Search Results (7,021)

Background/Objectives: In metastatic breast cancer (MBC) treated with CDK4/6 inhibitors, baseline neutrophil-to-lymphocyte ratio (NLR) is an established prognostic marker. On-treatment NLR dynamics have shown inconsistent associations with survival, and no prior study has applied a dominant-driver decomposition to classify patients by whether NLR change is neutrophil- or lymphocyte-driven. Methods: We retrospectively analyzed 352 patients with HR+/HER2− MBC treated with ribociclib. Using paired neutrophil and lymphocyte counts at baseline and at approximately 12 weeks (before cycle 4), a log-linear decomposition classified patients into four NLR-trajectory phenotypes by the dominant driver of change. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using a 4-month landmark approach with multivariable Cox models, with consistency evaluated across four thresholds, tertiles, and a continuous model. Secondarily, NLR change was compared across five response-trajectory groups. Results: NLR trajectory was not associated with PFS in any specification (multivariable hazard ratio [HR] 1.15 per standard deviation [SD], 95% CI 0.97–1.37, p = 0.12) but was independently associated with OS (HR 1.40 per SD, 95% CI 1.18–1.67, p < 0.001), confirmed on bootstrap resampling. Adding NLR trajectory improved discrimination (C-index +0.04) and fit (likelihood-ratio p < 0.001). The OS effect was time-varying, attenuating beyond 24 months. NLR trajectory was unrelated to dose-limiting neutropenia (p = 0.58) or dose reduction (p = 0.69). Primary refractory patients showed blunted NLR decline versus responding or stable patients (p = 0.005), independent of baseline NLR. Conclusions: On-treatment NLR trajectory is a correlate of OS, independent of PFS, dose-limiting neutropenia, and dose reduction, in ribociclib-treated MBC, distinct from direct tumor control. Prospective validation is warranted. Full article

Background: Ripretinib, a switch-control kinase inhibitor approved for advanced gastrointestinal stromal tumor (GIST), inhibits primary and secondary KIT and PDGFRA mutations. Real-world data from Western and Middle Eastern populations remain limited. We report outcomes from a molecularly characterized Israeli multicenter cohort. Methods: We conducted a multicenter retrospective cohort study across seven university-affiliated medical centers in Israel. Patients with advanced GIST receiving Ripretinib at any treatment line were eligible. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and response was assessed according to modified RECIST v1.1. Results: Sixteen patients were identified (median age, 67.5 years; 75.0% received Ripretinib in the fourth-line setting). KIT exon 11 mutations were present in 62.5% of patients, including five with secondary resistance mutations involving exon 13 or exons 17/18. Median PFS was 7.0 months (95% CI, 2.0–13.0) and median OS was 14.7 months (95% CI, 4.4–NR). Individual outcomes varied substantially, with PFS ranging from 2.0 to 60.2 months and OS from 2.2 to 60.2 months. Three patients achieved complete responses, with PFS of 20.0, 33.6, and 60.2 months. ORR was 56.3% (CR, n = 3; PR, n = 6) and DCR was 81.3%. No dose reductions or treatment discontinuations due to adverse events were documented; however, adverse events were recorded in only 4 of 16 patients. Conclusions: Ripretinib demonstrated clinical activity in this small, heavily pre-treated cohort. The relatively high ORR and wide variability in outcomes should be interpreted cautiously given the small sample size, retrospective design, and absence of central radiological review. Durable responses were observed in some patients with KIT exon 11 and secondary exon 17/18 mutations, but this exploratory observation does not establish a predictive molecular subgroup. Larger prospective studies with systematic molecular, radiological, and safety assessment are warranted. Full article

