| 1. |
- Trouw, Leendert, et al.
(författare)
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C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation.
- 2005
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 201:12, s. 1937-1948
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Tidskriftsartikel (refereegranskat)abstract
- After cell death, via apoptosis or necrosis, the uptake of dead cells by neighboring cells or phagocytes prevents the release of intracellular content. An array of molecules, including initiation molecules of the complement system, are involved in marking dead cells for uptake. After binding of these molecules, complement activation takes place, which when uncontrolled might result in a proinflammatory state. In the current study we demonstrate that complement inhibitor, C4b-binding protein (C4BP), binds strongly to necrotic cells, irrespective of the cell type used or the method of induction. After binding of the C4BP–protein S (PS) complex to necrotic cells via PS-phosphatidylserine and C4BP-DNA interactions, C4BP-PS inhibits complement activation on these cells. C4BP binds DNA via a patch of positively charged amino acids, mainly on the second complement control domain of the C4BP α-chain (affinity constant: 190 nM). Furthermore, C4BP limits DNA release from necrotic cells and inhibits DNA-mediated complement activation in solution. The C4BP–necrotic cell interaction also occurs in vivo as necrotic areas of arteriosclerotic plaques and of various cancers stain strongly positive for C4BP. This study describes a novel mechanism in which C4BP limits the inflammatory potential of necrotic cells.
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| 2. |
- Trouw, Leendert, et al.
(författare)
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C4b-binding protein is present in affected areas of myocardial infarction during the acute inflammatory phase and covers a larger area than C3.
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: During myocardial infarction reduced blood flow in the heart muscle results in cell death. These dying/dead cells have been reported to bind several plasma proteins such as IgM and C-reactive protein (CRP). In the present study we investigated whether fluid-phase complement inhibitor C4b-binding protein (C4BP) would also bind to the infarcted heart tissue. METHODS AND FINDINGS: Initial studies using immunohistochemistry on tissue arrays for several cardiovascular disorders indicated that C4BP can be found in heart tissue in several cardiac diseases but that it is most abundantly found in acute myocardial infarction (AMI). This condition was studied in more detail by analyzing the time window and extent of C4BP positivity. The binding of C4BP correlates to the same locations as C3b, a marker known to correlate to the patterns of IgM and CRP staining. Based on criteria that describe the time after infarction we were able to pinpoint that C4BP binding is a relatively early marker of tissue damage in myocardial infarction with a peak of binding between 12 hours and 5 days subsequent to AMI, the phase in which infiltration of neutrophilic granulocytes in the heart is the most extensive. CONCLUSIONS: C4BP, an important fluid-phase inhibitor of the classical and lectin pathway of complement activation binds to jeopardized cardiomyocytes early after AMI and co-localizes to other well known markers such as C3b.
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| 3. |
- Butt, Salma, et al.
(författare)
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Parity in relation to survival following breast cancer.
- 2009
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 1532-2157 .- 0748-7983. ; 35, s. 702-708
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The present study examines the association between parity and survival following breast cancer diagnosis. METHODS: Medical records of 4453 women diagnosed with breast cancer in Malmö, Sweden, between 1961 and 1991 were analysed. All women were followed until 31 December 2003, using the Swedish Cause-of-Death Registry. Breast cancer specific mortality rate was calculated in different levels of parity. Corresponding relative risks, with 95% confidence intervals (CI), were obtained using Cox's proportional hazards analysis. All analyses were adjusted for potential prognostic factors and stratified for age, menopausal status and diagnostic period. RESULTS: As compared to women with one child, nulliparity (RR 1.27: 95% CI 1.09-1.47), and high parity (four or more children) (1.49: 1.20-1.85) were positively associated with a high mortality from breast cancer. When adjusted for potential confounders, the association was only statistically significant for high parity (1.33: 1.07-1.66). In the analyses stratified on age and menopausal status, there was a similar positive association between high parity and breast cancer death in all strata, although only statistically significant among women older than 45years of age or postmenopausal. Nulliparity was associated with breast cancer death in women that were younger than 45years of age (1.28: 0.79-2.09) or premenopausal (1.30: 0.95-1.80), but these associations did not reach statistical significance. There was no association between nulliparity and breast cancer death in women older than 45years of age or postmenopausal. All associations were similar in analyses stratified for diagnostic period. CONCLUSION: Women with four or more children have a poor breast cancer survival as compared to women with one child.
