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71.
I Sayers J Hawley CE Stewart CK Billington A Henry JR Leighton-Davies SJ Charlton IP Hall 《British journal of pharmacology》2009,158(1):277-286
Background and purpose:
Indacaterol is a novel β2-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human β2-adrenoceptor and in human primary airway smooth muscle (ASM) cells.Experimental approach:
Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human β2-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3′,5′-cyclic-monophosphate production was used as an outcome measure.Key results:
In both the low- and high-expression recombinant GEVT ‘wild type’ cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the β2-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3′,5′-cyclic-monophosphate in response to β2-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol.Conclusions and implications:
These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of β2-adrenoceptors. 相似文献72.
CE Vitor CP Figueiredo DB Hara AF Bento TL Mazzuco JB Calixto 《British journal of pharmacology》2009,157(6):1034-1044
Background and purpose:
α- and β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α- and β-amyrin (α,β-amyrin) on an experimental model of colitis in mice.Experimental approach:
Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with α,β-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-κB (NF-κB) and phospho-cyclic AMP response element-binding protein (CREB)Key results:
TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,β-amyrin (3 mg·kg−1, i.p.) or dexamethasone (1 mg·kg−1, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. α,β-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1β levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-κB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,β-amyrin and dexamethasone.Conclusions and implications:
Systemic administration of α,β-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-κB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,β-amyrin to control inflammatory responses in bowel disease. 相似文献73.
74.
Vincent Vandecaveye Frederik De Keyzer Piet Dirix Maarten Lambrecht Sandra Nuyts Robert Hermans 《Neuroradiology》2010,52(9):773-784
In the head and neck, squamous cell carcinoma is one of the most common tumour types. Currently, the primary imaging modalities
for initial locoregional staging are computed tomography and—to a lesser extent—magnetic resonance imaging, whilst [18F]fluorodeoxyglucose (FDG) positron emission tomography has additional value in the detection of subcentimetric metastatic
lymph nodes and of tumour recurrence after chemoradiotherapy (CRT). However, dependency on the morphological and size-related
criteria of anatomical imaging and the limited spatial resolution and FDG avidity of inflammation in metabolic imaging may
reduce diagnostic accuracy in the head and neck. Diffusion-weighted magnetic resonance imaging (DWI) is a noninvasive imaging
technique that measures the differences in water mobility in different tissue microstructures. Water mobility is likely influenced
by cell size, density, and cellular membrane integrity and is quantified by means of the apparent diffusion coefficient. As
such, the technique is able to differentiate tumoural tissue from normal tissue, inflammatory tissue and necrosis. In this
article, we examine the use of DWI in head and neck cancer, focussing on technique optimization and image interpretation.
Afterwards, the value of DWI will be outlined for clinical questions regarding nodal staging, lesion characterization, differentiation
of post-CRT tumour recurrence from necrosis and inflammation, and predictive imaging towards treatment outcome. The possible
consequences of adding DWI towards therapeutic management are outlined. 相似文献
75.
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77.
C. N. Sternberg W. W. ten Bokkel Huinink J. F. Smyth V. Bruntsch L. Y. Dirix N. A. Pavlidis H. Franklin S. Wanders N. Le Bail S. B. Kaye 《British journal of cancer》1994,70(2):376-379
Docetaxel (Taxotere), a new semisynthetic taxoid, is a potentially important chemotherapeutic agent for the treatment of cancer. Forty patients with bidimensionally measurable advanced adenocarcinoma of the colon were treated with docetaxel 100 mg m-2 every 3 weeks as a 1 h infusion without routine premedication. Thirty-nine patients were eligible: 23 males and 16 females. Median age was 60 years (range 41-75) and WHO performance status 1 (0-2). Prior adjuvant chemotherapy was performed in four patients and prior radiotherapy in nine patients. Bidimensionally measurable disease sites included: liver in 26 patients, lymph nodes and abdominal/peritoneal masses in 13, lung/mediastinal masses in ten and subcutaneous nodes in four. The median number of cycles given was 2 (range 1-15). Thirty-three patients were evaluable for response. One patient (3%) achieved a complete response and two (6%) (95% confidence limits 0-14%) a partial response. Side-effects were similar to those observed in other studies. Docetaxel, given at this dosage and schedule, has minimal activity in the treatment of colorectal carcinoma. 相似文献
78.