Traditional phenol-formaldehyde (PF) resin adhesives rely on petroleum-based phenolic monomers, facing dual pressures from resource constraints and environmental concerns. Lignin, an abundant renewable aromatic polymer in wood cell walls with a molecular structure rich in phenolic hydroxyl groups, serves as an ideal bio-based precursor for producing green PF resins. Developing lignin-based phenol-formaldehyde (LPF) resins not only enables the high-value utilization of forest biomass but also aligns with sustainable development strategies. However, the large-scale industrial application of lignin remains challenging due to its inherent drawbacks, such as low reactivity. This review focuses on lignin-modified PF resins, systematically summarizing the main physicochemical modification methods—including phenolation, hydroxymethylation, demethylation, and depolymerization activation—along with their mechanisms of influence on resin properties. It compares and discusses the advantages and disadvantages of different modification routes, analyzes current key technical bottlenecks, and prospects future development directions, aiming to provide a reference for research and application of forest-based green adhesive materials. This review concludes that the combination of physical pretreatment and targeted chemical modification is the most promising approach for enhancing lignin reactivity and resin performance. Future research should prioritize developing green modification technologies, such as those based on deep eutectic solvents (DESs) and aqueous systems, and establish quantitative structure–property relationships for lignin-based resins to accelerate the transition of lignin-based phenolic resins from laboratory research to industrial-scale production. Full article

Vaccines have demonstrated greater efficiency in providing immunoprotection against bacterial species, making them potentially valuable in aquaculture. In this study, twenty-four outer membrane proteins (OMPs) of Pseudomonas fluorescens were cloned, purified, and 16 OMP mouse antisera were prepared, with titers all exceeding 1:3200. Subsequently, these 16 antisera were used to passively immunize crucian carp (Carassius auratus) followed by challenge with the pathogenic bacteria. The results showed that five OMP antisera (PF0542, SurA, PF1798, PF2253, and PF4616), as well as the whole OMP serum, provided immune protection rates exceeding 60% against P. fluorescens and Aeromonas hydrophila infection (p < 0.05). Moreover, these five OMP antisera reduced the mRNA expression of inflammatory cytokines and antioxidant factors (p < 0.05), and exerted protective effects on the structural integrity of the kidney, spleen, and intestinal tissues. In addition, active immunization of crucian carp with these five identified OMPs followed by pathogen challenge demonstrated that these proteins could activate non-specific immune responses in fish, confer immune protection against P. fluorescens and A. hydrophila infection, reduce the mRNA expression of inflammatory cytokines and antioxidant factors (p < 0.05), and protect the tissue structure of the kidney, spleen, and intestine. Collectively, these five OMPs (PF0542, SurA, PF1798, PF2253, and PF4616) can activate immune responses in crucian carp, confer protection against bacterial infection, and exhibit reductions in inflammatory/oxidative responses associated with protection following bacterial challenge, and as well as viscera structure-maintaining effects. Therefore, the five OMPs hold promise as vaccine candidates against bacterial infections (P. fluorescens and A. hydrophila) for both passive and active immunization in fish. Full article

The increasing demand for electrified rail transportation has intensified power quality (PQ) challenges, including harmonics, voltage imbalance, and low power factor (PF). These issues have driven the development of advanced traction power supply systems, particularly co-phase configurations, to improve power quality, enhance grid-connected stability, and strengthen the operational resilience of railway power infrastructure. This paper proposes a co-phase power supply system for high-speed railways that facilitates high-speed train operation by integrating power quality compensation technologies while reducing the required number of neutral sections by half, thereby improving the continuity and robustness of traction power delivery. To address PQ issues, a capacitive-coupled hybrid power quality conditioner (HPQC) incorporating renewable energy sources (RESs) into its DC link is introduced. Given the highly dynamic and time-varying nature of railway loads, a sliding mode control (SMC)-based robust control method is developed based on the state space model of the co-phase power supply system and the HPQC to provide a stable and rapid response to load variations and operational disturbances. The effectiveness and real-time implementation capability of the proposed approach are validated through real-time control hardware-in-the-loop (CHIL) simulations. Results from MATLAB/Simulink simulations and real-time CHIL testing demonstrate substantial harmonic reduction, improved power factor, reduced negative-sequence currents, and enhanced overall system efficiency. These outcomes confirm the suitability of the proposed system for modern high-speed railway applications and highlight its contribution to resilient traction power supply systems capable of maintaining reliable operation under highly variable loading conditions. Full article