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| 4. |
- Ekberg, Jenny, et al.
(författare)
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Expression of cyclin A1 and cell cycle proteins in hematopoietic cells and acute myeloid leukemia and links to patient outcome
- 2005
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Ingår i: European Journal of Haematology. - : Wiley-Blackwell Publishing Inc.. - 0902-4441 .- 1600-0609. ; 75:2, s. 106-115
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal expression of several key regulators essential for G1/S transitions has been implicated in tumorigenesis. A critical role of cyclin A1 in the development of acute myeloid leukemia (AML) has previously been demonstrated in transgenic mice. Our present study focused on the expression and prognostic significance of cyclin A1 and a panel of cell cycle regulatory proteins including cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 in bone marrow samples from 40 patients with AML. Freshly isolated CD34+ hematopoietic cells and bone marrow samples from 10 healthy donors were also assessed for cell type- and subcellular-specific expression of the cell cycle regulatory proteins. The level of cyclin A1 expression was the only factor that showed a significant correlation with patient outcome. In log-rank test stratified by levels of cyclin A1 expression, patients with high levels of cyclin A1 had significantly worse overall survival (OS) (P = 0.012) compared to those with low levels. Further, patients with high levels of cyclin A1 had significantly lower disease-free survival (DFS) (P = 0.028). Multivariate analysis indicated that cyclin A1 protein expression was an independent prognostic factor for predicting DFS (P = 0.035) and OS (P = 0.045). No correlation between cyclin A1 expression and age was found. However, expression of cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 did not show prognostic significance in these AML patients.
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| 5. |
- Holm, Caroline, et al.
(författare)
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Cyclin A1 expression and associations with disease characteristics in childhood acute lymphoblastic leukemia
- 2006
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Ingår i: Leukemia Research. - : Elsevier. - 0145-2126 .- 1873-5835. ; 30:3, s. 254-261
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Tidskriftsartikel (refereegranskat)abstract
- A critical cell cycle regulatory protein, cyclin A1, has been implicated in the development of acute myeloid leukemia (AML). Here, we have examined the expression and clinical significance of cyclin A1 in childhood acute lymphoblastic leukemia (ALL). Cyclin A1 was highly expressed in lymphoblastic leukemic cell lines and in 22 of 30 ALL patients (73%). Cyclin A1 expression correlated with patient age (P=0.006), but not with cytogenetic abnormalities. Patients with high levels of cyclin A1 had poorer event-free survival (57.9%) compared to patients with lower levels (75%).
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| 6. |
- Jögi, Annika, et al.
(författare)
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Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer
- 2009
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 22:12, s. 1564-1574
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Tidskriftsartikel (refereegranskat)abstract
- Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n = 1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (P<0.001), small tumors (P<0.001), estrogen receptor (ER) positivity (P<0.001) and Ki-67 negativity (P<0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30-0.79, P = 0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors. Modern Pathology (2009) 22, 1564-1574; doi:10.1038/modpathol.2009.124; published online 4 September 2009
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| 9. |
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| 10. |
- Aaltonen, Kirsimari, et al.
(författare)
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Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer
- 2009
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 113:1, s. 75-82
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Tidskriftsartikel (refereegranskat)abstract
- Cyclins D1 and E play an important role in breast carcinogenesis. High cyclin E expression is common in hormone receptor negative and high grade aggressive breast cancer, whereas cyclin D1 in hormone receptor positive and low grade breast cancer. Experimental data has suggested that cyclin D1 and E mediate cell proliferation by different mechanisms in estrogen receptor (ER) positive and negative breast cancer. To test this hypotheses in large breast cancer material and to clarify the histopathological correlations of cyclin E and D1, especially the association with proliferation, we analyzed cyclin E and D1 immunohistochemical expression on breast tumour microarrays consisting of 1348 invasive breast cancers. High cyclin D1 expression was associated with high grade (P < 0.0005), high cyclin A (P < 0.0005) and Ki67 (P < 0.0005) expression among ER positive but with low grade (P = 0.05) and low Ki67 (P = 0.01) expression among ER negative breast cancers. Cyclin E and D1 expression correlated positively in ER positive (P < 0.0005) but had a negative correlation in ER negative tumours (P = 0.004). Cyclin E associated with high grade among all tumours (P < 0.0005). In conclusion, the findings of this study show that cyclin D1 has separate roles, and proliferation is driven by different mechanisms in ER positive and negative breast cancers.
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