Search Results (1,787)

Background: Lavandula stoechas has attracted increasing attention for its potential anticancer properties; however, evidence regarding its effects on apoptotic signaling across different tumor types remains limited. Methods: In this study, the effects of dry and fresh ethanol extracts of Lavandula stoechas L. subsp. stoechas (LsDE and LsFE) were investigated in MDA-MB-231 triple-negative breast cancer, RT4 bladder carcinoma, and T98G glioblastoma cell lines, providing a comparative evaluation of their apoptotic effects. Long-term proliferative capacity was assessed using clonogenic survival assays, while apoptosis-related responses were evaluated by Annexin V–FITC/propidium iodide staining, quantitative RT-PCR of BAX and BCL2 and Western blot analysis of Bax, Bcl-2, and cleaved PARP1. Results: Both extracts significantly reduced clonogenic survival in all tested cancer cell lines, with LsDE showing stronger inhibitory effects in RT4 and T98G cells. Annexin V/PI analysis revealed cell type-dependent response patterns. In MDA-MB-231 cells, both extracts increased the proportion of PI-positive cells, suggesting a loss of membrane integrity, whereas RT4 cells exhibited increased early apoptotic and membrane-compromised populations. In contrast, T98G cells showed comparatively limited changes associated with apoptosis. Transcriptional analysis demonstrated extract- and cell line-specific modulation of the BAX/BCL2 ratio. Western blot analysis further demonstrated activation of mitochondrial apoptotic signaling through coordinated regulation of Bax and Bcl-2 and increased PARP1 cleavage. LsFE showed the strongest apoptosis-associated changes in MDA-MB-231 cells, whereas LsDE showed stronger effects in T98G cells, while both extracts were effective in modulating these proteins in RT4 cells. Conclusions: These findings indicate that ethanol extracts of L. stoechas impair long-term proliferative capacity and induce tumor type-dependent modulation of apoptosis-related markers. This study provides an integrated experimental framework that combines clonogenic survival assays, apoptosis analyses, gene expression, and protein-level measurements, supporting further investigation of L. stoechas extracts in cancer research. Full article

Background and Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular (CV) death and heart failure hospitalizations (HFH) in patients with heart failure with reduced ejection fraction (HFrEF). However, data regarding their use in combination with different doses of guideline-directed medical therapy (GDMT) remain limited. This study aimed to evaluate whether SGLT2i combined with low-dose conventional triple therapy is non-inferior to high-dose conventional triple therapy in preventing adverse cardiovascular outcomes. Materials and Methods: This retrospective observational study included 334 patients with HFrEF treated between 31 March 2018 and 31 March 2024. Of these, 110 received SGLT2i plus low-dose conventional triple therapy, and 224 received high-dose conventional triple therapy. A non-inferiority framework was applied to compare outcomes between groups. The primary endpoint was a composite of CV death and HFH, while secondary endpoints included the individual components. Results: The composite endpoint occurred more frequently in the SGLT2i plus low-dose group. After inverse probability of treatment weighting and multivariable Cox analysis, this group demonstrated a significantly higher risk of the composite outcome (adjusted HR 4.10, 95% CI 2.07–8.13; p < 0.001). CV death was similar between groups; however, HFH was significantly more frequent in the SGLT2i plus low-dose group. Conclusions: In patients with HFrEF, SGLT2i combined with low-dose conventional triple therapy did not demonstrate comparable clinical outcomes to high-dose conventional triple therapy in reducing CV death and HFH, particularly in patients with a higher baseline burden of disease severity. These findings underscore the importance of optimizing background GDMT dosing alongside the incorporation of SGLT2i into clinical practice. Full article

Background: Wrist osteomyelitis caused by Scedosporium apiospermum is exceedingly rare. Its indolent course and destructive potential may result in extensive bone loss and pose substantial diagnostic and therapeutic challenges. Methods: We report a case of chronic wrist osteomyelitis caused by Scedosporium apiospermum in a 68-year-old kidney–pancreas transplant recipient. Results: Following diagnosis, systemic antifungal therapy with voriconazole was initiated, and multiple surgical debridements were performed to achieve local disease control, resulting in a large defect of the carpus and distal forearm. Hand salvage was attempted using an osteocutaneous triple-barrel fibula flap. The postoperative course was complicated by congestion of the fibula skin island, which was managed with leech therapy. Subsequent infection with a multi-resistant Aeromonas spp. and Morganella morganii led to flap necrosis, ultimately requiring transradial forearm amputation. Conclusions: Destructive Scedosporium apiospermum osteomyelitis in immunocompromised patients is a major challenge for reconstructive surgeons. Interdisciplinary management is essential as mold eradication is only achievable through a combined surgical and antimicrobial approach. In advanced destructive osteomyelitis, the choice between limb salvage and amputation should be individualized, considering patient comorbidities, reconstructive risk, and patients’ preferences. This case highlights the importance of balancing careful indication and patient counseling in complex clinical scenarios. Full article

