Androgen receptor (AR) is frequently over-expressed and plays a critical role in the growth and progression of human prostate cancer. The therapy attempting to target AR signalling was established in ...decades ago but the treatment of prostate cancer is far from being satisfactory. The assignable cause is that our understanding of the mechanism of AR regulation and re-activation remains incomplete. Increasing evidence suggests that deubiquitinases are involved in the regulation of cancer development and progression but the specific underlying mechanism often is not elucidated. In the current study, we have identified ubiquitin-specific protease 14 (USP14) as a novel regulator of AR, inhibiting the degradation of AR via deubiquitinating this oncoprotein in the androgen-responsive prostate cancer cells. We found that (i) USP14 could bind to AR, and additionally, both genetic and pharmacological inhibition of USP14 accelerated the ubiquitination and degradation of AR; (ii) downregulation or inhibition of USP14 suppressed cell proliferation and colony formation of LNcap cells and, conversely, overexpression of USP14 promoted the proliferation; and (iii) reduction or inhibition of USP14 induced G0/G1 phase arrest in LNcap prostate cancer cells. Hence, we conclude that USP14 promotes prostate cancer progression likely through stabilization of AR, suggesting that USP14 could be a promising therapeutic target for prostate cancer.
•Graphene foams were fabricated by the chemical reduction of graphene oxide with l-ascorbic acid.•Comparison of the structure and MA properties of different graphene foams is presented.•Bandwidth ...(<−5 dB) can cover the whole Ku, X and half the Xc band with 3 wt% of graphene foam.•Comparison of properties of graphene foams and graphene powders is presented.
The graphene foam (GF) was prepared by reducing graphene oxide (GO) with l-ascorbic acid (l-AA), followed by freeze-drying. Through changing the initial concentration of GO solution, several GFs with different microstructure could be obtained. The higher the initial concentration of GO, the more obviously the layered stacking of graphene sheet. According to the study, GFs with honeycomb microstructure possessed excellent performance on microwave absorption (MA). When the concentration of GO was 2 mg/ml, the resulting sample GF2 showed the best MA properties. When the thickness of the sample GF2 was 2 mm and the mass content of GF2 in the sample was only 3 wt%, the absolute value of the maximum reflection loss (|RLmax|) of GF2 could reach 41.0 dB at 16.2 GHz. And 11 GHz bandwidth of RL less than −5 dB, covering the whole Ku, X and half the Xc band, was achieved by GF2 with the thickness of 3 mm.
Androgen receptor (AR) is expressed in approximately 70% of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously ...reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer. The current study aims to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with USP14 inhibition on breast cancer cells.
The combining effects of enzalutamide and USP14 inhibition on breast cancer cell proliferation and apoptosis and associated cell signaling were evaluated in vitro and in vivo.
USP14 inhibition via administration of IU1 or USP14-specific siRNA/shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo. Additionally, the combination of enzalutamide with USP14 inhibition/knockdown induced significant downregulation of AR proteins and suppression of AR-related signaling pathways, including Wnt/β-catenin and PI3K/AKT pathways. Moreover, AKT inhibition via MK2206 increased the antiproliferative and proapoptotic effects of enzalutamide+IU1 combined treatment.
Collectively, our data suggest that USP14 inhibition in combination with enzalutamide represents a potentially new therapeutic strategy for breast cancer.
MoS2-carbon composites which with different morphologies were synthesized by hydrothermal method and tested with respect to their application in hydrogen evolution reaction (HER). Their performances ...were compared to evaluate how the morphology influence HER. The obtained results showed that the composite containing amorphous MoS2 showed higher activity than composite which contains crystalline MoS2. The catalytic activity of composite was highly correlated to its active surface area which was controlled by the morphology. In addition, compared with composite which contains amorphous MoS2, the composite containing crystalline MoS2 showed higher durability in the long-term operation. However, in acidic and alkaline environments, the stability of composite containing amorphous MoS2 is better than which containing crystalline MoS2. The impedance measurements suggested that the high catalytic activity of the composite stems from the synergistic effect of MoS2 and carbon materials. The enhanced understanding of these highly active hydrogen evolution catalysts can facilitate the development of economical electrochemical hydrogen production systems.
•MoS2-carbon composites with different morphologies were successfully synthesized.•These composites have excellent catalytic performance for HER.•The catalytic activity and mechanism for HER were researched in great detail.
Constitutive activation of tyrosine kinase Bcr-Abl is the leading cause of the development and progression of chronic myeloid leukemia (CML). Currently, the application of tyrosine kinase inhibitors ...(TKIs) targeting the Bcr-Abl is the primary therapy for CML patients. However, acquired resistance to TKIs that develops overtime in the long-term administration renders TKIs ineffective to patients with advanced CML. Therefore, increasing studies focus on the amplified expression or activation of Bcr-Abl which is proposed to contribute to the advanced phase. Here, we show that S-phase kinase-associated protein 2 (SKP2) acts as a co-regulator of Bcr-Abl by mediating its K63-linked ubiquitination and activation. Further investigations show that USP10 as a novel deubiquitinase of SKP2 amplifies the activation of Bcr-Abl via mediating deubiquitination and stabilization of SKP2 in CML cells. Moreover, inhibition of USP10 significantly suppresses the proliferation of both imatinib-sensitive and imatinib-resistant CML cells, which likely depends on SKP2 status. This findings are confirmed in primary CML cells because these cells are over-expressed with USP10 and SKP2 and are sensitive to a USP10 inhibitor. Taken together, the present study not only provides a novel insight into the amplified activation of Bcr-Abl in CML, but also demonstrates that targeting the USP10/SKP2/Bcr-Abl axis is a potential strategy to overcome imatinib resistance in CML patients.
