Piperine Targets Different Drug Resistance Mechanisms in Human Ovarian Cancer Cell Lines Leading to Increased Sensitivity to Cytotoxic Drugs

Our goal was to examine the anticancer effects of piperine against the resistant human ovarian cancer cells and to explore the molecular mechanisms responsible for its anticancer effects. Our study used drug-sensitive ovarian cancer cell line W1 and its sublines resistant to paclitaxel (PAC) and topotecan (TOP). We analyzed the cytotoxic effect of piperine and cytostatic drugs using an MTT assay. The impact of piperine on protein expression was determined by immunofluorescence and Western blot. We also examined its effect on cell proliferation and migration. We noticed a different level of piperine resistance between cell lines. Piperine increases the cytotoxic effect of PAC and TOP in drug-resistant cells. We observed an increase in PTPRK expression correlated with decreased pTYR level after piperine treatment and downregulation of P-gp and BCRP expression. We also noted a decrease in COL3A1 and TGFBI expression in investigated cell lines and increased COL3A1 expression in media from W1PR2 cells. The expression of Ki67 protein and cell proliferation rate decreased after piperine treatment. Piperine markedly inhibited W1TR cell migration. Piperine can be considered a potential anticancer agent that can increase chemotherapy effectiveness in cancer patients.     

Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model

Ovarian cancer is the most common cause of gynecological cancer death. Cancer Stem Cells (CSCs) characterized by drug transporters and extracellular matrix (ECM) molecules expression are responsible for drug resistance development. The goal of our study was to examine the role of aldehyde dehydrogenase 1A1 (ALDH1A1) expression in paclitaxel (PAC) and topotecan (TOP) resistant ovarian cancer cell lines. In both cell lines, we knocked out the ALDH1A1 gene using the CRISPR/Cas9 technique. Additionally, we derived an ALDH1A1 positive TOP-resistant cell line with ALDH1A1 expression in all cells via clonal selection. The effect of ALDH1A1 gene knockout or clonal selection on the expression of ALDH1A1, drug transporters (P-gp and BCRP), and ECM (COL3A1) was determined by Q-PCR, Western blot and immunofluorescence. Using MTT assay, we compared drug resistance in two-dimensional (2D) and three-dimensional (3D) cell culture conditions. We did not observe any effect of ALDH1A1 gene knockout on MDR1/P-gp expression and drug resistance in the PAC-resistant cell line. The knockout of ALDH1A1 in the TOP-resistant cell line resulted in a moderate decrease of BCRP and COL3A1 expression and weakened TOP resistance. The clonal selection of ALDH1A1 cells resulted in very strong downregulation of BCPR and COL3A1 expression and overexpression of MDR1/P-gp. This finally resulted in decreased resistance to TOP but increased resistance to PAC. All spheroids were more resistant than cells growing as monolayers, but the resistance mechanism differs. The spheroids’ resistance may result from the presence of cell zones with different proliferation paces, the density of the spheroid, ECM expression, and drug capacity to diffuse into the spheroid.     

Displacements of Multiblock Geotechnical Structures Subjected to Seismic Excitation

A method is presented for calculations of irreversible displacements of multiblock structures subjected to seismic excitation. Use is made of the kinematic approach of limit analysis. To make the analysis tractable a hodograph representing distribution of accelerations in the structure is introduced. Distinction is made between soils conforming to the associative and nonassociative flow rules, and the importance of this distinction is demonstrated. The yield acceleration calculated for slopes comprised of soils conforming to the nonassociative flow rule is lower than that for a soil with the same strength parameters, but its deformation governed by the associative flow rule. Consequently, the displacements predicted for the former are larger. An example of a slope is demonstrated, but the method presented is applicable to other structures, such as retaining walls and embankments.     

