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Molecular determinants of response to PI3K/akt/mTOR and KRAS pathways inhibitors in NSCLC cell lines
Alice Iezzi Elisa Caiola Marika Colombo Mirko Marabese Massimo Broggini 《American journal of cancer research》2020,10(12):4488
Despite the impressive results obtained in the preclinical setting, all the inhibitors targeting two central cascades in cancer, the PI3K/akt/mTOR and the KRAS/MEK/ERK pathways, have shown, apart from very few exceptions, disappointing efficacy when translated to the clinic. One of the main reasons of their clinical failure seems to be the lack of a clear molecular determinant of response to these drugs. In this study, we tried to address this point by evaluating the cytotoxic activity of different inhibitors targeting the two pathways at different levels in a panel of ten NSCLC cell lines harboring alterations in PI3K, KRAS or both. We were not able to highlight a correlation between the presence of KRAS and PI3K mutations and a specific sensitivity to the different drugs used. Molecular analyses performed after equimolar treatments showed that, independently from the entity of the response, the drugs are able to modulate the activation of their targets. Interestingly, we found that p53 mutational status separates the cell lines according to their sensitivity to PI3K pathway inhibitors treatments. The alterations considered in the PI3K/akt/mTOR and in the KRAS/MEK/ERK pathways in the different NSCLC cell lines are not sufficient to drive treatment choice but rather p53 status is a potential biomarker for the activity of this class of drugs. 相似文献
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Johanne Martel-Pelletier Robert Mccollum John Dibattista Marie-Pierre Faure Jayne A. Chin Sylvie Fournier Marika Sarfati Jean-Pierre Pelletier 《Arthritis \u0026amp; Rheumatology》1992,35(5):530-540
Objective. To identify and investigate the kinetic binding properties of interleukin-1 receptors (IL-1R), and examine the abilities of the 2 IL-1 isoforms to stimulate metalloprotease synthesis, in normal and osteoarthritic (OA) chondrocytes. Methods. Receptor affinity and density were determined using radioligand binding experiments and flow cytometry. Immunocytochemical analysis and affinity cross-linking studies were performed for characterization of IL-1R. Results. While no difference in receptor affinity between normal and OA chondrocytes was noted in binding studies (kd ˜30 pM), a 2-fold increase in receptor density was found in OA chondrocytes as compared with normal chondrocytes (mean 4,069 sites/cell versus 2,315 sites/cell). Flow cytometry experiments also showed a significant increase in receptor density in OA cells, as well as an enhancement in the percentage of positive cells in diseased cartilage compared with normal. Binding data for both IL-1 isoforms revealed a single class of binding sites and receptor specificity. Factors such as IL-2, interferon-sγ, tumor necrosis factor α, and bovine insulin did not compete with IL-1β. By covalent ligand cross-linking and electrophoretic analysis, only type I IL-1R, a protein of 80 kd, was detected on chondrocytes. By immunocytochemical analysis, IL-1R was identified at the cell membrane level, in both normal and OA chondrocytes. The presence of nuclear staining was also observed, but only in OA chondrocytes. Recombinant human IL-1 (α and β) induced the secretion of stromelysin and collagenase in a dose-dependent manner. The IL-1 concentration required for half-maximal metalloprotease stimulation was 3–4 times lower in OA chondrocytes than in normal cells. Conclusion. These results indicate that OA chondrocytes have a higher sensitivity to the stimulation of metalloprotease synthesis by IL-1 than do normal cells. This could be related to the increased levels of IL-1R expressed in the OA cells. The implications of these findings with regard to the possible roles of IL-1 and IL-1R in the pathogenesis of OA are discussed. 相似文献
65.
