Search Results (1,433)

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited actionable targets, early recurrence, metastatic propensity, and variable responses to immune checkpoint blockade. Therapeutic resistance is closely associated with myeloid immunosuppression, in which tumor-associated macrophages (TAMs) promote T-cell exclusion, stromal remodeling, angiogenesis, metabolic dysfunction, and resistance to cytotoxic and immune-based therapies. Anthraquinone compounds, including emodin, aloe-emodin, rhein, and chrysophanol, may support TAM reprogramming by regulating tumor-cell stress responses, endoplasmic reticulum stress, immunogenic cell death-associated signaling, redox balance, immunometabolism, and STAT3/NF-κB-related inflammatory pathways. However, poor aqueous solubility, heterogeneous biodistribution, unstable systemic exposure, and potential off-target toxicity limit their translational development. Liposomal delivery offers a formulation strategy to improve solubilization, biodistribution, TAM-associated uptake/engagement, intracellular release, and therapeutic exposure windows. This review discusses anthraquinone-loaded liposomes for TAM reprogramming in TNBC by integrating mechanistic rationale, evidence boundaries, delivery logic, formulation determinants, and translational challenges, with particular attention to stress chaperone proteins, lipid composition, vesicle lamellarity, membrane phase state, responsive release, clinically relevant liposomal formulations, and clinical developability. Overall, anthraquinone-loaded liposomes are better positioned as immune microenvironment recalibration platforms or synergistic modulators in combination therapy rather than as standalone cytotoxic agents for TNBC. Full article

Background: Although single-inhaler triple therapy (SITT) improves COPD control, the specific structural and behavioral predictors of short-term clinical response following therapeutic simplification remain incompletely characterized. Methods: This prospective, multicenter observational study (N = 684) evaluated patients switching from triple therapy regimens involving multiple inhalers to SITT. A clinically meaningful response was defined as an intra-individual reduction of ≥2 points in the validated RADAR score at three months. Results: Therapeutic simplification reduced regimens requiring ≥4 inhalations/day from 46.1% to 14.3%, and poor behavioral adherence from 45.2% to 16.6%. Multivariable models identified an observed responder profile: higher baseline RADAR burden was the strongest predictor of improvement (aOR 2.00), whereas severe airflow limitation (FEV₁ < 50%) attenuated the response. Exploratory mediation analysis indicated that 88.6% of the observed clinical stabilization was not explained by measured adherence changes, and may therefore also encompass unmeasured behavioral, educational or device-related factors. Patients burdened with both high complexity and poor adherence showed the highest rate of combined structural–behavioral improvement (25.0% vs. 4.7% overall). Conclusions: Switching from MITT to SITT was associated with reduced treatment complexity, improved adherence profiles, and short-term improvement in RADAR-defined clinical control. Patients with greater baseline RADAR burden and regimen complexity showed larger observed improvements. Full article

New copper(II) (C1) and palladium(II) (C2) complexes with S,O-tetradentate ligand (L) derived from thiosalicylic and thiopropionic acids were synthesized. In cell-based assays, (C1) exhibited the most pronounced activity within the tested compound series and was therefore advanced for mechanistic evaluation in 4T1 triple-negative breast cancer cells. (C1) significantly reduced 4T1 cell viability by inducing early and late apoptosis, accompanied by mitochondrial membrane depolarization and enhanced cytochrome C release. Consistently, (C1) increased the Bax/Bcl-2 ratio, promoting a pro-apoptotic shift. In parallel, (C1) triggered autophagy, as evidenced by decreased p62 and LC3B levels, induced G0/G1 cell-cycle arrest, and suppressed proliferative signaling by downregulating Ki67, cyclin D, and phosphorylated AKT. The DNA-binding studies showed moderate to strong affinity, favoring minor groove binding, with higher affinity for (C1) than for (C2). Tryptophan fluorescence quenching indicated a strong interaction with BSA via a predominantly static mechanism, more pronounced for (C1). Molecular docking at the DNA and BSA binding sites corroborated experimental findings and suggested favorable interactions between the complexes and apoptosis-related proteins (CASP3, BAX, and BCL2). The integrated experimental and computational data identify (C1) as a biologically active compound with multimodal biological effects in vitro, supporting further structural optimization and mechanistic investigation. Full article

