The monotonic and cyclic behavior of commercially pure tantalum has been investigated at room temperature, in order to capture and understand the occurrence of the anomalous yield point phenomenon. ...Interrupted tests have been performed, with strain reversals (tensile or compressive loading) after an aging period. The stress drop is attributed to the interactions between dislocations and solute atoms (oxygen) and its macroscopic occurrence is not systematically observed. InfraRed Thermography (IRT) measurements supported by Scanning Electron Microscopy (SEM) pictures of the polished gauge length of a specimen during an interrupted tensile test reveal the nucleation and propagation of a strain localization band.
The KEMC (Kubin–Estrin–McCormick) phenomenological model accounting for strain aging has been identified for several loadings and strain rates at room temperature. Simulations on full specimen using the KEMC model do not show strain localization, because of the competition between viscosity and strain localization. However, a slight misalignment of the sample can promote strain localization.
This work is related to life prediction of high-pressure single crystal turbine blades. Stress and strain fields are first analysed at the tip of a static crack subjected to creep-fatigue loading, ...assuming an elasto-viscoplastic single crystal behaviour model. Local ratchetting effects are observed, depending on the distance from the crack-tip. Creep-fatigue loadings are compared with pure fatigue and pure creep loadings. The significant differences are pointed out, especially stress relaxation and amount of plastic slip. These results will be useful for the development of a new life prediction tool, based on local approach to fracture.
Three-dimensional Finite Element simulations of mode I crack tip fields in Compact Tension specimens are presented for elastic ideally-plastic F.C.C. single crystals. The computations are carried out ...within the framework of classical continuum crystal plasticity for three crack orientations: (001)110,(110)001 and (001)100. The attention is drawn on the strong differences between the plastic strain field obtained at the free surface and in the mid-section of the specimens. The results are compared, on the one hand, to analytical solutions for stationary cracks in single crystals under plane strain conditions and, on the other hand, to experimental tests on a single crystal nickel-based superalloy at room temperature. For this material, both octahedral and cube slip must be taken into account. A good agreement between experimental observations and numerical results is found in the structure of the strain localization bands observed at the free surface of (110)001 cracked specimens. In particular, the evidence of kink banding near the crack tip is provided, confirmed by EBSD orientation mapping. The measured values of local lattice rotation are in agreement with the Finite Element prediction.
Kinematic hardening plays an important role in strain localization phenomena under cycling loading. A single crystal constitutive model including non-linear kinematic hardening is presented. Using a ...heterogeneous distribution of kinematic hardening variable in a single crystal plate, a continuum model for the formation of intrusion/extrusion is proposed based on FE simulation. The attention is focused on ratchetting phenomena taking place in the localization band. A second example of strain localization is shown by the strain field at the crack tip in single crystals. 2D and 3D finite element computations of the crack tip field in a CT specimen are provided. They are compared to analytical solutions. The 3D computations show that slip activity is different in the bulk or at the surface of the specimen. The evolution of the crack tip field subjected to cyclic loading is investigated. Ratchetting phenomena are shown to take place in some of the localization bands.
Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor ...positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer.
Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt ...to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.
Breast cancer (BC) is the most common cancer among women worldwide. More than 70% of BC cases express estrogen receptor alpha (ERα), a central transcription factor that stimulates the proliferation ...of breast cancer cells, usually in the presence of estrogen. While most cases of ER-positive BC initially respond to antiestrogen therapies, a high percentage of cases develop resistance to treatment over time. The recent discovery of mutated forms of ERα that result in constitutively active forms of the receptor in the metastatic-resistance stage of BC has provided a strong rationale for the development of new antiestrogens. These molecules targeting clinically relevant ERα mutants and a combination with other pharmacological inhibitors of specific pathways may constitute alternative treatments to improve clinical practice in the fight against metastatic-resistant ER-positive BC. In this review, we summarize the latest advances regarding the particular involvement of point mutations of ERα in endocrine resistance. We also discuss the involvement of synonymous ERα mutations with respect to co-translational folding of the receptor and ribosome biogenesis in breast carcinogenesis.
