| 1. |
- Hillerdal, Gunnar, et al.
(författare)
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Treatment of Malignant Pleural Mesothelioma with Carboplatin, Liposomized Doxorubicin, and Gemcitabine A Phase II Study
- 2008
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Ingår i: JOURNAL OF THORACIC ONCOLOGY. - 1556-0864. ; 3:11, s. 1325-1331
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Tidskriftsartikel (refereegranskat)abstract
- Background: Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination or liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study.Methods: From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-Lip, but all the others were followed for at least 4 years or until death.Results: Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median Survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months.Conclusion: The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long Survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on "radical" Surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.
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| 2. |
- Mårtensson, Gunnar, et al.
(författare)
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The sensitivity of hyaluronan analysis of pleural fluid from patients with malignant mesothelioma and a comparison of different methods
- 1994
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Ingår i: Cancer. - 0008-543X .- 1097-0142. ; 73:5, s. 1406-1410
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hyaluronan may be used as a marker for malignant mesothelioma, thus indicating its mesodermal origin. METHODS: The sensitivity as a diagnostic test of three different methods for hyaluronan analyses of pleural fluid was examined in patients with biopsy-verified malignant pleural mesothelioma. RESULTS: A quantitative high-performance liquid-chromatography (HPLC) method was performed on fluids from 43 patients. Using a cutoff level of 100 mg/l, higher levels were noted in 30 (70%) patients, with a median value of 220 mg/l (mean, 560 mg/l; range, 20-6600 mg/l). An identical median value (220 mg/l) was obtained with a radioassay method when simultaneously performed on paired samples from 21 patients (correlation coefficient, 0.91). A qualitative precipitation test using 0.5% cetylpyridinium chloride combined with a quantitative viscosimetric method was significantly less sensitive (P < 0.01). CONCLUSION: Hyaluronan analyses is beneficial in distinguishing malignant mesothelioma if methods such as the evaluated HPLC or radioassay with a sensitivity of 70% toward mesothelioma are used and other known causes of elevated content are considered.
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| 3. |
- Scott, David R, et al.
(författare)
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Use of human papillomavirus DNA testing to compare equivocal cervical cytologic interpretations in the United States, Scandinavia, and the United Kingdom
- 2002
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Ingår i: Cancer. - : John Wiley and Sons Inc.. - 1097-0142 .- 0008-543X. ; 96:1, s. 14-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human papillomavirus (HPV) DNA testing may be useful in clarifying equivocal cervical cytologic interpretations. One application might be to standardize the meaning of equivocal interpretations from laboratories in various regions. Because international differences may be particularly marked, international comparisons of emerging data will require clear translations of "equivocal" and similar terms. METHODS: To perform a three-country comparison, the authors selected a morphologically diverse set of 188 conventional Papanicolaou tests initially classified as "squamous atypia" from a study of more than 20,000 women in Portland, Oregon (1989-1990). Previously, five U.S. expert cytopathologists independently interpreted the slides with screening cytotechnologists' marks in place. For this comparison, one British and two Scandinavian reviewers involved in HPV research reviewed the slides after original marks had been removed. The authors compared all eight reviewers' classifications of negative, equivocal, or abnormal in a series of pairwise comparisons using the kappa statistic. They then compared cytologic interpretations with HPV DNA testing. RESULTS: Oncogenic HPV DNA detection was significantly associated with increasingly abnormal interpretations for each reader. The British reader tended to rate tests as more abnormal than the American pathologists did, whereas the Scandinavians tended to rate tests as more normal. Reference to the HPV DNA standard clarified the tendency of readers to render systematically more or less severe interpretations. For example, the Scandinavian cytologists discounted subtle (often HPV-associated) changes in favor of cytologic certainty, making HPV triage of equivocal tests less applicable there. CONCLUSIONS: International research on cytopathology, particularly on the possible uses of HPV DNA testing, will require calibration of local cytologic definitions.
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| 4. |
- Darai-Ramqvist, Eva, et al.
(författare)
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Microenvironment-dependent phenotypic changes in a SCID mouse model for malignant mesothelioma
- 2013
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice.Methods: Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy.Results: Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line.Conclusion: Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation.
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| 5. |
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| 6. |
- Fransson, Per-Anders, et al.
(författare)
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Adaptation of Multi-Segmented Body Movements during Vibratory Proprioceptive and Galvanic Vestibular Stimulation.
