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Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. read more We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. link2 The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.In this work, we propose a novel approach for correcting multi-path interference (MPI) in Time-of-Flight (ToF) cameras by estimating the direct and global components of the incoming light. MPI is an error source linked to the multiple reflections of light inside a scene; each sensor pixel receives information coming from different light paths which generally leads to an overestimation of the depth. We introduce a novel deep learning approach, which estimates the structure of the time-dependent scene impulse response and from it recovers a depth image with a reduced amount of MPI. The model consists of two main blocks a predictive model that learns a compact encoded representation of the backscattering vector from the noisy input data and a fixed backscattering model which translates the encoded representation into the high dimensional light response. Experimental results on real data show the effectiveness of the proposed approach, which reaches state-of-the-art performances.RNAs transmit information from DNA to encode proteins that perform all cellular processes and regulate gene expression in multiple ways. From the time of synthesis to degradation, RNA molecules are associated with proteins called RNA-binding proteins (RBPs). The RBPs play diverse roles in many aspects of gene expression including pre-mRNA processing and post-transcriptional and translational regulation. In the last decade, the application of modern techniques to identify RNA-protein interactions with individual proteins, RNAs, and the whole transcriptome has led to the discovery of a hidden landscape of these interactions in plants. Global approaches such as RNA interactome capture (RIC) to identify proteins that bind protein-coding transcripts have led to the identification of close to 2000 putative RBPs in plants. Interestingly, many of these were found to be metabolic enzymes with no known canonical RNA-binding domains. Here, we review the methods used to analyze RNA-protein interactions in plants thus far and highlight the understanding of plant RNA-protein interactions these techniques have provided us. We also review some recent protein-centric, RNA-centric, and global approaches developed with non-plant systems and discuss their potential application to plants. We also provide an overview of results from classical studies of RNA-protein interaction in plants and discuss the significance of the increasingly evident ubiquity of RNA-protein interactions for the study of gene regulation and RNA biology in plants.The present study investigated the possibility of obtaining 3D printed composite constructs using biomaterial-based nanocomposite inks. The biopolymeric matrix consisted of methacrylated gelatin (GelMA). Several types of nanoclay were added as the inorganic component. Our aim was to investigate the influence of clay type on the rheological behavior of ink formulations and to determine the morphological and structural properties of the resulting crosslinked hydrogel-based nanomaterials. Moreover, through the inclusion of nanoclays, our goal was to improve the printability and shape fidelity of nanocomposite scaffolds. The viscosity of all ink formulations was greater in the presence of inorganic nanoparticles as shear thinning occurred with increased shear rate. Hydrogel nanocomposites presented predominantly elastic rather than viscous behavior as the materials were crosslinked which led to improved mechanical properties. The inclusion of nanoclays in the biopolymeric matrix limited hydrogel swelling due the physical barrier effect but also because of the supplementary crosslinks induced by the clay layers. The distribution of inorganic filler within the GelMA-based hydrogels led to higher porosities as a consequence of their interaction with the biopolymeric ink. The present study could be useful for the development of soft nanomaterials foreseen for the additive manufacturing of customized implants for tissue engineering.The synthesized understanding of the mechanical properties of negative Poisson's ratio (NPR) convex-concave honeycomb tubes (CCHTs) under quasi-static and dynamic compression loads is of great significance for their multifunctional applications in mechanical, aerospace, aircraft, and biomedical fields. In this paper, the quasi-static and dynamic compression tests of three kinds of 3D-printed NPR convex-concave honeycomb tubes are carried out. The sinusoidal honeycomb wall with equal mass is used to replace the cell wall structure of the conventional square honeycomb tube (CSHT). The influence of geometric morphology on the elastic modulus, peak force, energy absorption, and damage mode of the tube was discussed. The experimental results show that the NPR, peak force, failure mode, and energy absorption of CCHTs can be adjusted by changing the geometric topology of the sinusoidal element. Through the reasonable design of NPR, compared with the equal mass CSHTs, CCHTs could have the comprehensive advantages of relatively high stiffness and strength, enhanced energy absorption, and damage resistance. The results of this paper are expected to be meaningful for the optimization design of tubular structures widely used in mechanical, aerospace, vehicle, biomedical engineering, etc.The contact between solids in metal-forming operations often involves temperature-dependent viscoplasticity of the workpiece. In order to estimate the real contact area in such contexts, both the topography and the deformation behaviour should be taken into account. In this work, a deterministic approach is used to represent asperities in appropriately shaped quadratic surfaces. Such geometries are implemented in indentation finite element simulations, in which the indented material has thermo-viscoplastic properties. By creating a database of simulation data, investigations in terms of contact load and area for the specifically shaped asperities allow for an analysis on the influence of the material properties on the load-area relation of the contact. The temperature and viscoplasticity greatly define how much load is supported by a substrate due to an indenting asperity, but the description of the deformation behaviour at small values of strain and strain rate is also relevant. The pile-up and sink-in regions are very dependent on the thermo-viscoplastic conditions and material model, which consequently affect the real contact area calculation. The interplay between carried load and contact area of a full surface analysis indicates the role that different sized asperities play in the contact under different thermomechanical conditions.We sought to develop a cell-based cytotoxicity assay using human hepatocytes, which reflect the effects of drug-metabolizing enzymes on cytotoxicity. In this study, we generated luminescent human hepatoblastoma HepG2 cells using the mouse artificial chromosome vector, in which click beetle luciferase alone or luciferase and major drug-metabolizing enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are expressed, and monitored the time-dependent changes of CYP-mediated cytotoxicity expression by bioluminescence measurement. Real-time bioluminescence measurement revealed that compared with CYP-non-expressing cells, the luminescence intensity of CYP-expressing cells rapidly decreased when the cells were treated with low concentrations of aflatoxin B1 or primaquine, which exhibits cytotoxicity in the presence of CYP3A4 or CYP2D6, respectively. link3 Using kinetics data obtained by the real-time bioluminescence measurement, we estimated the time-dependent changes of 50% inhibitory concentration (IC50) values in the aflatoxin B1- and primaquine-treated cell lines. The first IC50 value was detected much earlier and at a lower concentration in primaquine-treated CYP-expressing HepG2 cells than in primaquine-treated CYP-non-expressing cells, and the decrease of IC50 values was much faster in the former than the latter. Thus, we successfully monitored time- and concentration-dependent dynamic changes of CYP-mediated cytotoxicity expression in CYP-expressing luminescent HepG2 cells by means of real-time bioluminescence measurement.

Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab.

Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly.

Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%).

mutations were detected in archival tumour of six participants (50%).

hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the

gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling.

Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT 02705859.

Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT 02705859.