Background/Objectives: Melatonin is a multifunctional indoleamine with recognized antitumor activity; however, its subtype-specific effects in breast cancer remain incompletely understood. This study aimed to investigate the impact of melatonin on cellular and metabolic processes associated with tumor progression in two human breast cancer cell lines representing distinct molecular subtypes: MCF-7 (luminal A) and MDA-MB-468 (triple-negative). Methods: Breast cancer cells were treated with micromolar concentrations of melatonin, and assays were performed to evaluate cell viability, migration, invasion, mitochondrial status, redox balance, protein expression, and biogenic amine profiles. Results: Melatonin significantly reduced cell viability, migration, and invasion in both cell lines, with more pronounced effects in MCF-7 cells. At the molecular level, melatonin downregulated key metabolic and hypoxia-related proteins, including GAPDH and HIF-1α, while citrate synthase was selectively reduced in MCF-7 cells, indicating suppression of mitochondrial metabolic capacity. This was accompanied by a reduction in mitochondrial status, reflected by decreased MitoGreen staining. Melatonin also induced redox imbalance, as evidenced by increased lipid peroxidation and protein carbonylation, along with subtype-dependent modulation of antioxidant enzymes. In addition, alterations in biogenic amine profiles were observed, suggesting broader metabolic remodeling. Conclusions: Collectively, these findings demonstrate that melatonin exerts subtype-dependent antitumor effects by targeting metabolic, mitochondrial, and redox pathways, supporting further investigation of melatonin as a potential therapeutic adjuvant in breast cancer, while recognizing that the concentrations used in this study exceed physiological circulating levels. Full article

Background: Dupilumab, a monoclonal antibody blocking IL-4Rα, has recently demonstrated efficacy in patients with type 2 (T2)-inflamed chronic obstructive pulmonary disease (COPD) in the BOREAS and NOTUS trials. Real-world experience in older patients with predominant chronic bronchitis phenotype remains limited. Methods: We report a single-centre case series of 12 consecutive patients with T2-inflamed COPD treated with dupilumab 300 mg every two weeks under a compassionate-use programme at San Carlo di Nancy Hospital, Rome (first administration: April 2025). Eligibility required ≥2 moderate or ≥1 severe exacerbation in the prior 12 months despite triple inhaled therapy and a blood eosinophil count ≥300 cells/µL. Follow-up ranged from 3 to 12 months, with 6 months pre-specified as the primary analysis timepoint; data at 9 and 12 months are reported as descriptive observations. Endpoints included paired changes in annualised exacerbation rate (AER), CAT score and item-level CAT, and FEV₁, with exploratory univariate Spearman analyses of candidate baseline predictors of response. Results: The cohort was elderly (mean age 73.6 ± 5.2 years, range 65–82), predominantly female (8/12, 67%) and characterised by a chronic bronchitis phenotype with high symptom burden (mean baseline CAT 22.8 ± 7.5; CAT item 2 [phlegm] median 3, IQR 3–4). Severe exacerbations decreased significantly (Wilcoxon p = 0.0156; mean AER 0.75 → 0.19 events/patient-year; 6/12 improved, 0/12 worsened). The mean cumulative function showed a standardised incidence ratio of 0.46 (95% CI 0.19–0.95; p = 0.033) versus the pre-dupilumab rate. Mean FEV₁ increased by +66 mL at 1 month (n = 11, paired Wilcoxon p = 0.025), +78 mL at 3 months (n = 10, p = 0.082) and +120 mL at 6 months (n = 10, p = 0.007). Total CAT decreased from 22.9 to 12.5 at 6 months (Friedman p = 0.0007), with the largest absolute reductions in item 2 (phlegm; Δ = −2.6 at 6 months, p < 0.001) and item 3 (chest tightness; Δ = −2.5 at 6 months, p = 0.002). Higher baseline CAT was associated with greater reduction in severe AER (Spearman ρ = −0.79, p = 0.002). Conclusions: In this elderly real-world cohort with phlegm-driven T2 COPD, dupilumab was associated with a significant decrease in severe exacerbations, a clinically meaningful gain in lung function and a marked improvement in mucus-related symptoms. Further studies are warranted to confirm these findings and to clarify whether the reduction in severe exacerbations translates into a measurable mortality benefit. Full article

