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51.
52.
Annemarie E. M. Post Johan Bussink Fred C. G. J. Sweep Paul N. Span 《Oncology research》2020,28(1):33-40
Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that
DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence
of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression
of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that
were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic
for several DNA damage repair pathways was investigated, as well as expression of genes involved in different
phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was
assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential
gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were
more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two
times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after
radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower
expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two
times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not
associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA
damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in
both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these
cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found. 相似文献
53.
S W Janssen A R Hermus W P Lange Q Knijnenburg J A van der Laak C G Sweep G J Martens A A Verhofstad 《Experimental and clinical endocrinology & diabetes》2001,109(5):273-282
Thus far, histopathological changes in the pancreatic islets of Zucker Diabetic Fatty (ZDF) rats, an animal model of type 2 diabetes mellitus (or non-insulin-dependent diabetes mellitus), have only been studied in male rats and in 18-weeks old rats or younger. In this study, we have examined in both male and female ZDF rats the histopathological changes longitudinally, from 6 to 32 weeks of age. We studied islet architecture and cellular distribution of the various islet hormones both in ZDF and control rats. In the ZDF rats, aging was initially associated with an enlargement of the islets. From 18 weeks onwards, no further enlargement was noted but islet boundaries became increasingly irregular, leading to the appearance of projections of endocrine cells into the surrounding exocrine tissue. At the islet boundaries as well as within the islets progressive fibrosis was observed with increasing amounts of collagen and reticular fibers. In the islets, staining intensity of both insulin and islet amyloid polypeptide (IAPP) increased slightly till 10 weeks of age and thereafter decreased rapidly. In contrast, the staining intensities of glucagon, somatostatin, and pancreatic polypeptide (PP) did not change. Even at the age of 32 weeks, just the beta-cells and not the other endocrine islet cells appear to be affected. In control rats, aging evoked only minor changes. Thus, we observed that during prolonged development of diabetes mellitus in both male and female ZDF rats histopathological changes in the pancreatic islets became progressively more severe, eventually leading to disintegration of the islets. 相似文献
54.
55.
C. G. Sweep J. Geurts-Moespot N. Grebenschikov J. H. de Witte J. J. Heuvel M. Schmitt M. J. Duffy F. J?nicke M. D. Kramer J. A. Foekens N. Brünner G. Brugal A. N. Pedersen T. J. Benraad 《British journal of cancer》1998,78(11):1434-1441
High levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in breast cancer tissue extracts have been associated with rapid disease progression. In these studies, different enzyme-linked immunosorbent assay (ELISA) kits have been applied for the quantification, and consequently the ranges of uPA and PAI-1 levels reported differ considerably. Therefore, the Receptor and Biomarker Study Group (RBSG) of the European Organization for Research and Treatment of Cancer (EORTC) and a consortium of the BIOMED-1 project ''Clinical Relevance of Proteases in Tumor Invasion and Metastasis'' initiated three collaborative between-laboratory assessment trials aimed at controlling uPA and PAI-1 antigen analyses. For this purpose, two control preparations were produced from different sources: pooled human breast cancer specimens (QC-240893) and human breast cancer xenografts raised in nude mice (QC-101094). The lyophilized preparations were stable for prolonged times (at least 3 and 27 months respectively) at 4 degrees C. Furthermore, a good parallelism following dilution was found for uPA and PAI-1. The data from QC trial no. 1 clearly indicated that acceptable between-laboratory coefficients of variation (CVs) for uPA (<8.2%) and PAI-1 (<16.6%) in QC-240893 could be achieved when the same type of ELISA kit (American Diagnostica) was used. From the second trial, in which ten EORTC laboratories each received five identical lyophilized QC-101094 samples, it appeared that the within-laboratory variations for uPA and PAI-1 determinations obtained by ''experienced'' laboratories were lower (<12.9%) than those from non-experienced laboratories (<36.4%). In a third QC trial, five BIOMED-1 laboratories, all of which employed ELISA procedures for uPA and PAI-1, participated in six subsequent quality assessment rounds receiving five samples of QC-101094. Although for each laboratory the within-run CVs for uPA as well as for PAI-1 were low (<7.8%), the between-run CVs were found to be considerably higher (up to 56.2% for uPA and to 27.6% for PAI-1). Consequently, because of the different ELISA formats used, the absolute analyte values measured in the different laboratories varied substantially. The use of ''common external standards'' in the different ELISAs resulted in a significant reduction of the between-laboratory CVs from 61.3% to 15.7% (uPA) and from 42.1% to 19.1% (PAI-1). The present data demonstrate that in multicentre studies the same ELISA kit should be used, and that external quality assurance (QA) is mandatory. Furthermore, it appears from the present study that standardization of the protein assay as a tissular parameter is imperative. 相似文献
56.