Heat-shock proteins as activators of the innate immune system 总被引:24,自引:0,他引:24
Wallin RP Lundqvist A Moré SH von Bonin A Kiessling R Ljunggren HG 《Trends in immunology》2002,23(3):130-135
Peptides bound or linked to heat-shock proteins (HSPs) of microbial or mammalian origin have been shown to elicit potent antigen-specific immunity. Some members of the HSP family, such as hsp60, hsp70, hsp90 and gp96, are able also to stimulate cells of the innate immune system directly and thus, act as 'danger'-signaling molecules. This effect is independent of HSP-associated peptides and, in many respects, resembles the effect of lipopolysaccharide (LPS). Here, we discuss the similarities between the responses to HSPs and LPS and also, emphasize that care must be taken when working with preparations of HSPs in experimental settings and interpreting experimental data. 相似文献
66.
Kristine Irtiseva Marika Mosina Anastasija Tumilovica Vjaceslavs Lapkovskis Viktors Mironovs Jurijs Ozolins Valentina Stepanova Andrei Shishkin 《Materials》2022,15(4)
Among the various methods for collecting oil spills and oil products, including from the water surface, one of the most effective is the use of sorbents. In this work, three-component bio-based composite granular adsorbents were produced and studied for oil products’ pollution collection. A bio-based binder made of peat, devulcanised crumb rubber from used tyres, and part fly ash as cenospheres were used for absorbent production. The structure, surface morphology, porosity, mechanical properties, and sorption kinetics of the obtained samples were studied. Composite hydrophobicity and sorption capacity to oil products, such as diesel fuel (DF) and motor oil (MO), were determined. The obtained pellets are characterised by a sufficiently pronounced ability to absorb oil products such as DF. As the amount of CR in the granules increases, the diesel absorption capacity increases significantly. The case of 30-70-0 is almost three times higher than the granules from homogenised peat. The increase in q is due to two factors: the pronounced surface hydrophobicity of the samples (Θ = 152°) and a heterogeneous porous granule structure. The presence of the cenosphere in the biocomposite reduces its surface hydrophobicity while increasing the diesel absorption capacity. Relatively rapid realisation of the maximum saturation by the MO was noted. In common, the designed absorbent shows up to 0.7 g·g−1 sorption capacity for MO and up to 1.55 g·g−1 sorption capacity for diesel. A possible mechanism of DF absorption and the limiting stages of the process approximated for different kinetic models are discussed. The Weber–Morris diffusion model is used to primarily distinguish the limiting effect of the external and internal diffusion of the adsorbate on the absorption process. 相似文献
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George M. Pamboris Marika Noorkoiv Vasilios Baltzopoulos Amir A. Mohagheghi 《Scandinavian journal of medicine & science in sports》2019,29(2):200-212
The acute effects of two dynamic stretching (DS) protocols on changes in the ankle range of motion (RoM), neuromechanical, and sensorimotor properties of the plantarflexor muscle group were examined. Eighteen participants received slow (SDS) or fast dynamic stretching (FDS) on two separate days. Outcome measures were assessed pre‐ and 2 minutes post‐interventions, and included maximum dorsiflexion angle, maximum isometric torque at neutral ankle position, maximum concentric and eccentric torques, force matching capacity, joint position sense and medial gastrocnemius muscle and tendon strain. Possibly and likely small increases in dorsiflexion RoM were observed after SDS (mean ± 90% confidence intervals; 1.8 ± 1.2°) and FDS (2.1 ± 1.2°), respectively. Very likely moderate decreases in muscle strain after SDS (?38.0 ± 20.6%) and possibly small decrease after FDS (?13.6 ± 21.2%) were observed. SDS resulted in a likely beneficial small increase in tendon strain (25.3 ± 29.7%) and a likely beneficial moderate increase after FDS (41.4 ± 44.9%). Effects on strength were inconsistent. Possibly small effect on positional error after SDS (?27.1 ± 37.5%), but no clear effect after FDS was observed. Both DS protocols increased RoM, and this was more due to an increase in tendon elongation rather than the muscle. However, SDS showed greater improvement than FDS in both neuromechanical and sensorimotor performance, and hence, SDS can be recommended as part of warm‐up in sporting contexts. 相似文献
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Analysis of gamma delta V region usage in normal and diseased human intestinal biopsies and peripheral blood by polymerase chain reaction (PCR) and flow cytometry. 总被引:1,自引:1,他引:1 下载免费PDF全文