Background/Objectives: Several trials have highlighted the importance of PARP inhibitors (PARPi) in the treatment of BRCA-associated breast cancers (BC), initiating changes in practice. However, data on the real-life outcomes of PARPi therapy is limited. In this study, we characterized the clinical characteristics and outcomes of patients with advanced BC and germline BRCA pathogenic variants (PVs) who received PARPi therapy. Methods: We conducted a retrospective single-institution cohort study of patients with advanced BC and germline BRCA1/2 PVs treated with PARPi. Outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Survival was estimated using Kaplan–Meier methods, and prognostic factors were evaluated using Cox regression analysis. Results: Of the 107 patients treated with PARPi, 48 (44.9%) and 59 (55.1%) had BRCA1 and BRCA2 PVs, respectively. Ninety-seven patients (90.7%) had invasive ductal carcinoma and 42 (39.3%) had triple-negative BC. Nineteen (17.8%) patients had de novo metastatic BC. Sixty-two (57.9%) patients received at least one line of systemic therapy before PARPi; 24 (22.4%) patients received prior platinum. ORR was 62.6%, and the median duration of response (DoR) was 7 months (range, 2.1–96.2). The median PFS was 9 months (95% CI, 6.9–10.5) and median OS was 25.8 months (95% CI, 18.7–31.5). In multivariable models for PFS, bone metastases (HR = 2.25; 95% CI, 1.40–3.61; p = 0.0008) and lung metastases (HR = 2.40; 95% CI, 1.45–3.98; p = 0.0007) were independently associated with increased risk of progression or death. In multivariable models for OS, brain metastases (HR = 3.54; 95% CI, 1.59–7.90; p = 0.0020), bone metastases (HR = 2.22; 95% CI, 1.27–3.88; p = 0.0050), and lung metastases (HR = 2.38; 95% CI, 1.38–4.11; p = 0.0018), were independently associated with increased risk of death. Conclusions: The clinical outcomes of our real-world patients are similar to those reported in previous clinical trials. In addition, metastatic site distribution was independently prognostic for survival outcomes and may support baseline risk stratification at the time of PARPi initiation. Further studies of predictive markers of response and resistance, as well as sequencing with platinums and combinations with other targeted agents, are needed to optimize the benefits of PARPi in this patient population. Full article

Background: Cysteine proteases of Clonorchis sinensis are potential diagnostic antigens, yet the performance of individual members within this diverse enzyme family requires systematic evaluation. This study aimed to assess the diagnostic potential of four recombinant cysteine proteases (rCsCP1–4) for human clonorchiasis. Methods: An indirect ELISA was developed to measure serum reactivity (IgG, IgG subclasses, IgA) against rCsCP1–4. The assay was validated using 180 microscopy-confirmed positive and 148 negative control sera. Samples were randomly split into training and validation sets (7.5:2.5). Diagnostic performance of single antigens and their combinations was evaluated using univariate and multivariate logistic regression and compared with a commercial kit. Key metrics included the area under the curve (AUC), sensitivity, specificity, accuracy, F1-score, and Kappa coefficient. Results: Four single antigen–antibody pairs showed high performance: rCsCP1-IgG4 (AUC = 0.928), rCsCP2-IgA (AUC = 0.863), rCsCP3-IgG1 (AUC = 0.920), and rCsCP4-IgG4 (AUC = 0.958). Among these, rCsCP1-IgG4, rCsCP3-IgG1, and rCsCP4-IgG4 outperformed the commercial kit, achieving higher sensitivity (92.0%, 96.0%, 96.0% vs. 86.0%), specificity (87.5%, 81.3%, 90.6% vs. 78.1%), accuracy (92.0%, 88.9%, 94.1% vs. 86.0%), and F1-scores (0.902, 0.902, 0.939 vs. 0.829). The Kappa values for rCsCP1-IgG4 (0.768) and rCsCP4-IgG4 (0.773) indicated substantial agreement with the microscopic standard. Multi-antigen combinations (triple or quadruple) further enhanced performance, achieving sensitivity and specificity > 98% with an AUC approaching 1.0. Conclusions: This study identifies rCsCP1 and rCsCP4, particularly in combination with IgG4 detection, as highly promising diagnostic targets for clonorchiasis. Multi-antigen combinations significantly improved diagnostic performance compared to single-antigen assays, offering a strategy for high-precision diagnosis. Furthermore, the efficacy of the rCsCP2-IgA pair suggests that detecting fecal secretory IgA could be a novel avenue for non-invasive, self-testing applications. Full article