Purple basil (Ocimum basilicum L.) is a medicinal plant widely recognized for its richness in bioactive compounds; however, its production in semi-arid regions is often constrained by soil and/or irrigation water salinity. Micronutrient fertilization may contribute to plant stress alleviation under salinity, since elements such as Mn, Mo, and Zn are involved in essential processes related to photosynthetic metabolism and physiological adjustment. This study aimed to evaluate the short-term effects of Mn, Mo, Zn, and their combinations on growth, gas exchange, and relative chlorophyll indices of purple basil plants subjected to severe NaCl stress under greenhouse conditions. The experiment was conducted under greenhouse conditions for 30 days in a randomized block design with nine treatments and four replicates: a non-saline control without micronutrients, a saline control without micronutrients, and plants exposed to 100 mM NaCl with substrate application of Mn, Mo, Zn, MoMn, ZnMo, ZnMn, or ZnMoMn. Micronutrient sources were applied to the substrate at 3.5 g kg⁻¹ according to each treatment. Fertilization with Mn, Mo, Zn, and their combinations enhanced plant stress alleviation under salinity compared with the saline control without micronutrients, with positive responses in growth and physiological performance, including increases in chlorophyll indices. The double combinations MoMn, ZnMo, and ZnMn attenuated the effects of NaCl, especially by increasing leaf area. Mn stood out for increasing net photosynthesis and water-use efficiency, whereas Mo and ZnMo were associated with higher relative chlorophyll indices. Although the triple combination ZnMoMn improved some traits compared with the saline control, its lower efficacy relative to selected single or double applications may indicate that the simultaneous supply of the three elements reduced specific synergistic effects, possibly due to nutritional imbalance or antagonistic interactions among micronutrients under severe salinity. Overall, micronutrient fertilization, particularly through specific double combinations, may contribute to short-term mitigation of NaCl-induced stress responses under controlled greenhouse conditions. Full article

Background/Objectives: Extramedullary disease (EMD) is an aggressive and treatment-resistant manifestation of multiple myeloma with limited therapeutic options, particularly in heavily pretreated patients. Methods: We conducted a retrospective study to evaluate the efficacy and safety of concurrent immune checkpoint inhibitors (ICIs) and radiation therapy (RT) in patients with EMD treated at Hackensack University Medical Center and John Theurer Cancer Center between January 2016 and May 2025. Patients were included if they had confirmed EMD and received nivolumab or pembrolizumab with concurrent RT. Results: A total of 21 patients were included, representing a high-risk cohort with a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease. The overall response rate (ORR) was 47.6%, with a clinical benefit rate of 57.1%. Despite these responses, median progression-free survival (PFS) and overall survival (OS) were 4 and 12 months, respectively. Notably, two patients achieved complete responses with nivolumab and RT early in their treatment course following cellular therapy and remain disease-free at last follow-up. The combination of ICIs and RT was generally well-tolerated, with manageable immune-related adverse events and no treatment-related deaths. Conclusions: These findings suggest that concurrent ICI and RT may provide a signal of treatment responses in a subset of patients with advanced EMD, although durability remains limited. Further prospective studies are warranted to further define the role of this combination and identify patients most likely to benefit. Full article

Against the backdrop of the transition of new-type urbanization towards high-quality development, the triple contradictions of population agglomeration, land constraints, and housing supply-demand imbalance have become increasingly prominent. The conventional binary framework of human–land relations can no longer meet the requirements of coordinated development within human settlement systems, creating an urgent need to examine the multi-system interactions among population, land, and housing in order to resolve spatial mismatch. Taking Guangzhou as a case study, this research integrates 2020 population census data, land-use data from the European Space Agency (ESA), housing-price data from the Anjuke platform, and multi-source data on related influencing factors, and conducts a systematic empirical analysis by combining coupling coordination analysis, a relative development model, and the geographical detector. The findings reveal that the coupling coordination level of population, land and housing in Guangzhou exhibits a concentric, ring-shaped distribution pattern with central agglomeration and peripheral decline. The relative development among the three systems can be classified into matching types including the core-differentiated type, the peripheral-imbalanced type, and the surrounding-equilibrium type. With respect to influencing factors, all pairwise interactions are of the bi-factor enhancement type, and the driving mechanism displays a three-stage dynamic evolution. This study enriches research on human–land relations, provides precise guidance for optimizing spatial allocation and alleviating housing mismatch conflicts in Guangzhou, and offers transferable practical experience for comparable cities in China seeking to advance the high-quality development of new-type urbanization. Full article

