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Träfflista för sökning "hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Klinisk medicin) hsv:(Cancer och onkologi) srt2:(2000-2004)"

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  • Bagwell, C B, et al. (författare)
  • DNA and cell cycle analysis as prognostic indicators in breast tumors revisited
  • 2001
  • Ingår i: Clinics in Laboratory Medicine. - : W B Saunders. - 0272-2712. ; 21:4, s. 875-895
  • Tidskriftsartikel (refereegranskat)abstract
    • Both DNA ploidy and S-phase ploidy are promising prognostic factors for node-negative breast cancer patients. Based largely on the analysis of one large study, much of the reported problems with these factors have been caused by some unappreciated complexities in categorizing DNA ploidy into low- and high-risk groups and the lack of some necessary adjustments to eliminate unwanted correlations between DNA S-phase and ploidy. When both DNA ploidy and S-phase are compensated properly, they become independent prognostic markers, forming a powerful prognostic model.
  • Bagwell, C B, et al. (författare)
  • Optimizing flow cytometric DNA ploidy and S-phase fraction as independent prognostic markers for node-negative breast cancer specimens
  • 2001
  • Ingår i: Cytometry. - : John Wiley and Sons Inc.. - 0196-4763 .- 1097-0320. ; 46:3, s. 121-135
  • Tidskriftsartikel (refereegranskat)abstract
    • Developing a reliable and quantitative assessment of the potential virulence of a malignancy has been a long-standing goal in clinical cytometry. DNA histogram analysis provides valuable information on the cycling activity of a tumor population through S-phase estimates; it also identifies nondiploid populations, a possible indicator of genetic instability and subsequent predisposition to metastasis. Because of conflicting studies in the literature, the clinical relevance of both of these potential prognostic markers has been questioned for the management of breast cancer patients. The purposes of this study are to present a set of 10 adjustments derived from a single large study that optimizes the prognostic strength of both DNA ploidy and S-phase and to test the validity of this approach on two other large multicenter studies. Ten adjustments to both DNA ploidy and S-phase were developed from a single node-negative breast cancer database from Baylor College (n = 961 cases). Seven of the adjustments were used to reclassify histograms into low-risk and high-risk ploidy patterns based on aneuploid fraction and DNA index optimum thresholds resulting in prognostic P values changing from little (P < 0.02) or no significance to P < 0.000005. Other databases from Sweden (n = 210 cases) and France (n = 220 cases) demonstrated similar improvement of DNA ploidy prognostic significance, P < 0.02 to P < 0.0009 and P < 0.12 to P < 0.002, respectively. Three other adjustments were applied to diploid and aneuploid S-phases. These adjustments eliminated a spurious correlation between DNA ploidy and S-phase and enabled them to combine independently into a powerful prognostic model capable of stratifying patients into low, intermediate, and high-risk groups (P < 0.000005). When the Baylor prognostic model was applied to the Sweden and French databases, similar significant patient stratifications were observed (P < 0.0003 and P < 0.00001, respectively). The successful transference of the Baylor prognostic model to other studies suggests that the proposed adjustments may play an important role in standardizing this test and provide valuable prognostic information to those involved in the management of breast cancer patients.
  • Baldetorp, Bo, et al. (författare)
  • Improved DNA flow cytometric, DNA ploidy, and S-phase reproducibility between 15 laboratories in analysis of breast cancer using generalized guidelines
  • 2003
  • Ingår i: Cytometry. - : John Wiley and Sons Inc.. - 0196-4763 .- 1097-0320. ; 56A:1, s. 1-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Lack of generalized guidelines for DNA flow cytometric analysis (FCM) may be the main reason for its limited use in the clinical management of breast cancer. Methods: After an initial interlaboratory reproducibility study (Round 1), we concluded that it was the evaluation of the DNA histograms rather than the technical performance of the analysis that was the main reason for discordant results between laboratories. Guidelines for the interpretation of DNA histograms were therefore drawn up. We present here data from a new reproducibility study (Round 11) using these guidelines. Results: For 10 laboratories also participating in Round 1, use of the guidelines increased the concordance in DNA ploidy status from 89% to 100% for the 46 samples used in both rounds. The concordance rate for SPF also increased; mean r(s)-value increased from 0.81 to 0.88, and mean kappa value (lower two-thirds versus upper third versus not reported) increased from 0.55 to 0.71. Five new laboratories, participating only in Round II, also agreed with the 10 original laboratories regarding DNA ploidy status. With the inclusion of all 15 laboratories, we obtained a mean r(s)-value of 0.81 and a mean kappa value of 0.72 for SPF. Conclusions: Generalized guidelines for DNA FCM increase interlaboratory agreement, which is highly important in clinical routines and in multicenter studies. Furthermore, inexperienced FCM laboratories using generalized guidelines can produce and interpret DNA FCM data equally as well as experienced laboratories. Cytometry Part A 56A:1-7, 2003. (C) 2003 Wiley-Liss, Inc.