The BiTemporal RDF (BiTRDF) model extends the standard RDF data model by integrating both valid time and transaction time, thus enabling the representation and querying of dynamic and historical knowledge. While the theoretical foundations of BiTRDF have been established, practical implementation strategies have not yet been systematically studied. This paper bridges this gap by exploring six alternative approaches to implementing BiTRDF, combining object-oriented programming and database-oriented designs using Python and PostgreSQL. We evaluate these approaches using six synthetic datasets ranging from 0.5 million to 16 million bitemporal triples. The evaluation focuses on memory consumption, data-loading time, and query performance as data load increases. The results show that all approaches perform comparably when the knowledge store fits in memory. As the dataset size grows beyond available RAM, database-oriented implementations achieve substantially better loading and query performance, while object-oriented implementations offer greater flexibility and extensibility. These findings demonstrate the feasibility of implementing BiTRDF using existing technologies and provide practical guidance for selecting appropriate implementation strategies based on data size, performance requirements, and extensibility needs. Full article

Background: Iron overload and its associated complications are major concerns in patients with transfusion-dependent β-thalassaemia (TDT). Iron chelation is an important part of TDT therapy with monotherapy or dual iron chelation being the most commonly used strategies. Evidence regarding the efficacy and safety of triple iron chelation therapy remains limited. Case presentation: We present the case of a 21-year-old immigrant from the Middle East with TDT and a history of irregular transfusion management without chelation therapy, leading to clinically significant iron overload. She was successfully treated with the combination of deferoxamine, deferasirox and deferiprone over a course of 8 years. Triple chelation therapy led to sustained reductions in serum ferritin levels and improvement in hepatic and cardiac iron burden on follow-up MRI, with good tolerability. Conclusions: This case highlights the potential role of triple iron chelation therapy as a therapeutic strategy in TDT patients with severe iron overload. Further studies are needed to establish optimal dosing, eligible patients and long-term safety. Full article

Electron correlation and quantum interference are pivotal in mesoscopic transport. We theoretically study the nonequilibrium transport dynamics of a triangular triple-quantum-dot (TTQD) molecule connected to fermionic reservoirs using the exact hierarchical equations of motion (HEOM) formalism. We demonstrate a counterintuitive transport signature in which the stationary current is significantly enhanced by increasing U, a behavior distinct from the suppression typically observed in linear quantum dot arrays. By analyzing the evolution of spectral functions, we attribute this enhancement to the interplay between Coulomb-interaction-induced energy shifts and quantum interference effects specific to the triangular topology. We also explore how the circulation of chiral currents and electrode coupling strength modulate these interaction effects. Finally, we present a three-dimensional map of the transport current as a function of inter-dot tunneling (t) and Coulomb interaction (U), illustrating their combined effect on the current magnitude and its applications. Full article

To address the imbalance between the shearing–mixing quality and energy efficiency of deepwater drilling mud mixers and breakthrough the limitations of existing independent single-objective analytical perspectives, the Eulerian solid–liquid two-phase numerical simulation was adopted in this study. Combined with a modified shear rate algorithm and a triple energy coupling analysis of shear rate, Lamb vortex energy and Enstrophy, the energy conversion and particle dispersion mechanisms inside the mixer under variable flow rates and solid concentrations were systematically investigated, and the performance differences between the first-generation and optimized mixers were clarified. Structural optimizations including an additional modular stator with a designed shear gap of 2 mm, improved blade profiles and shear angles to 14.2°, and miniaturized radial dimensions of the impeller and volute were implemented to achieve compact structural upgrading. The results demonstrate that high-energy regions are concentrated in the rotor–stator gap. After optimization, the peak shear rate increases from 12,010 s⁻¹ to 17,092 s⁻¹, representing a 42.3% enhancement. The peak Lamb vortex energy and the mean Enstrophy rise by 8.6% and 18.9%, respectively. Shear rate correlates weakly positively with Lamb vortex energy and strongly negatively with Enstrophy, revealing vortex sensitivity to flow velocity and tight coupling of viscous dissipation to particle concentration. The outlet coefficient of variation C_v decreases by 59.6%. Higher flow rates strengthen the coupling of shear and vortex energy, and higher solid concentrations weaken stator shear performance. The optimized mixer achieves synergistic improvements in shear efficiency and mixing quality, with over 50% enhancement in mud dispersion stability and more than 15%. Full article