Background: Lenvatinib is an established first-line therapy for radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC); however, real-world data, particularly from Asian populations with long-term follow-up, remain limited. Methods: We conducted a multicentre retrospective cohort study across seven public hospitals in Hong Kong. Adult patients with RAI-refractory DTC who received lenvatinib between 1 January 2010 and 31 March 2025 were included. Efficacy outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and duration of treatment. Landmark analyses were performed at 6 and 12 months after lenvatinib initiation. Safety outcomes included treatment-related adverse events graded according to CTCAE version 5.0. Results: A total of 82 patients were included, with a median follow-up of 24.7 (IQR, 14.2–46.6) months. The median age at treatment initiation was 69 years, and the median starting dose of lenvatinib was 14 mg. Median PFS was 31.0 months (95% CI, 16.6–40.8) and median OS was 46.8 months (95% CI, 33.6–67.6), with multivariable analyses identifying brain metastasis as the most consistent adverse prognostic factor. The ORR was 52.4% and the DCR was 82.9%. Treatment-related adverse events were common, most frequently hypertension (73.2%) and proteinuria (57.3%); grade ≥ 3 events occurred predominantly as hypertension (45.1%). Conclusions: Lenvatinib achieved durable clinical outcomes in patients with RAI-refractory differentiated thyroid cancer despite the frequent use of reduced starting doses. Treatment-related toxicities were common but generally manageable, allowing prolonged treatment in many patients. Full article

Background/Objectives: Lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint molecule that may contribute to immune escape in diffuse large B-cell lymphoma (DLBCL). This study aimed to characterize LAG-3 expression in neoplastic cells and tumor-infiltrating lymphocytes (TILs) and to investigate its associations with clinicopathological features and clinical outcome. Methods: This retrospective, single-center study included 210 patients with DLBCL diagnosed between 2007 and 2019. LAG-3 expression was evaluated immunohistochemically in whole-tissue sections. Tumor-cell expression was assessed according to the percentage and intensity of positive cells, while LAG-3-positive TILs were quantified as the mean number of positive lymphocytes per high-power field (HPF). Associations with clinicopathological parameters, treatment response, overall survival, and progression-free survival (PFS) were analyzed. Results: LAG-3 staining of varying intensity was observed in neoplastic cells in 177 cases (84.3%), and 82 cases (39.0%) were classified as LAG-3 positive using a 10% tumor-cell cut-off. The median number of LAG-3-positive TILs was 5/HPF. Male patients showed a higher percentage of LAG-3-positive tumor cells than female patients (p = 0.039). Moderate-to-strong tumor-cell staining was significantly more frequent in cases with >5 LAG-3-positive TILs/HPF than in those with ≤5 TILs/HPF (p = 0.018). LAG-3 expression parameters were not significantly associated with treatment response or overall survival. Univariate Cox regression analysis also showed no significant association between overall survival and LAG-3-positive TIL count, tumor-cell LAG-3 percentage, or staining intensity. Exploratory PFS analysis in 66 evaluable patients also showed no significant association with LAG-3 expression parameters. Conclusions: LAG-3 expression in DLBCL occurs in both neoplastic cells and TILs. The association between increased LAG-3-positive TILs and stronger tumor-cell expression supports further investigation of LAG-3 across both cellular compartments. No significant association with overall survival was observed in this cohort; however, the limited number of survival events precludes definitive conclusions regarding its prognostic significance. Further studies using standardized assessment methods and larger, clinically well-characterized cohorts are warranted. Full article