The deformation characteristics of subsidence and movement induced by mining under thin bedrocks and thick unconsolidated layers are researched using field measurement and the prediction method of ...artificial neural networks (ANN). Firstly, the occurrence characteristics of thin bedrock and thick unconsolidated layers were analyzed in a research coal field. Based on the measured data, the characteristics of ground movement show that the surface subsidence deformation of mining under thin bedrock is more intensive than that of mining under normal thickness bedrock. Such is evident through the settlement time concentrating, the maximum surface subsidence being greater than the thickness of coal seam, the distribution of ground movement and deformation being concentrated, the range extension being wide, the active period being intensive and concentrated, the surface damage being very serious, and the crack development being significant. A quantitative prediction method is made on mining subsidence under thin bedrocks and thick unconsolidated layers by means of ANN. The improved neural network was used for modeling and predicting the mining subsidence. The ANN output can reflect the change trend of ground movement and deformation. The forecasting results are in good agreement with the real observation results.
► Meaning of the term “thin bedrock” and “thick unconsolidated layer” is defined. ► Surface movement characteristics are researched by field measurement. ► Relationship between subsidence and influence factors is established by ANN. ► Forecasting results are in good agreement with the real results.
Abstract
The development of trench-arc-backarc (TABA) systems is uniquely associated with modern-style plate tectonics on Earth. The Qilian orogenic belt in NW China records the evolution history of ...the Proto-Tethys Ocean at the transition time from the Proterozoic to Phanerozoic. This paper presents systematic studies of petrography, U–Pb chronology and geochemistry on various rocks from a middle-ocean ridge (MOR)-type ophiolite belt, active continental margin and back-arc basin in the Qilian orogenic belt to address the development of a modern-style TABA system. Arc magmas include felsic intrusions with ages of 531 to 477 Ma and felsic-mafic arc volcanic rocks with ages of 506 to 439 Ma, showing distinctive features of typical magmatic rocks formed at an Andean-type continental margin. The back-arc basin is recorded by a 490- to 448-Ma suprasubduction zone (SSZ)-type ophiolite with boninite, and Silurian turbidite flysch formation. We establish a three-stage tectonic history from the initiation of subduction to the formation of a mature Japan-Sea-type back-arc basin at the active continental margin in the Early Paleozoic era. (1) Northward subduction of Proto-Tethys Ocean initiated and the Andean-type continental arc developed at ~530 to 500 Ma with continual crustal thickening; (2) a tectonic transition occurred from an Andean-type active continental margin to a West Pacific-type active continental margin at ~500 to 490 Ma with rapid thinning of crust to ~35 km; and (3) mature ocean basins and back-arc-basin (BAB) ophiolites were formed in the back-arc extensional environment at ~490 to 450 Ma.
Metal oxide semiconductor hetero- and homojunctions are commonly constructed to improve the performance of hydrogen sensors at room temperature. In this study, a simple two-step hydrothermal method ...was employed to prepare TiO2 films with homojunctions of rutile and anatase phases (denoted as TiO2-R/A). Then, the microstructure of anatase-phase TiO2 was altered by controlling the amount of hydrochloric acid to realize a more favorable porous structure for charge transport and a larger surface area for contact with H2. The sensor used a Pt interdigital electrode. At an optimal HCl dosage (25 mL), anatase-phase TiO2 uniformly covered rutile-phase TiO2 nanorods, resulting in a greater response to H2 at 2500 ppm compared with that of a rutile TiO2 nanorod sensor by a factor of 1153. The response time was 21 s, mainly because the homojunction formed by the TiO2 rutile and anatase phases increased the synergistic effect of the charge transfer and potential barrier between the two phases, resulting in the formation of more superoxide (O2−) free radicals on the surface. Furthermore, the porous structure increased the surface area for H2 adsorption. The TiO2-R/A-based sensor exhibited high selectivity, long-term stability, and a fast response. This study provides new insights into the design of commercially competitive hydrogen sensors.
Background. The prognosis of Infective endocarditis (IE) is poor, and we conducted this investigation to evaluate the worth of admission lymphocyte-to-white blood cell ratio (LWR) for prediction of ...short-term outcome in IE patients. Methods. We retrospectively assessed the medical records of 147 IE patients from January 2017 to December 2019. Patients were divided into the survivor group and nonsurvivor group. Univariate and multivariate analyses were applied to estimate the independent factors contribution to in-hospital death, and receiver-operator characteristic (ROC) curve was utilized to check the performance. Results. The levels of LWR (0.17 ± 0.08 vs. 0.10 ± 0.06) were significantly increased among the survivor group compared with the nonsurvivor group (P = 0.001). Multivariate analysis displayed that LWR (hazard ratio (HR): 1.755, 1.304–2.362, P < 0.001) was not interfered by other confounding factors for early death. Moreover, ROC analysis suggested that LWR (cutoff value = 0.10) performed the best among assessed indexes for the forecast of primary outcome (area under curve (AUC) = 0.750, 95% confidence interval (CI) = 0.634–0.867, P < 0.001, sensitivity = 70.0%, specificity = 76.4%), and the proportion of in-hospital mortality was remarkably inferior in patients with LWR > 0.10 than in those with LWR ≤ 0.10. (5.83% vs. 31.8%, P < 0.001). Conclusions. LMR is an independent, simple, universal, inexpensive, and reliable prognostic parameter to identify high-risk IE patients for in-hospital mortality.
Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, ...the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.
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