57.
Interleukin-1-induced nonspecific resistance to bacterial infection in mice is not mediated by glucocorticosteroids. 下载免费PDF全文
M T Vogels C G Sweep A R Hermus J W van der Meer 《Antimicrobial agents and chemotherapy》1992,36(12):2785-2789
Preexposure to a low dose of interleukin-1 (IL-1; 3 to 30 micrograms/kg) 24 h before a lethal gram-negative bacterial infection prolonged survival in normal and granulocytopenic mice. To examine whether this protective effect is mediated by glucocorticosteroids, we first measured corticosterone concentrations in mice after administration of 80 and 800 ng of IL-1. IL-1 induced a dose-dependent increase in corticosterone levels in plasma. Next, the corticosterone peak induced by a protective dose of IL-1 (800 ng) was simulated by administration of synthetic human adrenocorticotropic hormone 1-24 (ACTH) in normal and neutropenic mice. Although corticosterone levels induced by pretreatment with IL-1 or ACTH were virtually identical, the ACTH-induced corticosterone peak was not associated with protection against Klebsiella pneumoniae infection in normal mice and Pseudomonas aeruginosa infection in neutropenic mice. This indicates that the protective effect of IL-1 pretreatment against gram-negative bacterial infection is not mediated by elevated levels of glucocorticosteroids. In addition, we found that plasma corticosterone concentrations during K. pneumoniae infection were significantly lower after pretreatment with IL-1 than after pretreatment with ACTH or vehicle, probably reflecting the better physical condition of IL-1-treated mice. 相似文献
58.
Sprong T Pickkers P Geurts-Moespot A van der Ven-Jongekrijg J Neeleman C Knaup M Leroy D Calandra T van der Meer JW Sweep F van Deuren M 《Shock (Augusta, Ga.)》2007,27(5):482-487
Macrophage migration inhibitory factor (MIF) is a mediator of innate immunity and important in the pathogenesis of septic shock. Lipopolysaccharide (LPS) and tumor necrosis factor (TNF) alpha are reported to be inducers of MIF. We studied MIF and cytokines in vivo in patients with meningococcal disease, in human experimental endotoxemia, and in whole blood cultures using a newly developed sensitive and specific enzyme-linked immunosorbent assay. Twenty patients with meningococcal disease were investigated. For the human endotoxemia model, 8 healthy volunteers were intravenously injected with 2 ng/kg Escherichia coli LPS. Whole blood from healthy volunteers was incubated with LPS or heat-killed meningococci. Macrophage migration inhibitory factor concentration in blood was increased during meningococcal disease and highest in the patients presenting with shock compared with patients without shock. Plasma concentration of MIF correlated with disease severity, the presence of shock and with the cytokines interleukin (IL) 1beta, IL-10, IL-12, and vascular endothelial growth factor, but not with TNF-alpha. MIF was not detected in blood in experimental endotoxemia, nor after stimulation of whole blood with LPS or meningococci, although high levels of TNF-alpha were seen in both models. In conclusion, MIF is increased in patients with meningococcal disease and highest in the presence of shock. Macrophage migration inhibitory factor cannot be detected in a human endotoxemia model and is not produced by whole blood cells incubated with LPS or meningococci. 相似文献
59.