Metallurgical lifting equipment operates under prolonged heavy-load, high-impact, and complex working conditions. The resulting failure reports contain rich field knowledge applicable to fault diagnosis and predictive maintenance. Nevertheless, reliably extracting traceable, structured knowledge from procedural and implicit maintenance records remains a significant challenge. To address this, the paper proposes a generative information extraction method for large language models (LLMs) that integrates ontology schema with inference chain constraints, targeting knowledge extraction and knowledge graph construction from failure reports of metallurgical lifting equipment, named generative constrained information extraction for operations and maintenance (GCIE-OM). A domain ontology schema is first constructed, defining seven entity types and nine relation types to establish explicit knowledge boundaries for structured LLM generation. An inference chain-assisted structured parsing method, termed IC-ASP, is then designed to guide the model through a sequential extraction pipeline comprising scene identification, scope of entity boundary, inference of relation type, evidence traceability with localization, and triple output. This stepwise process strengthens the model’s capacity to comprehend equipment hierarchies, fault evolution chains, and maintenance action logic. Building on this, ChatGLM or LLaMA serves as the backbone model and is adapted to the target domain via LoRA fine-tuning. Entity alignment and character-level source localization mechanisms are further introduced to establish precise mappings between generated outputs and their textual evidence in the source documents. The extracted results are ultimately converted into standardized knowledge triples and stored in a Neo4j graph database. Based on this, a prototype system for generative information extraction is designed and implemented to demonstrate the practical effectiveness and adaptability of the proposed method. Experimental results show that the proposed method outperforms baseline methods across entity recognition, relation extraction, and structured output quality, providing robust knowledge support for fault tracing and predictive maintenance of metallurgical lifting equipment. Full article

The certification information of wheat varieties contains valuable breeding knowledge and plays an important role in germplasm resource management and breeding research. However, most certification information is stored in unstructured text form, making it difficult to support efficient knowledge acquisition and utilization. To address this issue, this paper investigates joint entity-relation extraction from wheat variety certification texts and its application to knowledge graph construction. Specifically, building on existing character-word fusion methods, we propose the Joint Entity-Relation Extraction for Wheat Variety Certification Texts (JERE-WVCT) to address indiscriminate incorporation of candidate features in character-word fusion that obscures key features, a lack of differentiated weight assignment for features, and severe imbalance across relation types. Within JERE-WVCT, a deep character-word fusion mechanism based on hierarchical filtering and ranking is designed to enhance the representation of domain-specific entities. In addition, relation labels are incorporated as prior knowledge to alleviate the impact of relation type imbalance and improve the model’s triple extraction capability. Experimental results show that JERE-WVCT achieves an F1 score of 96.78% on the wheat variety certification corpus, outperforming all baseline models. Based on the extracted triples, a wheat variety knowledge graph is constructed, and exploratory variety relationship analysis is conducted as a downstream application. The results demonstrate the effectiveness of the proposed model for structured knowledge acquisition and support graph-based exploration of wheat variety information. Full article

Gut microbiota-derived short-chain fatty acids (SCFAs) shape epithelial and immune homeostasis, yet systemic SCFA profiles may diverge from gut microbial composition due to absorption and host metabolism. We quantified fasting serum SCFAs in 36 surgically resected colorectal cancer (CRC) patients and 20 cancer-free controls using targeted high-performance liquid chromatography–triple quadrupole mass spectrometry, and integrated these data with fecal and serum bacterial DNA profiles generated by 16S ribosomal RNA sequencing and functional inference. CRC was associated with a distinct circulating SCFA pattern: total SCFAs and acetate were increased, branched SCFAs were higher, and butyrate and valerate were lower relative to controls. Despite this clear systemic signature, associations between serum SCFAs and the relative abundance (RA) of putative SCFA-producing genera were sparse and inconsistent across CRC and control groups, both when considering fecal producers and serum-detected taxa. Interestingly, the total RA of SCFA-producing genera was higher in controls in feces but higher in CRC in serum, further supporting compartment-specific decoupling. Finally, several circulating SCFAs showed inverse associations with indicators of tumor progression within CRC. These results motivate integrative microbiota–metabolite studies and validation in larger cohorts to clarify how circulating SCFAs relate to gastrointestinal disease biology and immune regulation. Full article

