Search Results (14,654)

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic disease posing significant therapeutic challenges. While anti-EGFR therapy has improved outcomes for patients with RAS and BRAF wild-type tumors, resistance remains a major hurdle, limiting treatment efficacy. The concept of negative hyperselection has emerged as a refinement of molecular profiling, identifying additional genomic alterations—such as HER2 and MET amplificationsand MAP2K1 mutations—that predict resistance to anti-EGFR agents. Studies incorporating these expanded assessments have demonstrated that nearly half of patients with RAS/BRAF wild-type tumors harbor alternative resistance biomarkers, underscoring the need for expanded selection criteria. Liquid biopsies, particularly circulating tumor DNA (ctDNA) analysis, have revolutionized precision oncology by providing a minimally invasive, real-time assessment of tumor dynamics. ctDNA-based hyperselection enables the detection of resistance-associated alterations, guiding treatment decisions with greater accuracy than conventional tissue biopsies. Recent trials support the predictive value of ctDNA-defined negative hyperselection, revealing superior outcomes for patients stratified through liquid biopsy. This narrative review explores the evolving role of molecular hyperselection in first-line anti-EGFR therapy, emphasizing the integration of ctDNA to refine patient selection, enhance therapeutic efficacy, and pave the way for personalized treatment strategies in metastatic CRC. Full article

Rheumatoid arthritis and periodontitis are comorbidities that share mutual pathways. IL-1β is a pro-inflammatory cytokine that plays a crucial role in both diseases. One of the treatment options for rheumatoid arthritis is the use of an IL-1 receptor antagonist (IL-1RA) such as anakinra. Anakinra tempers the disease by decreasing bone resorption and it could possibly stimulate bone formation. Here, we investigate the effect of anakinra in a periodontal disease setting on osteoclastogenesis by co-culturing periodontal ligament fibroblasts (PDLFs) and peripheral blood mononuclear cells (PBMCs) that contain monocytes, a source of osteoclast precursors, as well as by culturing PBMCs alone. The effect of anakinra on PDLF-mediated osteogenesis was studied under mineralization conditions. To mimic a chronic infection such as that prevalent in periodontitis, 10 ng/mL of IL-1β was added either alone or with 10 µg/mL of anakinra. Osteoclastogenesis experiments were performed using co-cultures of PDLF and PBMCs and PBMCs only. Osteoclastogenesis was determined through the formation of multinucleated cells in co-cultures of PDLF and PBMCs, as well as PBMCs alone, at day 21, and gene expression through qPCR at day 14. Osteogenesis was determined by measuring alkaline phosphatase activity (ALP) per cell at day 14. Anakinra is effective in downregulating IL-1β mediated leukocyte clustering and osteoclastogenesis in the co-cultures of both PDLF and PMBCs and PBMCs alone. Gene expression analysis shows that IL-1β increases the expression of the osteoclastogenic marker RANKL and its own expression. This higher expression of IL-1β at the RNA level is reduced by anakinra. Moreover, IL-1β downregulates OPG expression, which is upregulated by anakinra. No effects of anakinra on osteogenesis were seen. Clinically, these findings suggest that anakinra could have a beneficial systemic effect on periodontal breakdown in rheumatoid arthritis patients taking anakinra. Full article

Background: Histone deacetylases (HDACs) are enzymes that deacetylate histone proteins, impacting the transcriptional repression and activation of cancer-associated genes such as P53 and Ras. The overexpression of HDACs in breast cancer (BC) underscores their significance as therapeutic targets for modulating gene expression through epigenetic regulation. Methods: In this study, a novel series of SAHA (suberoylanilide hydroxamic acid) analogs were designed using an in silico ligand-based strategy. These analogs were then synthesized and evaluated for their HDAC-inhibitory capacity as well as their antiproliferative capacity on breast cancer cells. These compounds retained an aliphatic LINKER, mimicking the natural substrate acetyl-lysine, while differing from the hydroxamic fragment present in SAHA. Results: The synthesized compounds exhibited HDAC inhibitory activity, suggesting potential for binding to these pharmacological targets. Compounds 5b, 6a, and 6b were identified as promising candidates in the evaluation on breast cancer cell lines MCF-7 and MDA-MB-231 at 72 h. Specifically, compound 6b, which contains an N-trifluoroacetyl group as a zinc-binding group (ZBG), demonstrated an IC₅₀ of 76.7 µM in the MDA-MB-231 cell line and 45.7 µM in the MCF-7 cell line. In the non-tumorigenic cell line, the compound exhibited an IC₅₀ of 154.6 µM. Conversely, SAHA exhibited an almost negligible safety margin with regard to its cytotoxic activity when compared to breast cancer cells and healthy cells (MCF-10A). This observation underscores the elevated toxicity exhibited by hydroxamic acid-derived molecules. Conclusions: The bioisosteric modification of ZBG by N-trifluoroacetyl in 6a and 6b demonstrated favorable cytotoxic activity, exhibiting a higher safety margin. This study underscores the challenge of identifying novel ZBGs to replace hydroxamic acid in the development of HDAC inhibitors, with the objective of enhancing their physicochemical and toxicological profile for utilization in BC treatment. Full article