This study addresses the limited availability of unified experimental datasets comparing ribbed steel and smooth FRP bars embedded in the same hybrid-fiber high-performance concrete (HPC) matrix under identical conditions. It investigates the mechanical and bond behavior of a triple-fiber HPC combining hooked-end steel (ST), basalt (BA), and polypropylene (PP) fibers and reinforced with steel, GFRP, and CFRP bars of identical diameter and embedment. Under a uniform curing regime, the HFRC reached a compressive strength of approximately 82 MPa and exhibited a high fracture energy G_f approximately 3.7 kJ/m² with a stable post-peak response in a notched-beam test, demonstrating effective multi-scale crack bridging within a dense hybrid fiber network. Pull-out tests on 200 mm embedment revealed distinct interfacial mechanisms: ribbed steel developed a pronounced peak bond stress (τ_max = 13.05 MPa) and the largest bond energy (G_b = 146 N/mm) due to mechanical interlock, whereas smooth GFRP and CFRP showed low τ_max (=1.46 and 0.78 MPa) and smoothly decaying τ–s governed by adhesion–friction with G_b = 3–4 N/mm. A consistent experimental framework enabled direct mechanistic comparison of bond–slip behavior across reinforcement types without confounding matrix or curing variables. Simple constitutive laws calibrated to the experimental τ–s curves (ramp–softening for steel and ramp–plateau or exponential for FRP) captured the stiffness, strength, and energy hierarchy with low error. The main contribution of this study lies in providing a configuration-consistent reference dataset and calibrated bond–slip descriptions for hybrid-fiber HPC members reinforced with both steel and FRP bars. The results highlight the role of the hybrid fiber network in improving crack stability and provide design-oriented parameters for anchorage assessment and nonlinear bond–slip modeling. Although the results are based on a limited experimental program, they establish a mechanistically coherent basis for further optimization of hybrid HPC matrices and development of performance-based anchorage formulations in high-performance structural applications. Full article

Recently, CuBa₂Ca₃Cu₄O_10+δ (Cu1234) has garnered significant interest owing to its distinctive triple-high superconducting properties (118K high T_c, combined with high J_c and high H_irr at liquid nitrogen temperature at ambient pressure) and potential for practical applications. The Cu1234 is initially synthesized at high pressures and is stable at a room temperature range but tends to decompose upon heating above 300 °C at ambient. In this study, we investigate the thermal stability of Cu1234 through annealing at various temperatures and oxygen pressures. It is found that Cu1234 starts to decompose at approximately 350 °C, 550 °C, and 600 °C when annealed at 1 bar, 100 bar, and 150 bar oxygen pressure, respectively. Prior to decomposition, however, the superconducting properties remain largely unchanged. The decrease in oxygen occupancy within the BaO layer of the BaCuO_3−δ charge reservoir block is proposed to be the primary cause of the structural instability of Cu1234, while higher oxygen pressures retard oxygen loss from this block. Our result suggests that the decomposition temperature of Cu1234 will further increase with higher oxygen pressure, e.g., possibly to 800 °C at 260 bar if a linear extrapolation is adopted. This study offers important insights for fabricating Cu1234 tapes via the powder-in-tube method. Full article

