The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer ...relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.
Abstract
High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung ...cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
Summary
Peanut meal (PM), a by‐product of processing, is hard to recycle due to its poor functional properties affected by the processing environment. To increase its utilisation value, atmospheric ...cold plasma (ACP) technology was used to enhance the functional properties of PM. Results showed that the soluble protein concentration, water holding capacity, surface hydrophobicity, foaming and emulsifying properties of PM were significantly improved after ACP treatment. The changes in amino acid composition, surface element content, apparent conformation, Fourier transform infrared spectroscopy and secondary structure of the protein in PM indicated that ACP treatment promoted the interaction between components of PM by introducing oxygen‐containing groups and producing etching. The protein molecule tended to be flexible, so as to improve the overall function of PM. ACP could be an effective and promising method to improve the functional properties of agricultural by‐products for further utilisation.
Schematic diagram of the effect of cold plasma on the structure and functional properties of peanut meal.
This retrospective study was designed to explore whether neutrophil to lymphocyte ratio (NLR) is a prognostic factor in patients with coronavirus disease 2019 (COVID‐19). A cohort of patients with ...COVID‐19 admitted to the Tongren Hospital of Wuhan University from 11 January 2020 to 3 March 2020 was retrospectively analyzed. Patients with hematologic malignancy were excluded. The NLR was calculated by dividing the neutrophil count by the lymphocyte count. NLR values were measured at the time of admission. The primary outcome was all‐cause in‐hospital mortality. A multivariate logistic analysis was performed. A total of 1004 patients with COVID‐19 were included in this study. The mortality rate was 4.0% (40 cases). The median age of nonsurvivors (68 years) was significantly older than survivors (62 years). Male sex was more predominant in nonsurvival group (27; 67.5%) than in the survival group (466; 48.3%). NLR value of nonsurvival group (median: 49.06; interquartile range IQR: 25.71‐69.70) was higher than that of survival group (median: 4.11; IQR: 2.44‐8.12; P < .001). In multivariate logistic regression analysis, after adjusting for confounding factors, NLR more than 11.75 was significantly correlated with all‐cause in‐hospital mortality (odds ratio = 44.351; 95% confidence interval = 4.627‐425.088). These results suggest that the NLR at hospital admission is associated with in‐hospital mortality among patients with COVID‐19. Therefore, the NLR appears to be a significant prognostic biomarker of outcomes in critically ill patients with COVID‐19. However, further investigation is needed to validate this relationship with data collected prospectively.
Highlights
NLR is a significant prognostic biomarker of outcomes in critically ill patients with COVID‐19.
COVID‐19 is more likely to infected those elder men with chronic comorbidities.
NLR may also help in the early identification of older patients at higher risk of COVID‐19.
Close monitoring and timely intervention are needed for elderly patients with COVID‐19.
The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, ...we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in Myc
mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression.
Fe/N/C is a promising non‐Pt electrocatalyst for the oxygen reduction reaction (ORR), but its catalytic activity is considerably inferior to that of Pt in acidic medium, the environment of polymer ...electrolyte membrane fuel cells (PEMFCs). An improved Fe/N/C catalyst (denoted as Fe/N/C‐SCN) derived from Fe(SCN)3, poly‐m‐phenylenediamine, and carbon black is presented. The advantage of using Fe(SCN)3 as iron source is that the obtained catalyst has a high level of S doping and high surface area, and thus exhibits excellent ORR activity (23 A g−1 at 0.80 V) in 0.1 M H2SO4 solution. When the Fe/N/C‐SCN was applied in a PEMFC as cathode catalyst, the maximal power density could exceed 1 W cm−2.
A non‐precious Fe/N/C electrocatalyst was prepared through pyrolysis of Fe(SCN)3, poly‐m‐phenylenediamine, and carbon black. The obtained Fe/N/C catalyst has high level of S doping and high surface area, and thus exhibits excellent catalytic activity for the oxygen reduction reaction in acidic solution. A polymer electrolyte membrane fuel cell using this catalyst as the cathode can yield a maximal power density as high as 1.03 W cm−2.