P. B. Vermeulen D. Verhoeven H. Fierens G. Hubens G. Goovaerts E. Van Marck E. A. De Bruijn A. T. Van Oosterom L. Y. Dirix 《British journal of cancer》1995,71(2):340-343
The vascularisation of human primary colorectal carcinomas was studied immunohistochemically using the endothelial cell markers CD31 and factor VIII-related antigen. Tumour sections were systematically scanned at a magnification of x 100 to find areas of intense neovascularisation. Microvessel counts within these vascular ''hotspots'' were performed at magnification x 250. Regions in which tumour cords were surrounded by a collagen IV-positive basement membrane were compared with those in which this was absent and with normal mucosa. CD31 appeared to be a more sensitive marker for endothelial cells than factor VIII-related antigen (mean 185 +/- 59 and 120 +/- 38 microvessels mm-2). Within individual tumour sections microvessel counts in vascular hotspots with highest vessel density correlated significantly with microvessel counts in vascular hotspots with second highest vessel density (P < 0.01). Microvessel counts in tumour areas where collagen IV-positive basement membrane were absent exceeded those in areas where it was present (factor of 1.7) and those in normal mucosa (factor of 1.6). The differences in vessel density between individual tumours and the low variability in vessel density within individual tumours using this quantification technique allow us to investigate the prognostic value of vessel density in areas of intense neovascularisation in human primary colorectal carcinomas. 相似文献
79.
Microvessel density, endothelial cell proliferation and tumour cell proliferation in human colorectal adenocarcinomas* 总被引:4,自引:0,他引:4
Vermeulen P. B.; Verhoeven D.; Hubens G.; Van Marck E.; Goovaerts G.; Huyghe M.; De Bruijn E. A.; Van Oosterom A. T.; Dirix L. Y. 《Annals of oncology》1995,6(1):59-64
BACKGROUND: Thymidine incorporation studies performed in animal rumour models,revealed major differences in endothelial cell proliferationwhen tumour tissue was compared with normal tissue. The fractionof proliferating endothelial cells is reported to be increasedby a factor of 30 to 40 in tumour tissue. PATIENTS AND METHODS: To make it possible to analyze the endothelial cell proliferationin human tumours, an immuno-histochemical double staining techniquecomprising CD31, an endothelial cell marker, and Ki-67, a proliferationmarker, was developed. Endothelial cell proliferation was analysedin 21 primary human colorectal adenocarcinomas and in the adjacentmucosa. RESULTS: Proliferating endothelial cells were found throughout the entirecarcinoma. The mean overall endothelial cell labeling index(ECU) was 9.9% (range, 5.418.0), and the labeling indexof endothelial cells in areas of intense neovascularisationwas even higher. Mean ECLI in the vascular hot spots was 21.0%(range, 6.835.0), and the mean tumour cell labeling index(TCLI) in the maximally Ki-67 immunostained areas was 78.3%(range 47.089.7). In 14 of 21 carcinomas, these areaswere predominantly found at the luminal margin of the tumour,as were the vascular hot spots. A significant positive correlationwas found between tumour vascularity, measured in the vascularhot spots, and tumour cell proliferation, measured in the maximallyKi-67 immu-nostained areas (p < 0.05). To analyse this relationin more detail, microvessel density (MVD), TCLI and ECLI weredetermined per x400 microscopic field by scanning in sequencefrom the luminal tumour margin to the invasive tumour base.In all tumours, the pattern of the MVD per x 400 field, fromthe luminal margin to the tumour base, was similar to that ofthe TCLI and ECLI. CONCLUSIONS: These findings confirm that the fraction of cycling endothelialcells is higher in human colorectal carcinoma than in the adjacentmucosa which suggests that endothelial cells are proliferatingin most of the individual capillaries in tumour tissue. Regionaldifferences in MVD correlate with differences in tumour cellproliferation in these tumours. angiogenesis, colorectal tumours, endothelial cell proliferation, tumour cell proliferation, microvessel density 相似文献
80.