Breast cancer is the most common malignant tumor in women worldwide. Triple-negative cancers have the worst prognosis, due to the low effectiveness of current therapies. In recent years, research has been conducted on the relationship between inflammatory process and the development of malignant tumors, including breast cancer. One of the elements influencing the inflammatory process is interleukins. These are small protein molecules belonging to the cytokine family that participate in the function of the human immune and hematopoietic systems. Interleukins are still being studied, and this is an area with significant knowledge gaps. More than 60 cytokines have been designated as interleukins over time, but not all of these designations are consistently used or universally accepted. In the available literature, we have only found information on 41. This is the first review to detail all 41 interleukins and their effects on breast cancer development. The review shows that interleukins affect the development of both locally advanced breast cancer and the development of distant metastases, mainly to the bones. Clinical trials are also underway in these areas: some have failed, and others are still ongoing. Due to the lack of success in the use of interleukins in the treatment of breast cancer, the latest strategies are based on combining several elements of the inflammatory process pathway occurring in breast cancer. This can probably bring us closer to therapeutic success in this area. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by the absence of estrogen and progesterone receptors, as well as the lack of human epidermal growth factor 2 receptor overexpression. TNBC is associated with early onset, high metastatic potential, therapeutic resistance, and poor clinical outcomes exacerbated by the limited availability of effective targeted therapies. Advances in multi-omics profiling have further stratified TNBC into distinct molecular subtypes, each exhibiting unique genomic, epigenomic, and immune-related features that influence therapeutic responsiveness. This review explores the interplay between TNBC molecular heterogeneity, immune evasion mechanisms, and epigenetic regulation. TNBC demonstrates variable immunogenicity, with tumor-infiltrating lymphocytes serving as important prognostic and predictive biomarkers. However, immune escape commonly occurs through tumor microenvironment remodeling, T-cell exhaustion, cancer stem cell enrichment, and immune checkpoint pathways activation. Although immune checkpoint inhibitors have improved outcomes in selected patients, particularly in combination with chemotherapy, primary and acquired therapeutic resistance remain a significant challenge. Emerging evidence highlights the central role of epigenetic mechanisms in regulating immune-related gene expression and shaping the tumor immune microenvironment. Epigenetic silencing of antigen presentation machinery, interferon signaling pathways, and chemokine expression contributes to immune evasion and immunotherapy resistance. Importantly, pharmacological modulation of epigenetic regulators can restore immune recognition and induce “viral mimicry” through reactivation of endogenous retroelements, thereby enhancing antitumor immunity. Collectively, this review underscores the therapeutic potential of integrating epigenetic therapies with immunotherapy and chemotherapy to overcome immune resistance in TNBC. A deeper understanding of epigenetic-immune interactions may facilitate the development of more precise and effective treatment strategies tailored to TNBC molecular subtypes. Full article

Ground-vehicle manufacturers and their suppliers must shorten development cycles to remain competitive. This paper presents a novel design framework that accelerates the traditional V-model development lifecycle by enabling digital twins and hardware-in-the-loop testing. As a case study, the design of active suspension actuators to address comfort shortfalls that hinder automated driving has been selected. A hybrid suspension architecture combining a continuously controlled hydraulic damper with an auxiliary electromechanical actuator has been proposed. The hybrid system achieves lower energy consumption than purely electromechanical suspensions while overcoming the bandwidth limitations of conventional hydraulic active suspensions. Control is implemented using the Triple Skyhook algorithm and benchmarked against a baseline strategy. Results demonstrate that the proposed framework accelerates actuator design iteration and that the proposed suspension delivers superior performance with improved efficiency and bandwidth. Full article

Aflatoxin B1 (AFB1) poses a serious threat to global food and feed safety. Laccase-based enzymatic degradation represents a promising green strategy for AFB1 removal; however, its industrial application is severely limited by the rapid thermal inactivation of wild-type enzymes under high-temperature processing conditions (>70 °C). Here, we engineered the thermal stability of a laccase from Bacillus amyloliquefaciens B10 through an integrated strategy combining computational structural biology with semi-rational design. By coupling molecular dynamics (MD) simulations with folding free-energy (ΔΔG) calculations, we identified key flexible regions associated with thermal instability and subsequently implemented iterative saturation mutagenesis. The best single mutant, R196C, retained more than 96% relative activity after heat treatment at 80 °C for 10 min. Further iterative mutational stacking progressively enhanced thermostability: the R90E/R196C double mutant showed 1.25-fold higher activity at 80 °C than R196C, and the R90E/R196C/H54F triple mutant showed a further 1.16-fold increase over the double mutant. The final quadruple mutant, R90E/R196C/H54F/R253I, achieved 86.9% AFB1 degradation at 80 °C after 24 h. High-temperature MD simulations (100 ns at 353.15 K) indicated that the enhanced thermostability was associated with reduced conformational flexibility, lower radius of gyration (Rg) and solvent-accessible surface area (SASA), and a coil-to-β-sheet transition that contributed to stabilization of the protein core. In addition, efficient secretory expression of the engineered enzyme was achieved in Pichia pastoris, reaching 3.0 U/mL, while the crude enzyme maintained more than 70% activity at 80 °C. Collectively, these results provide a practical basis for the rational engineering and scalable production of thermostable biocatalysts for AFB1 detoxification-related applications of AFB1 control, and offer broader insights into the targeted enhancement of thermal stability in industrial enzymes. Full article