Summary
This paper proposes a three‐dimensional coupled hydrothermal model for fractured rock based on the finite‐discrete element method to simulate fluid flow and heat transport. The 3D coupled ...hydrothermal model is composed of three main parts: a heat conduction model for the rock matrix, a heat transfer model for the fluid in the fractures (including heat conduction and heat convection), and a heat exchange model between the rock matrix and the fluid in the fractures. Four examples with analytical solutions are provided to verify the model. A heat exchange experiment of circulating water in a cylindrical granite sample with one fracture is simulated. The simulation results agree well with the experimental results. The effects of the fracture aperture, fluid viscosity, and pressure difference on the heat exchange between the fluid and rock are studied. Finally, an application concerned with heat transport and fluid flow in fractured rock is presented. The simulation results indicate that the 3D fully coupled hydrothermal model can capture the fluid flow and temperature evolution of rocks and fluids.
A fully coupled 3D hydro-mechanical model with real porous seepage is presented for simulating hydraulic fracturing. In this model, fluid flow in a fracture is expressed by 2D fracture seepage in the ...broken joint elements based on the Cubic law, while fluid flow in the rock matrix is represented by 3D porous seepage in the tetrahedral elements based on Darcy's law. Several problems that have closed-form solutions and a 3D fracturing problem are given to verify the model. The simulation results show that the model can capture crack initiation and propagation, and the fluid pressure evolution during hydraulic fracturing.
Efforts to tune the performance of organic/inorganic composites are hindered owing to a lack of knowledge related to the interfacial interaction mechanisms. Here we investigated the interfacial ...structure, dynamics, energetics and mechanical properties between calcium silicate hydrates (C-S-H) and polymers by molecular dynamics (MD) simulation. In this work, polyethylene glycol (PEG), polyvinyl alcohol (PVA) and polyacrylic acid (PAA) are intercalated into nanometer channel of C-S-H sheets to construct the model of polymer/C-S-H composite. In the interfacial region, the calcium ions near the surface of C-S-H play mediating role in bridging the functional groups in the polymers and oxygen in the silicate chains by forming Os-Ca-Op bond. In addition to ionic bonding, the bridging oxygen (C-O-C) in the PEG, hydroxyl (C-OH) in the PVA and carboxyl groups (-COOH) in the PAA provide plenty oxygen sites to form H-bonds with silicate hydroxyl, interlayer water and calcium hydroxyl in C-S-H substrate. The interfacial binding energy is dependent on polarity of functional groups in the polymers, the stability of the H-bond and Ca-O bond, ranking in the following order: E(PAA)> E(PVA) > E(PEG). The PVA with small number of H-bonds formed between oxygen in PVA and water molecules, resulting in increasing the mobility of confined water in the interlayer region. On the other hand, PAA and PVA, with strong polarity, can provide more number of non-bridging oxygen sites that widely distributed along the polymer chains to associate with more calcium ions and H-bonds. Furthermore, uniaxial tensile test is utilized to study the mechanical behavior of the composites. The incorporation of polymers, strengthening the H-bonds in the interfacial region and healing the defective silicate chains, can inhibit the crack growth during the loading process, which both enhance the cohesive strength and ductility of the C-S-H gel. In particular, the intercalated PAA increases the Young's modulus, tensile strength and fracture strain of C-S-H gel to 22.27%, 19.2% and 66.7%, respectively. The toughening mechanism in this organic/inorganic system can provide useful guidelines for polymer selection, design, and fabrication of C-S-H/polymer nanocomposites, and help eliminate the brittleness of cement-based materials from the genetic level.
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•A 2D fully coupled hydro-mechanical finite-discrete element model with real pore seepage is proposed.•The model can simulate the deformation and fracture of rock with an arbitrary complex fracture ...network driven by fluid pressure.•The proposed method can capture crack initiation and propagation, the interaction of hydraulic fractures and natural fractures, and the fluid pressure distribution in the rock mass.
Based on the finite-discrete element method (FDEM), a 2D fully coupled model with real pore seepage is proposed. This model can solve the problem of the deformation and fracture of porous medium driven by fluid. In this model, the fluid flow in the fracture is expressed by the cubic law, while the fluid flow in the rock matrix is characterized by Darcy's law and solved by the finite volume method. The interaction between pore seepage and fracture seepage is realized at the fracture. Three analytical solutions are presented to verify the correctness of the proposed model. The results show that the numerical solutions agree well with the analytical solutions. In addition, a hydraulic fracturing problem with a complex fracture network is studied using this model. The simulation results show that the model can capture the fracture initiation, propagation, and intersection, the interaction of natural fractures and newly generated fractures, and the evolution of fluid pressure during hydraulic fracturing. The model can be used not only to simulate hydraulic fracturing in shale gas and geothermal mining but also to solve a series of geomechanical problems related to the effect of fluid. Thus, this model has broad application prospects.
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