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81.
Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells. 相似文献
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83.
Singh P Reimer CL Peters JH Stepp MA Hynes RO Van De Water L 《The Journal of investigative dermatology》2004,123(6):1176-1181
The fibronectins (FN) comprise a family of adhesive extracellular matrix proteins thought to mediate important functions in cutaneous wounds. Plasma fibronectin (pFN) extravasates for days from intact hyperpermeable vessels following injury whereas mRNAs encoding the cellular fibronectins (cFN) that include two segments, termed EIIIA (EDA) and EIIIB (EDB), are expressed by wound cells. Wounds in mice null for pFN appear to heal normally whereas those in EIIIA null mice exhibit defects, suggesting that cFN may play a role when pFN is missing. Integrin alpha9beta1, a receptor for several extracellular matrix proteins as well as the EIIIA segment, is expressed normally in the basal layer of squamous epithelia. We report results from immunohistochemistry on healing wounds demonstrating that EIIIA-containing cFN are deposited abundantly but transiently from day 4 to 7 whereas EIIIB-containing cFN persist at least through day 14. Elevated expression of alpha9beta1 is seen in basal and suprabasal epidermal keratinocytes in wounds. The spatial expression patterns of cFN and alpha9beta1 are distinct, but overlap in the dermal-epidermal junction, and both are expressed contemporaneously. These observations suggest a role for alpha9beta1-EIIIA interactions in wound keratinocyte function. 相似文献
84.
Most countries in oriental Asia have not yet experienced the 'western' coronary heart disease (CHD) epidemic despite substantial economic development. An exception has been Singapore. We compared mortality and CHD risk factors in Singapore with two Oriental locations, Hong Kong and mainland China, which have not experienced the CHD epidemic. Mortality data from World Health Statistics Annuals age standardised for each location and were supplemented by local data. Risk factor data was obtained from population-based surveys using similar protocols in each location. Measures included diet, blood lipids, blood pressure, height and weight. CHD mortality in the year chosen for comparison, 1994, was significantly higher for Singapore Chinese males [108 (95.2-119.1)] than Chinese males in Hong Kong [44.3 (40.2-48.2)] or China [45.5 (44.2-46.8)]. Female CHD mortality was also relatively higher in Singapore Chinese. The only CHD risk factor markedly higher in Singapore Chinese was serum cholesterol; Singapore males [5.65 (5.55-5.75)], females [5.60 (5.50-5.70)], Hong Kong males [5.21 (5.11-5.31)], females [5.20 (5.10-5.29)] and China males [4.54 (4.46-4.62)], females [4.49 (4.42-4.55)]. Dietary differences in saturated fat consumption were consistent with this. Although there was little difference in total fat intake, a higher consumption of dietary saturated fat and lower consumption of polyunsaturated fat, accompanied by higher serum cholesterol, appear to explain the relatively high CHD mortality in Singapore compared with Hong Kong and mainland China. Differences in body mass index, blood pressure and smoking between locations did not explain the differences in CHD mortality. 相似文献
85.
BACKGROUND: Androgens play a critical role in proliferation and survival of prostate cancer cells, but the mechanisms leading to these effects are poorly understood. ErbB receptor tyrosine kinases have been implicated in the development of prostate cancer. METHODS: We examined the interaction between the ErbB receptors and androgens using the LNCaP androgen-sensitive prostate tumor model. RESULTS: In the absence of androgens, the cells have low levels of ErbB1 and relatively high levels of ErbB2. Addition of androgens to the medium reversed the ratio; ErbB1 levels rose and ErbB2 levels dropped in response to treatment with the synthetic hormone, R1881. Expression of ErbB activating ligands was found to be constitutive and androgen-independent. The androgen-induced proliferation of LNCaP cells was completely inhibited by the addition of the small molecule ErbB1 tyrosine kinase inhibitors CGP59326 and the bispecific inhibitor (PKI166) for ErbB1 and ErbB2 to the culture medium. Furthermore, in the absence of androgens the relatively low proliferative level was further significantly reduced in the presence of CGP59326. Inhibition of PI3K activity by LY294002 led to induction of apoptosis in androgen-deprived LNCaP cells. Androgen-mediated rescue from LY294002-induced apoptosis was inhibited by addition of CGP59326 to the cells. CONCLUSIONS: These results suggest a model whereby androgens promote an increase in the activity of the epidermal growth factor (EGF)-network by increasing ErbB1 levels, and this activity of is essential for androgen-induced proliferation and survival of the prostate cancer LNCaP cell line. 相似文献
86.
The major goal in cancer treatment is the eradication of tumor cells. Under stress conditions, normal cells undergo apoptosis; this property is fortunately conserved in some tumor cells, leading to their death as a result of chemotherapeutic and/or radiation-induced stress. Many malignant cells, however, have developed ways to subvert apoptosis, a characteristic that constitutes a major clinical problem. Gilmore et al. recently described the ability of ZD1839, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), to induce apoptosis of mammary cells that are dependent upon growth factors for survival. Furthermore, they showed that the major effector of the EGFR-targeted therapy is BAD, a widely expressed BCL-2 family member. These results are promising in light of the role of the EGFR in breast cancer development. 相似文献
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88.
Hynes BJ Luck JC Wolbrette DL Bhatta L Khan M Samii S Naccarelli GV 《Current opinion in cardiology》2003,18(1):32-38
Atrial fibrillation and heart failure are very common cardiac disorders, and both are associated with symptoms, significant morbidity, and mortality. Studies have attempted to determine the prognostic significance of atrial fibrillation in patients with heart failure. Whether atrial fibrillation is an independent risk factor of mortality remains controversial. Multiple trials using either pharmacologic or nonpharmacologic therapies in an attempt to manage atrial fibrillation have been developed. The purposes of this review are to present an overview of atrial fibrillation in patients with heart failure and to discuss the prevalence, prognostic significance, complications, mechanisms, and trials that have formed the therapies presently used. 相似文献
89.
90.
Eight consecutive pilon fractures of the finger proximal interphalangeal joint and one of the interphalangeal joint of the thumb were treated by closed reduction and application of a new dynamic external fixator. The average range of movement achieved was 12 degrees -88 degrees and there were no serious complications. The technique described offers an effective and simple solution for treatment of pilon fractures of the interphalangeal joint. 相似文献