Abstract: Background: Within the solar ultraviolet (UV) spectrum, ultraviolet A rays (UVA, 320–400 nm), although less energetic than ultraviolet B rays (UVB, 280–320 nm), constitute at least 95% of solar UV radiation that penetrates deep into the skin The UV rays are associated with both epidermal and dermal damage resulting from the generation of reactive oxygen species (ROS). Among them, the longest UVA wavelengths (UVA1, 340–400 nm) can represent up to 75% of the total UV energy. Therefore, UVA radiation is linked to various acute and chronic conditions, including increased skin pigmentation and photoaging. Despite many advances in the skin photoprotection category, there is still a growing demand for natural daily photoprotection active ingredients that offer broad protection against skin damage caused by UVA exposure. In our quest to discover new, disruptive, next generation of photoprotective ingredients, we were drawn to pomegranate, based on its diverse polyphenolic profile. We investigated the pericarp of the fruit, so far considered as byproducts of the pomegranate supply chain, to design a novel patented extract “POMAOX” with a desired spectrum of phenolic components comprising of αβ-punicalagins, αβ-punicalins and ellagic acid. Methods: Antioxidant properties of POMAOX were measured using in-tubo standard tests capable of revealing a battery of radical oxygen species (ROS): peroxyl radical (ORAC), singlet oxygen (SOAC), superoxide anion (SORAC), peroxynitrite (NORAC), and hydroxyl radical (HORAC). In vitro, confirmation of antioxidant properties was first performed by evaluating protection against UVA-induced lipid peroxidation in human dermal fibroblasts (HDF), via the release of 8 iso-prostanes. The protection offered by POMAOX was further validated in a 3D in vitro reconstructed T-Skin^TM model, by analyzing tissue viability/morphology and measuring the release of Matrix Metallopeptidase 1 (MMP-1) & pro-inflammatory mediators (IL-1α, IL-1ra, IL-6, IL-8, GM-CSF, and TNF-α) after UVA1 exposure. Results: POMAOX displayed strong antioxidant activity against peroxynitrite (NORAC) at 1.0–3.0 ppm, comparable to the reference vitaminC, as well as singlet oxygen (SOAC) at 220 ppm, and superoxide radicals with a SORAC value of 500 ppm. Additionally, POMAOX demonstrated strong photoprotection benefit at 0.001% concentration, offering up to 74% protection against UVA-induced lipid peroxidation on HDF, in a similar range as the positive reference, Vitamin E at 0.002% (50 µM), and with higher efficacy than ellagic acid alone at 5 µM. Moreover, our pomegranate-derived extract delivered photoprotection at 0.001%, mitigating dermal damages induced by UVA1, through inhibition of MMP-1 and significant inhibition of pro-inflammatory mediators release (including IL-1α, IL-1ra, IL-6, IL-8, GM-CSF, and TNFα) on an in vitro reconstructed full-thickness human skin model with a similar level of protection to that of Vitamin C tested at 0.035% (200 µM). Conclusions: Overall, the novel pomegranate-derived extract “POMAOX” significantly reduced the impact of UVA on human skin, due to its broad-spectrum antioxidant profile. These findings suggest that POMAOX could offer enhanced protection against the detrimental effects of UV exposure, addressing the growing consumer demand for strong photoprotection with skincare benefits. Full article

Cyanobacteria isolated from extreme habitats are promising in biotechnology due to their high adaptability to unfavorable environments and their specific natural products. Therefore, these organisms are stored under a reduced light supply in multiple collections worldwide. However, it remains unclear whether these strains maintain constitutively expressed primary metabolome features associated with their unique adaptations. To address this question, a comparative analysis of primary metabolomes of twelve cyanobacterial strains from diverse extreme habitats was performed by a combined GC-MS/LC-MS approach. The results revealed that all these cyanobacterial strains exhibited clear differences in their patterns of primary metabolites. These metabolic differences were more pronounced for the strains originating from ecologically different extreme environments. Extremotolerant terrestrial and freshwater strains contained lower strain-specifically accumulated primary metabolites than extremophilic species from habitats with high salinity and alkalinity. The latter group of strains was highly diverse in amounts of specific primary metabolites. This might indicate essentially different molecular mechanisms and metabolic pathways behind the survival of the microorganisms in saline and alkaline environments. The identified strain-specific metabolites are discussed with respect to the metabolic processes that might impact maintaining the viability of cyanobacteria during their storage and indicate unique adaptations formed in their original extreme habitats. Full article