Understanding the stress sensitivity of multiscale pore fracture structures (PFS) in coals with different ranks is critical for evaluating coalbed methane (CBM) reservoir behavior. In this study, low-rank and high-rank coals were subjected to effective confining pressure loading–unloading tests under constant pore pressure, and the dynamic evolution of PFS was investigated using low-field nuclear magnetic resonance (LF-NMR), nuclear magnetic resonance imaging (NMRI), and fractal analysis. For the tested specimens, the Fengjiata low-rank coals exhibited higher proportions of seepage pores (SPs) and generally greater stress sensitivity, whereas the Sijiazhuang high-rank coals were dominated by adsorption pores (APs) and showed comparatively stable PFS. SPs are more sensitive to effective stress than APs, and stress-induced pore deformation shows partial irreversibility after unloading. Furthermore, an NMR-based method was proposed to quantify stress-dependent pore compressibility, revealing that pore compressibility decreases logarithmically with increasing effective stress due to the progressive loss of compressible pore space. These findings provide new insights into the multiscale stress response of coal pore fracture systems and improve the evaluation of stress-sensitive permeability evolution in CBM reservoirs. Full article

Precision fermentation (PF) yields single, well-characterized recombinant proteins, such as dairy and egg white proteins, at an industrial scale, and several products have reached the market. Numerous PF-derived proteins, including ovomucoid and β-lactoglobulin, are known allergens designed as exact structural copies of their native homologs; hence, assessments center on equivalence rather than novel hazards. Therefore, the current tiered scheme of allergen database comparison, digestibility testing, and serum immunoglobulin E binding assays is applicable. Nevertheless, residual host cell proteins, altered host-dependent enzymatic glycosylation, and process-related impurities render PF-derived products imperfect replicas, and thermal and high-pressure processing, enzymatic hydrolysis, and non-enzymatic glycation can modify linear or conformational epitopes, thereby reducing IgE binding or generating neoepitopes. Because these effects depend on structural attributes acquired during production, including folding stability, disulfide bonding, glycosylation, and proteolytic resistance, PF-derived proteins and native proteins may respond differently to identical processing. This review explores the molecular attributes acquired at each stage of PF production and the epitope changes originating during processing, reevaluates the current assessment scheme, and outlines considerations for a premarket safety framework reflecting realistic processing and consumption conditions. Full article

Background and Objectives: Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is an aggressive resistance phenotype arising during metastatic castration-resistant prostate cancer (mCRPC). Because metastatic biopsy is not routinely feasible in advanced disease, real-world data on clinically defined t-NEPC/aggressive-variant prostate cancer (AVPC)-like disease remain limited. We aimed to characterize the clinical features, treatment patterns, survival outcomes, and prognostic factors of this clinically defined phenotype. Materials and Methods: We retrospectively reviewed 354 patients with prostate cancer treated at our institution between 2010 and 2020. Seventy-four patients with mCRPC who were clinically identified as having a t-NEPC/AVPC-like phenotype and had a treatment plan for platinum- and/or etoposide-based neuroendocrine-directed systemic therapy were included. Overall survival (OS) and radiographic progression-free survival (rPFS) were estimated using the Kaplan–Meier method, and prognostic factors were evaluated using Cox regression analyses. Results: At clinical identification of the phenotype, the median age was 66.4 years, and visceral metastases were present in 67.6% of patients, most commonly in the liver (55.4%). Median intervals from prostate cancer diagnosis and CRPC onset to clinical identification of the phenotype were 47.5 and 22.7 months, respectively. Neuroendocrine-directed therapy was initiated in 72 patients; platinum–etoposide was the most common first-line regimen (n = 41, 55.4%). Median OS was 4.4 months (95% confidence interval [CI], 2.9–5.8), and median rPFS was 3.5 months (95% CI, 2.7–4.2). In an exploratory, unadjusted analysis, median OS did not differ significantly between doublet chemotherapy and monotherapy (7.0 vs. 3.5 months; p = 0.167). Gleason score ≥9, hemoglobin <12 g/dL, and albumin <3.5 g/dL were independently associated with inferior OS. Conclusions: The clinically defined t-NEPC/AVPC-like phenotype was associated with an aggressive clinical course and poor survival. Earlier recognition, improved biomarker-based diagnostic strategies, and more effective therapeutic approaches are needed. Full article

