Search Results (121)

Guidelines for the first-line treatment of Hormone Receptor-positive, HER2-negative advanced or recurrent breast cancer have shifted to combination therapies of a CDK4/6 inhibitor and endocrine therapy. However, determining an optimal subsequent therapy following CDK4/6 inhibitor progression remains challenging, especially for tumors lacking actionable mutations. Real-world data suggest that fulvestrant monotherapy is frequently selected in this post-CDK4/6 inhibitor setting. This review examines its therapeutic potential in this evolving landscape. A systematic literature search using PubMed and ClinicalTrials.gov identified 153 clinical trials published between 2017 and November 2024, from which ten studies met our strict inclusion criteria, focusing solely on fulvestrant monotherapy. These trials encompassed 1038 patients who had prior exposure to CDK4/6 inhibitors. The selected studies were categorized into three groups: monotherapy trials (EMERALD, SERENA-2, AMEERA-3, and ELAINE-1), combination therapy trials (CAPItello-291 and VERONICA), and CDK4/6 inhibitor rechallenge trials (post-MONARCH, PACE, PALMIRA, and MAINTAIN). The median progression-free survival for fulvestrant monotherapy was 3.18 months (range 1.9–5.3 months). Factors affecting the efficacy of fulvestrant monotherapy in second-line therapy include prior treatments, treatment duration, and genetic mutations. Given that the efficacy of fulvestrant was short-lived in the second or subsequent lines, participating in clinical trials is a vital option until a novel alternative treatment choice becomes available. Full article

Patients with treatment-refractory/relapsing germ cell tumors (GCTs) have a dismal prognosis due to a lack of any effective therapy. Moreover, the efficacy of newly approved targeted therapies remains unexplored for cisplatin-resistant GCTs. Previously, it was demonstrated that folate receptor α (FRα) is overexpressed in many tumor types and efficiently targeted by the antibody–drug conjugate (ADC) mirvetuximab soravtansine (MIRV) in cisplatin-resistant cancers. We hypothesized that FRα represents an attractive target for treating treatment-refractory GCTs. We determined the expression of the FOLR1 gene in a broad range of GCT cell lines and tumor xenografts. We tested the antitumor efficacy of MIRV on cisplatin-resistant GCT cells in vitro and explored the ability of MIRV treatment to induce a bystander effect in the direct coculture of FRα-high and FRα-low cells. We found that the FOLR1 gene has significantly higher expression in testicular GCTs (TGCTs) than in normal testicular tissue. FOLR1 is highly expressed in the TCam2, JEG3, JAR, and NOY1 cell lines and their respective cisplatin-resistant variants. MIRV treatment induced apoptosis and a potent antiproliferative effect in cisplatin-resistant GCT cells in adherent and 3D spheroid cultures in vitro. A significant decrease in FRα-low 2102EP_R_NL cells was observed in the presence of FRα-high NOY1_R_SK in the presence of 12.5 nM MIRV, showing a potent bystander effect in the direct coculture. Immunohistochemical analysis confirmed significantly higher Folr1 protein expression in patients with TGCTs postchemotherapy than in chemo-naïve patients, as well as in patients with an unfavorable prognosis. In this study, we present data suggesting that the FOLR1 gene is highly expressed in (T)GCT cells in vitro and in vivo, and anti-FRα-targeting therapies should be investigated as a treatment modality in a subset of patients with TGCTs. Moreover, MIRV induced significant antitumor and bystander effects, thus showing its potential in further preclinical exploration and drug repurposing for a salvage treatment regime in refractory (T)GCT disease. Full article

Decision support systems (DSSs) can improve decision making in integrated pest management (IPM), but are still underutilised despite proven environmental and economic benefits. To overcome the barriers to DSS adoption, this study analyses survey data from 31 farmers and 94 farm advisors, researchers and developers across 11 European countries. Using machine learning techniques, respondents were first categorised into clusters based on their responses to the questionnaire. The clusters were then explained using classification trees. For each cluster, customised approaches were proposed to overcome the barriers to DSS adoption. For farmers, these include building trust through co-development, offering free trials, organising practical workshops and providing clear instructions for use. For farm advisors and researchers, involvement in the development of DSS and giving them access to information about the characteristics of the DSS is crucial. IPM DSS developers should focus on 14 key recommendations to improve trust and the ease of use, increase the transparency of DSS descriptions and validation, and extend development to underserved sectors such as viticulture and vegetable farming. These recommendations aim to increase the uptake of DSSs to ultimately improve the implementation of IPM practises and help reduce the risk and use of pesticides across Europe despite the ever-growing challenges in agriculture. Full article