The improvement of PBF manufacturing accuracy has been an urgent problem to solve. The columnar-to-equiaxed transition of rapid solidification during laser powder bed fusion (L-PBF) has been reported, while its influence on the accuracy and surface roughness of fabricated 316L micro-lattice structures remains to be studied. This study presents a novel fully coupled finite volume method for cellular automata (CA), integrated with response surface methodology (RSM), which is applied to investigate the columnar-to-equiaxed transition influence on the accuracy and surface roughness of ultra-precision additive manufactured 316L lattice structure by L-PBF. It is proven that the higher overlap is identified as the optimal strategy for improving both surface quality and dimensional accuracy. Both the CA model prediction and the experimental results reveal that the effect of latent heat releases from the grain refinement on the adhesion of the surrounding powder is an increment of the surface roughness, while the decrement of the surface quality and accuracy. The overlap strategy is promoted to be the most suitable measure to achieve both high surface quality and manufacturing accuracy. The surface roughness Ra (SP) can rapidly decrease by 68.6%, and the mean diameters decrease by 18.7% under the overlap strategy. Full article

This study evaluates the effects of three mechanical pre-treatment methods on S235JRG2 steel sheets: blasting with a synthetic corundum (F40), blasting with steel shot (S170), and grinding with synthetic corundum (P40). Untreated samples served as a reference. The analysis of mechanical pre-treatments focused on surface integrity, including measurements of surface roughness parameters Ra and Rz (ISO 21920-2) and subsurface microhardness (ISO 6507-1). Zinc coatings were assessed through mechanical testing (cupping test, ISO 1520) and corrosion testing in a neutral salt spray environment (ISO 9227), with results evaluated using digital image analysis. Experimental findings indicate that electroplated zinc deposition rates are influenced by surface roughness, while subsurface microhardness has no significant effect. In contrast, for hot-dip galvanizing, both parameters impact the process. The mechanical properties of electroplated zinc coatings are further affected by steel surface integrity, whereas hot-dip zinc coatings are primarily governed by intermetallic phase formation, making the influence of steel surface integrity statistically negligible. Corrosion testing revealed that blasting with a synthetic corundum is particularly unsuitable, as it leads to numerous inhomogeneities in both coating types, accelerating corrosion degradation. Full article

We have carried out a numerical study of hydrodynamic processes in the hybrid-aligned channel of a compressible liquid crystal (HACLC) under the effect of a temperature gradient $\nabla T$ applied across a liquid crystal film. Calculations based on the classical Leslie–Ericksen theory showed that under the effect of $\nabla T$, the HACLC sample settles down to a stationary flow regime with both horizontal u and vertical w components of velocity $\mathbf{v}$, and the direction and magnitude of $\mathbf{v}$ are strongly effected by the direction of $\nabla T$. Calculations also showed that the relaxation of the stress tensor components ${\sigma }_{\mathrm{ij}}(z,t)(\mathrm{i},\mathrm{j}=\mathrm{x},\mathrm{z})$ in the hybrid-aligned compressible nematic microvolume is determined by the direction and magnitude of the thermomechanical force. Full article

Smart city operation assumes dynamic infrastructure in various aspects. However, organization and process modelling require domain expertise and significant efforts from modelers. As a result, such processes are still not well supported by IT systems and still mostly remain manual tasks. Today, machine learning technologies are capable of performing various tasks including those that have normally been associated with people; for example, tasks that require creativeness and expertise. Generative adversarial networks (GANs) are a good example of this phenomenon. This paper proposes an approach to generating organizational and process models using a GAN. The proposed GAN architecture takes into account both tacit expert knowledge encoded in the training set sample models and the symbolic knowledge (rules and algebraic constraints) that is an essential part of such models. It also pays separate attention to differentiable functional constraints, since learning those just from samples is not efficient. The approach is illustrated via examples of logistic system modelling and smart tourist trip booking process modelling. The developed framework is implemented in a publicly available open-source library that can potentially be used by developers of modelling software. Full article