A reliable determination of the onset of void coalescence is critical to the modelling of ductile fracture. Numerical models have been developed but rely mostly on analyses on single defect cells, ...thus underestimating the interaction between voids. This study aims to provide the first extensive analysis of the response of microstructures with random distributions of voids to various loading conditions and to characterize the dispersion of the results as a consequence of the randomness of the void distribution. Cells embedding a random distribution of identical spherical voids are generated within an elastoplastic matrix and subjected to a macroscopic loading with constant stress triaxiality and Lode parameter under periodic boundary conditions in finite element simulations. The failure of the cell is determined by a new indicator based on the loss of full rankedness of the average deformation gradient rate. It is shown that the strain field developing in random microstructures and the one in unit cells feature different dependencies on the Lode parameter
L
owing to different failure modes. Depending on
L
, the cell may fail in extension (coalescence) or in shear. Moreover the random void populations lead to a significant dispersion of failure strain, which is present even in simulations with high numbers of voids.
The teleost fish are thought to lack the mineralocorticoid hormone aldosterone but possess mineralocorticoid receptor (MR) homologs. Here we describe the characterization of two rainbow trout ...(Oncorhynchus mykiss) MRs, called rtMRa and rtMRb. The open reading frame of rtMRa cDNA encoded a protein of 1041 amino acids. The rtMRb predicted protein sequence is similar, differing in only 10 amino acids in the nonconserved A/B domain and lacking a three-amino acid insertion between the two zinc fingers of the C domain. Expression of rtMR mRNA (sum of both forms), measured in juvenile trout by real-time RT-PCR, shows that the transcripts are ubiquitous. Expression was significantly higher in brain than the other tissues studied (eye, trunk kidney, head kidney, gut, gills, liver, spleen, ovary, heart, white muscle, skin). Hormonal stimulation of receptor transactivation activity was studied in COS-7 cells transiently cotransfected with receptor cDNA and a mouse mammary tumor virus-luciferase reporter. The mineralocorticoids 11-deoxycorticosterone and aldosterone were more potent enhancers of rtMRa transcriptional activity (EC50 = 1.6 ± 0.5 × 10−10 and 1.1 ± 0.4 × 10−10 m, respectively) than the glucocorticoids cortisol and 11-deoxycortisol (EC50 = 1.1 ± 0.3 × 10−9 and 3.7 ± 1.9 × 10−9 m, respectively). A similar response was observed in transactivation assays with rtMRb. These results are discussed in the view of reported circulating levels of corticosteroids in trout.
Approximately 80% of breast cancer (BC) cases express the estrogen receptor (ER), and 30-40% of these cases acquire resistance to endocrine therapies over time. Hyperactivation of Akt is one of the ...mechanisms by which endocrine resistance is acquired. Apigenin (Api), a flavone found in several plant foods, has shown beneficial effects in cancer and chronic diseases. Here, we studied the therapeutic potential of Api in the treatment of ER-positive, endocrine therapy-resistant BC. To achieve this objective, we stably overexpressed the constitutively active form of the Akt protein in MCF-7 cells (named the MCF-7/Akt clone). The proliferation of MCF-7/Akt cells is partially independent of estradiol (E2) and exhibits an incomplete response to the anti-estrogen agent 4-hydroxytamoxifen, demonstrating the resistance of these cells to hormone therapy. Api exerts an antiproliferative effect on the MCF-7/Akt clone. Api inhibits the proliferative effect of E2 by inducing G2/M phase cell cycle arrest and apoptosis. Importantly, Api inhibits the Akt/FOXM1 signaling pathway by decreasing the expression of FOXM1, a key transcription factor involved in the cell cycle. Api also alters the expression of genes regulated by FOXM1, including cell cycle-related genes, particularly in the MCF-7/Akt clone. Together, our results strengthen the therapeutic potential of Api for the treatment of endocrine-resistant BC.
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