Background/Objectives: Clinical outcomes with immune checkpoint inhibitors (ICIs), such as nivolumab, vary among patients with metastatic non-small cell lung cancer (NSCLC). The Lung Immune Prognostic Index (LIPI) may help stratify prognosis. This study evaluated the prognostic significance of LIPI in patients receiving second- or third-line nivolumab and developed a nomogram for individualized survival estimation. Methods: This single-center retrospective study included 142 patients with metastatic NSCLC who received second- or third-line nivolumab between February 2022 and December 2024, after progression on platinum-based chemotherapy. LIPI was calculated from baseline values obtained within 14 days before nivolumab initiation, based on a derived neutrophil-to-lymphocyte ratio (dNLR) > 3 and lactate dehydrogenase (LDH) > 225 U/L (institutional upper limit of normal), classifying patients as good-, intermediate-, or poor-risk (0, 1, or 2 factors, respectively). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method; independent prognostic factors were assessed by multivariable Cox regression, and a prognostic nomogram combining ECOG performance status, serum albumin, and LIPI was developed and internally validated. Results: By LIPI, 34.5%, 45.1%, and 20.4% of patients were at good, intermediate, and poor risk, respectively. Objective response and disease control rates were 29.6% and 55.6%. Median OS and PFS were 19.3/8.0/3.1 and 8.6/3.1/2.5 months across good, intermediate, and poor LIPI groups (log-rank p < 0.001). In multivariable analysis, ECOG 2 (hazard ratio [HR], 4.94), albumin per 1 g/dL (HR 0.27), and poor versus good LIPI (HR 3.74) were independently associated with OS. A nomogram combining these three factors showed acceptable discrimination (optimism-corrected Harrell C-statistic 0.742). Conclusions: LIPI was independently associated with prognosis in this cohort. Combining LIPI with ECOG and albumin may aid individualized risk assessment, pending external validation. Full article

Fringe projection profilometry (FPP) is widely used for high-precision three-dimensional measurement, but its performance is severely degraded when measuring non-Lambertian surfaces with complex reflectance. In such cases, fringe saturation and low modulation lead to unreliable phase values and missing reconstructed data. To address this problem, this paper proposes a photometric feature-guided phase inpainting method for high-dynamic-range FPP. Within the proposed FPP with multi-illumination framework, fringe images are used for phase calculation, while multi-illumination images provide additional photometric cues for phase inpainting. A photometric feature-guided phase inpainting network is designed to extract photometric features from multi-illumination images and fuse them with the damaged phase map. The network is trained on a large-scale synthetic dataset and validated using a prototype system. In standard copper-sphere measurements, PF-PINet increases the average reliable reconstruction ratio from 81.85% to 84.31% while maintaining comparable reconstruction accuracy, indicating that the proposed method can improve measurement completeness for non-Lambertian surfaces. Full article

Background: Approximately 13% of NSCLC cases have KRAS G12C mutations. As therapeutic strategies targeting KRAS G12C-mutant NSCLC evolve, it is important to understand clinical presentation and current outcomes for these patients. Methods: This retrospective study used data from two US nationwide databases, an electronic health records (EHR) database and a clinico-genomic database (CGDB) of EHR data linked to data from comprehensive genomic profiling tests. Eligible patients had advanced NSCLC, initiated first-line therapy from August 2018 to December 2022, and had KRAS test results. Clinicopathologic characteristics, treatments, real-world progression-free survival (rwPFS), and overall survival (OS) were analyzed. Results: There were 1227 patients with KRAS G12C-mutant NSCLC in the EHR database and 447 in the CGDB. First-line regimen was platinum-based chemotherapy plus pembrolizumab for 46% and pembrolizumab monotherapy for 20%. Less than 40% of patients received second-line therapy. Median (95% CI) OS for KRAS G12C-mutant NSCLC patients in the EHR was 17.0 (15.2–18.9) months. Variables significantly associated with shorter OS included PD-L1 <1%, brain metastases, STK11 co-mutation, and poor performance status. Patients treated with platinum-based chemotherapy plus pembrolizumab had median rwPFS of 5.3 (4.5–7.3) months and OS of 12.8 (11.1–17.3) months in the CGDB; median OS was 15.6 (12.5–18.6) months in the EHR. Patients with PD-L1 ≥ 50% treated with pembrolizumab monotherapy had median rwPFS of 4.6 (3.0–15.6) months and OS of 20.4 (10.3–38.5) months in the CGDB; median OS was 22.1 (18.7–30.7) in the EHR. Conclusions: These data provide a real-world benchmark of outcomes for patients with KRAS G12C-mutant NSCLC receiving the current standard of care and indicate an unmet need for more effective first-line therapies. Full article