Power transmission lines transfer energy between power plants and substations by means of a linear chain of towers. These towers are often situated over extensive distances, sometimes in regions that are difficult to access. Wireless sensor networks present a viable solution for monitoring these long chains of towers due to their wide coverage, ease of installation and cost-effectiveness. The proposed LoRaBUS approach implements and analyses the benefits of a linear topology using a mixture of LoRa and LoRaWAN protocols. This approach is designed to enable automatic detection of nearby nodes, optimise energy consumption and provide a prioritised transmission mode in emergency situations. On remote, hard-to-reach towers, a prototype fire protection system was implemented and tested. The results demonstrate that LoRaBUS creates a self-configurable linear topology which proves advantageous for installation processes, node maintenance and troubleshooting node failures. The discovery process collects data from a neighbourhood to construct the network and to save energy. The network’s autonomous configuration can be completed within approximately 2 min. In addition, energy consumption is effectively reduced 25% by dynamically adjusting the transmission power based on the detected channel quality and the distance to the nearest neighbour nodes. Full article

In this paper, we propose a generalized-chirp spread spectrum (G-CSS) that can have various modulation orders and offers superior bit error rate (BER) performance to improve the communication performance of existing chirp-based modulation/demodulation schemes. The proposed G-CSS sets frequency bins with different modulation orders at the start and end points of the symbol and selects frequency bins based on the bits to be transmitted, modulating the signal using corresponding chirps. Therefore, the proposed method allows for independent design of modulation orders at the start and end of the symbol, enabling signal design and flexible transmission tailored to the transmission rate required by the system. Through computer simulations and practical ocean experiments, we compared and analyzed the BER performances of the proposed G-CSS with existing up/down-CSS and long-range CSS (LoRa-CSS). The proposed G-CSS demonstrated a superior BER performance at the same transmission rate. Full article

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, and current treatments have significant side effects. Cannabidiol (CBD), a compound derived from Cannabis sativa, has demonstrated promising anticancer properties. However, further investigation is required to elucidate its underlying molecular mechanisms. Methods: Network pharmacology and molecular docking analysis approaches were utilized. Molecular targets of CBD and CRC-associated genes were identified using the Swiss Target Prediction, Malacards, and DisGeNet databases. Protein–protein interactions were analyzed using the STRING and Cytoscape. Ontology enrichment was conducted using ShinyGO, and gene expression and immune infiltration were evaluated with UALCAN and TISIDB. Results: We found 95 common genes between CRC and CBD targets. Six major genes (ANXA5, IGF1R, JAK2, MAPK8, MDM2, and PARP1) were particularly interesting due to their high connectivity and role in relevant metabolic pathways. The results of the molecular docking analysis indicated that CBD interacts favorably with these genes, modulating critical pathways such as RAS/MAPK and PI3K-AKT/FoxO, which are involved in cell proliferation, apoptosis, and cell cycle regulation. ANXA5 and JAK2 were identified as particularly relevant, as they correlated significantly with immune cell infiltration, suggesting a role in the immunoregulation of the tumor microenvironment. Conclusions: CBD has the potential to modulate key molecular processes in CRC through specific pathways and core genes, presenting itself as a possible complementary therapy to improve efficacy and reduce the adverse effects of conventional treatments. Full article

An advanced model of ionic surfactant micellization has been developed. The structural and kinetic properties of micelles were analyzed in parallel from a universally accepted point of view and taking into account the principles of quantum mechanics, the phenomenon of ion pairing in the Stern layer, the symmetry considerations, and the chaos theory. It was shown that a micelle can be considered as a layered fullerene-like structure with a cavity in its center, possessing the solid-like properties of micelles in radial directions and the liquid-like properties in the perpendicular ones, allowing for water penetration between the surfactant head group and nearby methylene groups. The dimensions of the minimal fullerene-like structure formed by the terminal hydrogen atoms of surfactant methyl groups around the central cavity, unable to be occupied by surfactant tail fragments, were estimated. It was indicated that permanently occurring surfactant self-organization/disintegration needs a probabilistic description and revision of processes occurring in micellar systems built by ionic surfactants. It was noted that the probabilistic approach alters the mechanism of colloidal dissolution of hydrocarbon compounds and their solubilization by micelles. The advanced model proposes the same macroscopic properties of micelles as the classical one but modifies the structural characteristics of micelles on the nanoscale. Full article

This paper presents the results of processing and systematizing data from laboratory and numerical experiments to correct the distortions of laser radiation propagating through a randomly inhomogeneous medium. The information obtained allows for an accurate estimation of the effectiveness of compensating for turbulent fluctuations in the refractive index along the beam propagation path. Experimentally derived radiation parameters were compared with corresponding values calculated using an optical system model. Limitations of the numerical simulation, stemming from inherent model constraints, were identified, as were discrepancies between experimental and theoretical results, and a reason for these discrepancies was provided. Full article