Radstake TR van Lent PL Pesman GJ Blom AB Sweep FG Rönnelid J Adema GJ Barrera P van den Berg WB 《Annals of the rheumatic diseases》2004,63(6):696-702
OBJECTIVE: To assess whether DC from RA produce altered cytokine levels and whether this is regulated by triggering of Fc gamma receptors (FcgammaR). METHODS: The production of proinflammatory (TNFalpha, IL1, IL6), Th1 (IL12, IFNgamma), and Th2 (IL10) cytokine profiles of immature DC (iDC) from patients with RA and healthy subjects upon triggering of FcgammaR dependent and independent pathways was investigated. iDC, derived from blood monocytes by standardised protocols, were stimulated with immune complexes (IC) at day 6 for 48 hours and, subsequently, for 2 days with LPS in the presence or absence of IC or IFNgamma, resulting in fully matured DC (mDC). IL1, IL6, TNFalpha, IFNgamma, IL12, and IL10 levels in supernatants were measured by ELISA and RIA. RESULTS: mDC from patients with RA showed a markedly increased production of IL1, IL6, TNFalpha, and IL10 compared with DC from healthy donors. Triggering of FcgammaR decreased the production of proinflammatory cytokines IL1, IL12, and IFNgamma by iDC and mDC in RA and controls. The production of IL6 and TNFalpha decreased in patients with RA, whereas it was increased in controls. Triggering of FcgammaR independent mechanisms using IFNgamma increased the production of proinflammatory and Th1 cytokines, which was more pronounced in RA. CONCLUSION: FcgammaR dependent pathways influence cytokine production by DC. A skewed balance towards proinflammatory and Th1 cytokines in RA can, at least partly, be restored by triggering FcgammaR on DC in RA. Insight into the mechanism which determines the FcgammaR balance might lead to new strategies to abrogate Th1 driven inflammatory processes in RA. 相似文献
60.
Ronday HK; Te Koppele JM; Greenwald RA; Moak SA; De Roos JA; Dijkmans BA; Breedveld FC; Verheijen JH 《Rheumatology (Oxford, England)》1998,37(1):34-38
The plasminogen activation system is one of the enzyme systems held
responsible for bone and cartilage degradation in rheumatoid arthritis
(RA). In this study, we evaluated the effect of tranexamic acid (TEA), an
inhibitor of plasminogen activation, on urinary collagen cross-link
excretion and radiological joint damage in rat adjuvant arthritis (AA) and
on urinary collagen cross-link excretion in patients with RA. In the animal
study, adjuvant arthritis was induced in male Lewis rats. From day 7
onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was
administered orally. Study groups consisted of TEA-treated normal rats (C +
TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA
+ TEA) or with placebo (AA + plac). To monitor joint destruction, urinary
collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was
measured by high-performance liquid chromatography at days 14 and 21.
Radiological evaluation of joints was performed at day 21. In the patient
study, TEA was administered to nine patients with RA as adjuvant medication
(approximately 20 mg/kg body weight, three times daily) for 12 weeks.
Urinary HP and LP excretion levels were measured before and during TEA
treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA
rats, a significant reduction of HP and a tendency towards a reduction of
LP excretion were found compared with AA + plac rats (P < 0.05), at day
14, whereas the HP/LP ratio did not change. No difference was observed in
HP, LP excretion, HP/LP ratio and radiological damage score between the
TEA- and placebo-treated AA rats at day 21. In RA patients, a significant
reduction of HP and LP excretion was found during the TEA treatment period
(P < 0.05). After the cessation of TEA treatment, HP and LP excretion
increased towards baseline levels. No effect on disease activity was
observed. The plasmin antagonist TEA reduced the excretion of collagen
pyridinoline cross-links in both experimental and rheumatoid arthritis. As
such, this study not only supports the involvement of the plasminogen
activation system in the destructive phase of arthritis, but also suggests
a beneficial effect of therapeutic strategies directed against inhibition
of matrix proteolysis.
相似文献