  • Bardi, G, et al. (författare)
  • Tumor karyotype predicts clinical outcome in colorectal cancer patients
  • 2004
  • Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 1527-7755. ; 22:13, s. 2623-2634
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC). Patients and Methods Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates. Results In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patients with stage I and II carcinomas, none of the clinicopathologic variables could independently predict patient survival, whereas the presence of structural chromosomal aberrations was the only independent predictor of poor prognosis. In the subset of patients with stage III carcinomas, the presence of structural changes of chromosome 8 was a stronger independent predictor of prognosis than was tumor grade. Conclusion Cytogenetic tumor features are valuable predictors of prognosis in CRC patients. The tumor karyotype should therefore be taken into account in the clinical management of patients with this disease, especially for patients having cancers of the early or intermediate stages I, II, and III.
  • Baselga, J, et al. (författare)
  • Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
  • 2002
  • Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 1527-7755. ; 20:21, s. 4292-4302
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
  • Baust, H., et al. (författare)
  • Evidence for radiosensitizing by gliotoxin in HL-60 cells : implications for a role of NF-kappa B independent mechanisms
  • 2003
  • Ingår i: Oncogene. - 0950-9232 .- 1476-5594. ; 22:54, s. 8786-8796
  • Tidskriftsartikel (refereegranskat)abstract
    • Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radio-sensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.
  • Belting, Mattias (författare)
  • Heparan sulfate proteoglycan as a plasma membrane carrier
  • 2003
  • Ingår i: Trends in Biochemical Sciences. - : Elsevier. - 0167-7640. ; 28:3, s. 145-151
  • Tidskriftsartikel (refereegranskat)abstract
    • The plasma membrane defines the border of living cells and provides a barrier to extracellular components. Advances in molecular biology have resulted in the development of novel therapeutic strategies (e.g. gene therapy and cellular protein delivery) which rely on the entry of charged macromolecules into the intracellular compartment. Recent reports demonstrate an intriguing role for heparan sulfate proteoglycans in cellular internalization of viruses, basic peptides and polycation-nucleic-acid complexes and the possibility that they have important implications for gene transfer and protein delivery to mammalian cells. This review focuses on heparan sulfate proteoglycan as a plasma membrane carrier.
  • Bengtsson, Therese (författare)
  • Functional analysis of the alpha10beta1 integrin
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The aim of this thesis was to study the function of the integrin a10b1. Integrins mediate signals between cells and their environment and regulate several cellular processes such as cell migration, proliferation and differentiation. The a10b1 integrin is expressed mainly by chondrocytes, the only cell type present in cartilage, and facilitates binding of the chondrocytes to the extracellular matrix molecule collagen. However, the function of the a10b1 integrin in cartilage is not known. In this thesis we describe the structure of the mouse a10b1 integrin gene and report the finding of two alternatively spliced extracellular forms of the a10b1 integrin. We also demonstrate the chromosomal localization of the human and mouse a10 integrin genes. To analyze the role of this collagen-binding integrin during development and in adult mice we generated a mouse deficient in the a10b1 integrin, by gene targeting deletion. We found that a10b1–null mice suffered from a mild chondrodysplasia, and that they had shorter limbs than normal mice. The mutant mice showed structural defects in the growth plate and decreased chondrocyte proliferation. Further studies have revealed that the a10b1 integrin appears to be the only collagen-binding integrin expressed in the growth plate of 8-week old mice. Together, these data show that the a10b1 integrin plays an important role in the regulation of chondrocyte function and bone development.
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