Dynamic buckling of thin-walled viscoplastic columns

The purpose of this paper is the analysis of strain-rate effect in dynamic stability of thin-walled orthotropic column of closed rectangular cross-section, subjected to in-plane pulse loading of finite duration. For the solution the first-order shear deformation theory displacement field is employed with the Green–Lagrange strain tensor application. The effect of strain rate sensitivity is included in the framework of the viscoplasticity constitutive Perzyna model for material behaviour under high strain rate loading. The numerical results are obtained with the finite element method application. In the performed analysis the strain-rate effect influence on the dynamic buckling load is examined as well as the initial imperfections of walls, pulse shape and the orthotropy ratio are considered. The results of dynamic criteria application are compared furthermore.     

PD-L1 Inhibitors: Different Classes,Activities, and Mechanisms of Action

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.     

Hydrogel of biodegradable cellulose derivatives. I. Radiation‐induced crosslinking of CMC

Radiation crosslinking of carboxymethylcellulose (CMC) with a degree of substitution (DS) from 0.7 to 2.2 was the subject of the current investigation. CMC was irradiated in solid‐state and aqueous solutions at various irradiation doses. The DS and the concentration of the aqueous solution had a remarkable affect on the crosslinking of CMC. Irradiation of CMC, even with a high DS, 2.2 in solid state, and a low DS, 0.7 in 10% aqueous solution, resulted in degradation. However, it was found that irradiation of CMC with a relatively high DS, 1.32, led to crosslinking in a 5% aqueous solution, and 20% CMC gave the highest gel fraction. CMC with a DS of 2.2 induced higher crosslinking than that with a DS of 1.32 at lower doses with the same concentration. Hence, it was apparent that a high DS and a high concentration in an aqueous solution were favorable for high crosslinking of CMC. It is assumed that high radiation crosslinking of CMC was induced by the increased mobility of its molecules in water and by the formation of CMC radicals from the abstraction of H atoms from macromolecules in the intermediate products of water radiolysis. A preliminary biodegradation study confirmed that crosslinked CMC hydrogel can be digested by a cellulase enzyme. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 78: 278–283, 2000     

Space mapping optimization of waveguide filters using finite element and mode‐matching electromagnetic simulators

For the first time in design optimization of microwave circuits, the aggressive space mapping (SM) optimization technique is applied to automatically align electromagnetic (EM) models based on hybrid mode‐matching/network theory simulations with models based on finite‐element (FEM) simulations. SM optimization of an H‐plane resonator filter with rounded corners illustrates the advantages as well as the challenges of the approach. The parameter extraction phase of SM is given special attention. The impact of selecting responses and error functions on the convergence and uniqueness of parameter extraction is discussed. A statistical approach to parameter extraction involving 𝓁₁ and penalty concepts facilitates a key requirement by SM for uniqueness and consistency. A multipoint parameter extraction approach to sharpening the solution uniqueness and improving the SM convergence is also introduced. Once the mapping is established, the effects of manufacturing tolerances are rapidly estimated with the FEM accuracy. SM has also been successfully applied to optimize waveguide transformers using two hybrid mode‐matching/network theory models: a coarse model using very few modes and a fine model using many modes to represent discontinuities. ©1999 John Wiley & Sons, Inc. Int J RF and Microwave CAE 9: 54–70, 1999.     

Parameterization of arbitrary geometrical structures for automated electromagnetic optimization

This paper presents the theoretical foundation of the geometry capture technique. Geometry capture facilitates user‐parameterization, through graphical means, of arbitrary 2D and 3D geometrical structures. This makes it possible to optimize the shape and dimensions of geometrical objects in an automated electromagnetic design process by adjusting the user‐defined parameters subject to explicit numerical bounds and implicit geometrical constraints. ©1999 John Wiley & Sons, Inc. Int J RF and Microwave CAE 9: 73–85, 1999     

Power scaling of a fiber master oscillator power amplifier system using a coherent polarization beam combination

A new coherent polarization beam combination (CPBC) architecture was employed to combine four amplified beams and produce over 25 W of coherent output with 94% efficiency and nearly diffraction-limited beam quality. The individual beams were produced by a fiber master oscillator power amplifier system and their phases were controlled and locked using servo-controlled phase modulators. The CPBC approach relies on a coherent superposition of orthogonal polarization states and allows the combination of an arbitrary number of beams with arbitrary power ratios.