- 2007
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Ingår i: Journal of Vestibular Research. - 1878-6464. ; 17:1, s. 47-62
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Tidskriftsartikel (refereegranskat)abstract
- Control of orthograde posture and use of adaptive adjustments constitutes essential topics of human movement control, both in maintenance of static posture and in ensuring body stability during locomotion. The objective was to investigate, in twelve normal subjects, how head, shoulder, hip and knee movements and torques induced towards the support surface were affected by vibratory proprioceptive and galvanic vestibular stimulation, and to investigate whether movement pattern, body posture and movement coordination were changed over time. Our findings suggest that the adaptive process to enhance stability involves both alteration of the multi-segmented movement pattern and alteration of body posture. The magnitude of the vibratory stimulation intensity had a prominent influence on the evoked multi-segmented movement pattern. The trial conditions also influenced whether the posture were altered and if these posture adjustments were done directly at stimulation onset or gradually over a longer period. Moreover, the correlation values showed that the subjects, primarily during trials with vibratory stimulation alone, significantly increased the body movement coordination at stimulation onset and maintained this movement pattern throughout the stimulation period. Furthermore, when exposed to balance perturbations the test subjects synchronized significantly the head and torso movements in anteroposterior direction during all trial conditions.
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| 7. |
- Hillerdal, Gunnar, et al.
(författare)
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Treatment of malignant pleural mesothelioma with liposomized doxorubicine : prolonged time to progression and good survival. A Nordic study
- 2008
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Ingår i: The Clinical Respiratory Journal. - 1752-6981 .- 1752-699X. ; 2:2, s. 80-85
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Malignant pleural mesothelioma (MPM) has a poor prognosis and there is limited effect of treatment. Lately, pemetrexed and cisplatin have been established as the standard treatment. Objectives: The present study was planned in 1998, when there was no standard treatment. Single-dose doxorubicine had, in small studies, accomplished remissions, and the Scandinavian Mesothelioma Groups therefore decided to test a liposomized form of this drug, which had shown limited toxicity but good efficacy in a few small studies. Methods: Fifty-four evaluable patients with histologically verified and inoperable MPM were treated with liposomized doxorubicine 40 mg/m2, every 4 weeks for six cycles. Results: In all, 29 patients (54%) received at least six treatments. The quality of life remained good during the study. Hematologic toxicity was very low. Palmo–plantar erythema occurred in 11 patients (20%), thereof 7 grade II but none was severe and none was dose-limiting. There were four partial responses (7%). The median time to progression (TTP) was 5 months, the median survival was 12 months, and at 24 months, 22% were still alive. Conclusion: Liposomized doxorubicine has a low toxicity and is well tolerated; there were a remarkably long TTP and a good survival. Thus, despite the low response rate, liposomized doxorubicine remains an interesting drug for the treatment of malignant mesothelioma.
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| 8. |
- Jacobson, Annica, 1974-
(författare)
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Regulation of hyaluronan biosynthesis : Expression in vitro and importance for tumor progression
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyaluronan, a component of the extracellular matrix, is synthesized by either of three hyaluronan-synthesizing enzymes termed Has1, Has2 and Has3. The expression level of each Has gene varies between cell types of mesenchymal origin and is differentially regulated in response to external stimuli. For example, stimulation of mesothelial cells with PDGF-BB induced an up-regulation of the Has2 gene, whereas the Has1 and Has3 genes remained unaffected. The induction of Has2 gene expression correlated well with increased Has2 protein levels and accumulation of hyaluronan. Moreover, treatment of mesothelial cells with hydrocortisone suppressed hyaluronan synthesis in cell culture primarily through down-regulation of the Has2 gene. Thus, among the Has isoforms, Has2 seems to be most markedly regulated in response to external stimuli.In an attempt to investigate the importance of hyaluronan in tumor progression, the hyaluronan synthesizing enzyme Has2 and the hyaluronan degrading enzyme Hyal1 were over-expressed in a rat colon adenocarcinoma cell line, PROb. We found that Has2 gene over-expression in colon carcinoma cells promoted cell growth in vitro and progression of transplantable tumors. In contrast, over-expression of Hyal1 lead to a considerable reduction of growth rates both in vivo and in vitro. A linear correlation between tumor growth rate and hyaluronan amount in tumor tissue was observed. In another tumor model, experimental anaplastic thyroid carcinoma, the effects of TGF-β inhibition on hyaluronan and collagen contents in tumor xenografts were investigated. We found that inhibition of TGF-β, a stimulator of hyaluronan and collagen synthesis, lead to reduced collagen deposition whereas the hyaluronan levels in stromal tissue only marginally differed. Our results indicate that a high ratio of collagen to hyaluronan may be characteristic of a pathogenic mechanism that leads to elevated interstitual tumor pressure.
