika, et al.
(författare)
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Characterization and Control of Powder Properties for Additive Manufacturing
- 2015
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Ingår i: JOM. - : Springer Science and Business Media LLC. - 1047-4838 .- 1543-1851. ; 67:3, s. 549-554
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Tidskriftsartikel (refereegranskat)abstract
- Powder characterization and handling in powder metallurgy are important issues and the required powder properties will vary between different component manufacturing processes. By understanding and controlling these, the final material properties for different applications can be improved and become more reliable. In this study, the metal powders used in additive manufacturing (AM) in terms of electron beam melting and selective laser melting have been investigated regarding particle size and shape using dynamic image analysis. In parallel, powder flow characteristics have been evaluated with a powder rheometer. Correlations within the results have been found between particle shape and powder flow characteristics that could explain certain effects of the powder processing in the AM processes. The impact, however, in the processing performance as well as in ultimate material properties was found to be limited.
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