| 11. |
- Olsson-Strömberg, Ulla, et al.
(författare)
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Imatinib activity in vitro in tumor cells from patients with chronic myeloid leukemia in chronic phase and blast crisis
- 2006
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Ingår i: Anti-Cancer Drugs. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4973 .- 1473-5741. ; 17:6, s. 631-639
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.
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| 12. |
- Sanchez, Javier, et al.
(författare)
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Surface-adsorbed fibrinogen and fibrin may activate the contact activation system
- 2008
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 122:2, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: This study was designed to investigate whether fibrinogen, soluble desAA-fibrin, and insoluble desAABB-fibrin are able to induce clotting by triggering the plasma contact activation system when adsorbed to polystyrene. MATERIALS AND METHODS: The above-mentioned substances were individually prepared on polystyrene meshwork squares, and then exposed to a purified FXII solution or non-calcium containing plasma (citrated and dialyzed normal pooled plasma) in polystyrene cuvettes coated with surface-immobilized heparin, to completely block contact activation and the coagulation mechanism that might be induced by the cuvette surfaces. Sodium glass beads were used as the reference material. RESULTS: On exposure to purified FXII solution and plasma, all the tested materials adsorbed and activated FXII to varying degrees. This activation led to the formation of FXIa in the exposed plasma, with the highest activation occurring upon exposure to glass, desAA-fibrin and desAABB-fibrin and the lowest upon exposure to fibrinogen-adsorbed or unmodified polystyrene meshwork squares. Following recalcification, in cuvettes with surface-immobilized heparin, a spectrophotometric assay showed that the surface-exposed plasma aliquots clotted within 5 min after contact with glass, within 10 to 15 min after contact with the two forms of fibrin, and somewhat longer after contact with adsorbed fibrinogen. The longest lag phase, close to 20 min, occurred in plasma exposed to unmodified polystyrene meshwork. Whole blood deposited in surface heparinized cuvettes directly from the cubital vein did not clot during the observation time (2 h). CONCLUSIONS: These results indicate that domains induced by conformational changes in adsorbed fibrinogen and fibrin are capable of activating adsorbed proenzymes and that various forms of fibrin are considerably stronger activators of the contact activation system than are adsorbed fibrinogen or a polystyrene meshwork. The delayed coagulation in plasma exposed to the unmodified polystyrene meshwork can be explained by a two-step process: first, adsorption of fibrinogen, and second, activation of FXII. Under our experimental conditions, the adsorption and activation of FXII on fibrinogen and fibrin seems to be an important mechanism for triggering coagulation.
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| 13. |
- Westerberg, Marcus, 1990-
(författare)
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Prostate cancer incidence, treatment and mortality : Empirical longitudinal register-based studies and methods for handling missing data
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The diagnostic activity for prostate cancer has increased substantially in Sweden, primarily due to increased use of prostate-specific antigen (PSA) testing in asymptomatic men, and this has led to a large increase in diagnoses. There have also been changes in the diagnostic workup, guidelines, treatment strategies, and more effective treatments have been introduced in different phases of the disease. This thesis aims to increase the understanding of consequences of changes in diagnostic activity and treatment, with a focus on empirical studies, methodological development, and handling of missing data.In paper I, the survival of men with metastatic prostate cancer was investigated across calendar time periods by use of Kaplan-Meier analyses and Cox regression. The median survival from diagnosis increased with six months comparing men diagnosed 1998-2001 with men diagnosed 2010-2015, while median PSA decreased.In paper II, a discrete time multivariate longitudinal model was combined with a proxy for the unobserved level of diagnostic activity to produce prognoses of incidence and mortality. Simulations indicated that a higher diagnostic activity was associated with fewer men diagnosed with metastatic disease and fewer prostate cancer deaths.In paper III, we looked for clinical variables predictive of the survival of men with castration-resistant prostate cancer (CRPC). A new data base was created including longitudinal data on prescriptions of hormonal treatment, PSA, and cause of death. We found that PSA doubling time and PSA at time of CRCP were highly predictive and could be used for treatment decision.In paper IV, we estimated annual incidence of metastatic prostate cancer using different methods for handling missing data in metastatic status (M stage). Missing data in M stage was high and varied over calendar time and risk groups, yet each method indicated a downward trend in incidence. Although men with unknown metastatic status cannot be assumed to have nonmetastatic disease in general, this may be reasonable among those with tumour characteristics that indicate a low risk of metastases.In paper V, the estimation of multivariate longitudinal models was considered in a context where some events are observed on a coarser level (e.g. grouped) at some time points, causing gaps in the data. The likelihood function, score and observed information were derived under an independent coarsening mechanism. A simulation study was conducted comparing properties of several estimators including direct maximum likelihood and Monte Carlo Expectation Maximisation.
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