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| 9. |
- Javadi, Joman, et al.
(författare)
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Syndecan-1 Overexpressing Mesothelioma Cells Inhibit Proliferation, Wound Healing, and Tube Formation of Endothelial Cells
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The transmembrane proteoglycan syndecan-1 (SDC-1) is an important mediator of cell-matrix interactions. The heparan sulfate side-chains of SDC-1 can bind to a multitude of growth factors, cytokines, and chemokines, thereby regulating a plethora of physiological and pathological processes, including angiogenesis. The extracellular region of SDC-1 can be released from the cell surface by the action of sheddases including matrix metalloproteinase-7 and 9, resulting in a soluble protein that is still active and can act as a competitive activator or inhibitor of the cell surface receptor. Accelerated shedding and loss of cell surface SDC-1 is associated with epithelial to mesenchymal transition (EMT) and achievement of a more invasive phenotype in malignant mesothelioma (MM). Transfection with SDC-1 reverts the morphology in epithelioid direction and inhibits the proliferation and migration of MM cells. This study aimed to investigate the role of SDC-1 in angiogenesis. We demonstrate that overexpression and silencing of SDC-1 alters the secretion of angiogenic proteins in MM cells. Upon SDC-1 overexpression, several factors collectively inhibit the proliferation, wound closure, and tube formation of endothelial cells, whereas SDC-1 silencing only affects wound healing. Malignant mesothelioma (MM) is an aggressive tumor of the serosal cavities. Angiogenesis is important for mesothelioma progression, but so far, anti-angiogenic agents have not improved patient survival. Our hypothesis is that better understanding of the regulation of angiogenesis in this tumor would largely improve the success of such a therapy. Syndecan-1 (SDC-1) is a transmembrane heparan sulfate proteoglycan that acts as a co-receptor in various cellular processes including angiogenesis. In MM, the expression of SDC-1 is generally low but when present, SDC-1 associates to epithelioid differentiation, inhibition of tumor cell migration and favorable prognosis, meanwhile SDC-1 decrease deteriorates the prognosis. In the present study, we studied the effect of SDC-1 overexpression and silencing on MM cells ability to secrete angiogenic factors and monitored the downstream effect of SDC-1 modulation on endothelial cells proliferation, wound healing, and tube formation. This was done by adding conditioned medium from SDC-1 transfected and SDC-1 silenced mesothelioma cells to endothelial cells. Moreover, we investigated the interplay and molecular functional changes in angiogenesis in a co-culture system and characterized the soluble angiogenesis-related factors secreted to the conditioned media. We demonstrated that SDC-1 over-expression inhibited the proliferation, wound healing, and tube formation of endothelial cells. This effect was mediated by a multitude of angiogenic factors comprising angiopoietin-1 (Fold change +/- SD: 0.65 +/- 0.07), FGF-4 (1.45 +/- 0.04), HGF (1.33 +/- 0.07), NRG1-beta 1 (1.35 +/- 0.08), TSP-1 (0.8 +/- 0.02), TIMP-1 (0.89 +/- 0.01) and TGF-beta 1 (1.35 +/- 0.01). SDC-1 silencing increased IL8 (1.33 +/- 0.06), promoted wound closure, but did not influence the tube formation of endothelial cells. Pleural effusions from mesothelioma patients showed that Vascular Endothelial Growth Factor (VEGF) levels correlate to soluble SDC-1 levels and have prognostic value. In conclusion, SDC-1 over-expression affects the angiogenic factor secretion of mesothelioma cells and thereby inhibits endothelial cells proliferation, tube formation, and wound healing. VEGF could be used in prognostic evaluation of mesothelioma patients together with SDC-1.
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| 10. |
- Johansson, Henrik J., et al.
(författare)
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Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer
- 2013
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 4:3175
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Tidskriftsartikel (refereegranskat)abstract
- About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen.
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