Plants have long been used as sources of natural compounds with therapeutic benefits, providing molecules capable of inhibiting multiple kinases. Many medicinal plants are recognized for their anticancer properties and may offer ways to mitigate the adverse effects of conventional cancer treatments. In this study, the potential of Ziziphus mucronata methanol extract as a kinase inhibitor was assessed using the MTT assay, a universal kinase assay, and a human phosphokinase antibody array, along with a GC-MS analysis of volatile anticancer compounds. The MTT assay revealed strong cytotoxicity in A549 cells, with an IC₅₀ of 31.25 µg/mL, while HeLa cells showed weaker cytotoxicity with an IC₅₀ of 125 µg/mL. In comparison, paclitaxel exhibited potent inhibitory effects on A549 cells (IC₅₀ of 31.25 µg/mL) and moderate inhibition on HeLa cells (IC₅₀ of 65 µg/mL). Enzyme activity, measured by ADP production in the ADP-Glo assay, indicated that the extract inhibited protein kinase activity in both A549 and HeLa cells after 24 h of treatment. Additionally, the human phosphokinase antibody array, which includes 44 pre-spotted kinases, showed that the extract downregulated multiple phosphorylated kinases in both cell lines. Some of the affected kinases, such as TOR, Fyn, HcK, Fgr, STAT5b, PLC-γ1, p38α, ERK1/2, AMPKA, Akt1/2, GSK-3α/β, MSK1/2, CREB, RSK1/2/3, PLC-γ1, and STAT5a are critical regulators of various cellular processes, including apoptosis, differentiation, and proliferation. The findings of this study suggest that extract from Z. mucronata may have the capacity to regulate protein kinase activity, highlighting their significant potential as growth inhibitors for cancer cells. Full article

This study investigates the use of three different quadrature schemes, as well as an iterative quadrature methodology, to analyze vibrations in magneto-electro-thermo-elastic nanobeams. Individual MATLAB programs for each method are developed with the goal of minimizing errors in comparison to accurate findings, as well as determining the execution time for each strategy. This study shows that the Discrete Singular-Convolution Differential Quadrature Method with a Regularized Shannon Kernel (DSCDQM-RSK) and specified parameters produces the best accurate and efficient results for this particular situation. A subsequent parametric study is carried out to determine the effect of various factors on the vibrated nanobeam, including boundary conditions, material types, linear and nonlinear elastic foundation properties, nonlocal parameters, length-to-thickness ratios, external electric and magnetic potentials, axial forces, and temperature variations. Important discoveries include insights into the relationship between fundamental frequency, linear elastic foundation features, axial loads, external magnetic fields, temperature fluctuations, and material types. According to this study, these findings could be critical in the development of sophisticated nanostructures made from magneto-electro-thermo-elastic materials for use in a variety of electromechanical applications. This would entail utilizing nanobeams’ unique properties in applications such as sensors, resonators, and transducers for nanoelectronics and biology. Full article

Mechanical belt sanding is critical in the manufacturing of bamboo and bamboo products, where surface roughness is commonly used to quantitatively evaluate the surface quality. In this study, flattened bamboo workpieces were sanded using P80 and P120 abrasive belts to create different surfaces. The linear roughness parameters, namely Rz, Ra, Rq, Rsk, Rku, and Rmr(c), were measured using both a stylus profilometer and a 3D profilometer. Statistical t-tests were conducted to determine the significance of differences between the two methods. Additionally, roughness profiles were analyzed in the frequency domain using Fast Fourier Transform (FFT) and Power Spectral Density (PSD) methods. A Random Forest (RF) regression model was also developed to predict the roughness values and figure out the dominant factors between granularity and measurement methods. The results revealed that both the stylus and 3D profilometers provided reliable comparisons of Rz, Ra, Rq, and Rmr (50%) for different grit sizes. However, resolution differences between the two methods were found to be critical for accurately interpreting roughness values. Variations in Rsk and Rku highlighted differences in sensitivity and detection range, particularly at finer scales, between the two methods. The stylus profilometer, with its higher spatial resolution and finer sampling density, demonstrated greater sensitivity to finer surface details. This was consistent with the FFT and PSD analyses, which showed that the stylus profilometer captured higher-frequency surface components more effectively. Furthermore, the RF model indicated that the choice of measurement method had negligible impact on the evaluation of the selected roughness parameters, suggesting that standardizing measurement techniques may not be essential for consistent roughness assessments of sanded bamboo surfaces. Full article

Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL. Full article

In this study, the effects of cutting speed and feed rate on the roughness parameters R_a, R_z, R_sk, R_ku, R_pk, R_vk, and A₂ were examined during machining with coated carbide tools in a dry environment. The authors introduced the R_vk/R_pk ratio, a coefficient that facilitates a simpler evaluation of surface wear resistance. Specifically, if this ratio is greater than 1, the surface is more wear-resistant, while values less than 1 indicate a higher tendency for surface wear. The Taguchi OA method was used to analyze and identify the significance of technological parameters on output characteristics. Based on the results, it was established that feed rate has the greatest impact on all output characteristics. The highest cutting force was measured at a cutting speed of 60 m/min and a feed rate of 0.15 mm/rev, attributed to the fact that at lower cutting speeds, the base material does not soften while the cross-sectional area of the chip increases. To achieve the lowest R_a and R_z surface roughness, a cutting speed of 100 m/min and a feed rate of 0.05 mm/rev are recommended. If the goal is to enhance surface wear resistance and improve oil retention capability, machining with a cutting speed of 80–100 m/min and a feed rate of 0.15 mm/rev is advisable, as the coarser machining increases both the R_vk/R_pk ratio and the oil-retaining pocket size, which together improve the wear resistance of the machined surface. Full article

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy. Full article

Thyroid carcinoma (THCA) ranks among the most prevalent cancers globally. Integrating advanced genomic and proteomic analyses to construct a protein-based prognostic model promises to identify effective biomarkers and explore new therapeutic avenues. In this study, proteomic data from The Cancer Proteomics Atlas (TCPA) and clinical data from The Cancer Genome Atlas (TCGA) were utilized. Using Kaplan–Meier, Cox regression, and LASSO penalized Cox analyses, we developed a prognostic risk model comprising 13 proteins (S100A4, PAI1, IGFBP2, RICTOR, B7-H3, COLLAGENVI, PAR, SNAIL, FAK, Connexin-43, Rheb, EVI1, and P90RSK_pT359S363). The protein prognostic model was validated as an independent predictor of survival time in THCA patients, based on risk curves, survival analysis, receiver operating characteristic curves and independent prognostic analysis. Additionally, we explored the immune cell infiltration and tumor mutational burden (TMB) related to these features. Notably, our study proved a novel approach for predicting treatment responses in THCA patients, including those undergoing chemotherapy and targeted therapy. Full article

Cellular molecules interact with one another in a structured manner, defining a regulatory network topology that describes cellular mechanisms. Genetic mutations alter these networks’ pathways, generating complex disorders such as autism spectrum disorder (ASD). Boolean models have assisted in understanding biological system dynamics since Kauffman’s 1969 discovery, and various analytical tools for regulatory networks have been developed. This study examined the protein–protein interaction network created in our previous publication of four ASD patients using the SPIDDOR R package, a Boolean model-based method. The aim is to examine how patients’ genetic variations in INTS6L, USP9X, RSK4, FGF5, FLNA, SUMF1, and IDS affect mTOR and Wnt cell signaling convergence. The Boolean network analysis revealed abnormal activation levels of essential proteins such as β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD. These proteins affect gene expression, translation, cell adhesion, shape, and migration. Patients 1 and 2 showed consistent patterns of increased β-catenin activity and decreased MTORC1, RPS6, and eIF4E activity. However, patient 2 had an independent decrease in Cadherin and SMAD activity due to the FLNA mutation. Patients 3 and 4 have an abnormal activation of the mTOR pathway, which includes the MTORC1, RPS6, and eIF4E genes. The shared mTOR pathway behavior in these patients is explained by a shared mutation in two closely related proteins (SUMF1 and IDS). Diverse activities in β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD contributed to the reported phenotype in these individuals. Furthermore, it unveiled the potential therapeutic options that could be suggested to these individuals. Full article