Malaria is a life-threatening global disease, and despite artemisinin-based combination therapies (ACTs) as first-line treatment, emerging drug-resistant Plasmodium strains necessitate novel antimalarial agents. This study investigated the antiplasmodial potential of Eurycoma harmandiana Pierre (EH) root extract, a medicinal plant closely related to Eurycoma longifolia Jack (EL). The extract and its derived compounds were evaluated using in vitro antiplasmodial and cytotoxicity assays. The active compounds were further investigated by parasite morphological analysis, molecular docking against quadruple-mutant Plasmodium falciparum dihydrofolate reductase (qmPfDHFR), molecular dynamics (MD) simulations, and in silico prediction of drug-likeness, pharmacokinetic properties, and toxicity. The ethanolic extract exhibited potent antiplasmodial activity (IC₅₀ = 0.51 µg/mL) with low cytotoxicity (CC₅₀ = 31.68 µg/mL) and a high selectivity index (SI = 62.11). Quassinoids showed the strongest activity (IC₅₀ = 0.13–0.87 µM), whereas alkaloids displayed good to moderate activity. The extract and two promising bioactive quassinoids, eurycomanone (1) and glaucarubolone (5), disrupted intraerythrocytic parasite development. Molecular docking and MD simulations demonstrated that glaucarubolone (5) exhibited favorable predicted interactions with qmPfDHFR, along with favorable predicted drug-like properties, pharmacokinetic profiles, and low toxicity. This study provides the first report of the antiplasmodial activity of Eurycoma harmandiana, highlighting it as a promising alternative source of bioactive compounds against Plasmodium parasites. Glaucarubolone (5) may represent a promising scaffold for further investigation toward the development of novel antimalarial agents. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent malignancy. While Cemiplimab has transformed the treatment landscape across various disease stages, reliable pretreatment biomarkers for risk stratification remain lacking.. The Global Immune–Nutrition–Inflammation Index (GINI) is a composite biomarker integrating systemic inflammation and nutritional status into a single score. This study aimed to evaluate the prognostic value of the pretreatment GINI in patients with cSCC receiving Cemiplimab across all treatment settings. Methods: This retrospective cohort study evaluated 73 patients with unresectable, locally advanced, or metastatic cSCC treated with Cemiplimab between 2020 and 2023. Pretreatment laboratory parameters were extracted to calculate the GINI score. Receiver operating characteristic (ROC) curve analysis determined the optimal GINI cutoff to stratify patients into low- and high-GINI groups. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed using Kaplan–Meier curves and multivariable Cox proportional hazards models. Results: An optimal GINI cutoff of 74.4 divided the cohort into low-GINI (38%) and high-GINI (62%) groups. In the multivariable Cox regression models, a high pretreatment GINI remained independently associated with both inferior OS (adjusted HR 2.51, 95% CI 1.05–6.01, p = 0.039) and inferior PFS (adjusted HR 3.22, 95% CI 1.45–7.14, p = 0.004). When compared against five established inflammatory biomarkers (NLR, PLR, LMR, PNI, and CAR), the GINI consistently demonstrated comparable prognostic performance across multiple statistical approaches. Conclusions: The pretreatment GINI is a candidate prognostic marker for patients with cSCC undergoing Cemiplimab therapy. Given its cost-effectiveness and ready availability from routine clinical laboratory workups, the GINI score may improve prognostic risk stratification and could potentially inform risk assessment and clinical monitoring in real-world oncological practice. Full article