This work investigates the tribological behavior of a machined S355JR structural steel in dry sliding conditions for the development of an innovative seismic dissipation system. Flat-ended pins and disks were made of the same structural steel to simulate the conformal contact of different device parts. Pins were machined by turning, while disks were milled and turned to obtain a nominal average surface Ra roughness ranging from 0.8 µm to 6.3 µm. The influence of the surface roughness on the coefficient of friction (COF), specific wear rate (SWR), and time to steady-state (TSS) was investigated. Tribological tests were conducted reciprocating motion in dry sliding conditions to simulate the operating conditions of the device, with 1 Hz and 2 Hz reciprocating frequencies and an applied normal load of 50 N. The Rsk and Rku roughness parameters helped to better understand the tribological response of milled and turned disks, having an influence on the TSS and SWR. Full article

In this paper, one of the great challenges faced by silicon-based biosensors is resolved using a biomaterial multilayer. Tiny biomolecules are deposited on silicon substrates, producing devices that have the ability to act as iridescent color sensors. The color is formed by a coating of uniform microstructures through the interference of light. The system exploits a flat, RNA-aptamer-coated silicon-based surface to which captured microbes are covalently attached. Silicon surfaces are encompassed with the layer-by-layer deposition of biomolecules, as characterized by atomic force microscopy and X-ray photoelectron spectroscopy. Furthermore, the results demonstrate an application of an RNA aptamer chip for sensing a specific bacterium. Interestingly, the detection limit for the microbe was observed to be 2 × 10⁶ CFUmL⁻¹ by visually observed color changes, which were confirmed further using UV-Vis reflectance spectrophotometry. In this report, a flexible method has been developed for the detection of the pathogen Sphingobium yanoikuyae, which is found in non-beverage alcohols. The optimized system is capable of detecting the specific target microbe. The simple concept of these iridescent color changes is mainly derived from the increase in thickness of the nano-ordered layers. Full article

Petanin, an acylated anthocyanin from the Solanaceae family, shows potential in tyrosinase inhibitory activity and anti-melanogenic effects; however, its mechanism remains unclear. Therefore, to investigate the underlying mechanism of petanin’s anti-melanogenic effects, the enzyme activity, protein expression and mRNA transcription of melanogenic and related signaling pathways in zebrafish using network pharmacology, molecular docking and molecular dynamics simulation were combined for analysis. The results showed that petanin could inhibit tyrosinase activity and melanogenesis, change the distribution and arrangement of melanocytes and the structure of melanosomes, reduce the activities of catalase (CAT) and peroxidase (POD) and enhance the activity of glutathione reductase (GR). It also up-regulated JNK phosphorylation, inhibited ERK/RSK phosphorylation and down-regulated CREB/MITF-related protein expression and mRNA transcription. These results were consistent with the predictions provided through network pharmacology and molecular docking. Thus, petanin could inhibit the activity of tyrosinase and the expression of tyrosinase by inhibiting and negatively regulating the tyrosinase-related signaling pathway ERK/CREB/MITF through p-JNK. In conclusion, petanin is a good tyrosinase inhibitor and anti-melanin natural compound with significant market prospects in melanogenesis-related diseases and skin whitening cosmetics. Full article

Improvement of the surface quality of machined parts is essential in order to avoid excessive and costly post-processing. Although non-conventional processes can efficiently carry out the machining of difficult-to-cut materials with high productivity, they may also, for various reasons, be related to increased surface roughness. In order to optimize the surface quality of generated surfaces in a reliable way, surface profiles obtained during these processes must be adequately modeled. However, given that most studies have focused on Ra or Rz indicators or are based on the assumption of a normal distribution for the profile heights, relevant models cannot accurately represent the surface characteristics that exist in a real machined surface with a high degree of accuracy. Thus, in the present study, a new modeling approach based on the use of a statistical probability distribution for the surface profile height is proposed. After six different distributions were evaluated on the basis of a three-stage procedure involving different roughness indicators pertaining to the abrasive waterjet (AWJ) milling of pockets, it was found that, although it is not possible to model the nominal values of every roughness parameter simultaneously, in several cases, it is possible to approximate the values of critical indicators such as Ra, Rz, Rsk, Rku and Rp/Rv ratio by Weibull distribution with a sufficient degree of accuracy. Full article