Multiple three-phase machine drives are inherently fault-tolerant due to their multiphase structure; however, they remain susceptible to inverter-related faults. A common fault is the loss of gate signals in one inverter leg, resulting in an open-phase condition. Under such conditions, a reverse conduction path is established through the freewheeling diodes of the faulted leg, leading to uncontrolled freewheeling diode current generation. The resulting freewheeling diode current becomes particularly critical in the field-weakening region, when the back-EMF may exceed the DC-link voltage and a large reverse current can occur. This paper derives an analytical expression for real-time prediction of the freewheeling diode current in a triple three-phase surface-mounted permanent magnet synchronous machine drive. The method is applicable in both the constant-torque and field-weakening regions. The analytical prediction is validated through comparison with both experimentally measured and numerically simulated freewheeling diode current waveforms over a wide range of operating points, including no-load and loaded conditions. The results show that the proposed model accurately reproduces the envelope and conduction boundaries, while maintaining good agreement with simulations and measurements. The predicted current can be utilized in post-fault control, fault detection, and sensorless position estimation. Full article

Rice monoculture systems, often involving double- or triple-cropping cycles annually, require intensive agricultural practices that can lead to land degradation. This study evaluates land degradation within the long-term rice monoculture systems of Nakhon Sawan, Thailand, using the Sustainable Development Goal 15.3.1 framework. By focusing exclusively on persistent rice-growing areas, the study minimized the confounding signals of land-use conversion, allowing for an evaluation of the trajectories driven by combined agricultural management and climatic factors. The assessment integrated land use and land cover (LULC), soil organic carbon (SOC) stocks, and land productivity. Findings indicate that 83% of the original paddy area remained long-term monoculture, with LULC-related degradation limited to 4% of the original paddy cultivation area. While SOC depletion was observed in a few districts, a broader potential carbon accretion trend was identified across the province, likely driven by sustainable post-harvest practices such as stubble retention and organic amendments. Land productivity analysis revealed partial stress only in a few districts. The study demonstrated that long-term rice cultivation did not result in widespread deterioration of soil health on an aggregate provincial scale; however, district-localized degradation hotspots suffering from soil organic carbon depletion and climate-induced productivity stress were identified, demanding targeted regional management. Full article

Background: Type 2 diabetes is projected to affect millions of people annually as the number of cases rises year on year. This includes children. Treating diabetes and its related comorbidities has a huge economic impact and puts pressure on healthcare providers. Understanding the disease at a molecular level is key for developing better therapeutics. The protein Islet Amyloid Polypeptide (IAPP) or amylin is important for glucose regulation; however, it is also instrumental in type 2 diabetes pathology. Human IAPP can misfold into oligomers and amyloid fibrillar aggregates within pancreatic islets, promoting β-cell dysfunction and death, contributing to progressive insulin deficiency and worsening hyperglycaemia. Methods: Based on previous studies on mutations at residues 18, 28 and 31,we have designed three novel IAPP analogues (two double and one triple mutant) to assess whether the combined amino acid substitutions impact fibril formation, solubility and toxicity. Results: All three of our analogues show a reduced propensity to aggregate and are more soluble than wild type IAPP. Compared with pramlintide, a clinically prescribed synthetic analogue of human amylin, all of our analogues appeared to have similarly reduced toxicity and improved solubility relative to human IAPP. Additionally, two of our analogues exhibited a markedly slower rate of fibril formation. Conclusions: Our results highlight the importance of targeting multiple residues as a promising strategy for developing improved diabetes therapeutics in the future. Full article

Background/Objectives: Antimicrobial peptides (AMPs) are promising candidates against multidrug-resistant bacteria, although their clinical translation is frequently limited by cytotoxicity. In this study, we investigated whether combinations of structurally related oligomeric analogs could cooperatively enhance bacterial membrane targeting while redistributing the associated cytotoxic burden. Methods: Monomeric, dimeric, and tetrameric AMPs were evaluated through antimicrobial susceptibility testing, checkerboard interaction assays, RAW 264.7 macrophage cytotoxicity assays, and all-atom molecular dynamics simulations, including biased membrane insertion and umbrella sampling analyses. In addition, we introduced the Combinatorial Therapeutic Index (CTI) as an exploratory metric to estimate the predicted reduction in cytotoxic burden associated with peptide combinations. Results: Cytotoxicity varied substantially among oligomeric forms, with larger and more hydrophobic peptides, particularly tetramers, exhibiting the highest cytotoxicity. Additive effects were observed in checkerboard assays involving linear, dimeric, and tetrameric forms, supporting the redistribution of the toxic burden and enabling the beneficial membrane-interaction properties of hydrophobic linear peptides to be leveraged at lower cytotoxic cost. Predicted therapeutic improvement ranged from approximately twofold for the SET-M33:L33 combination to nearly ninefold for the SET-M33:DIM-33:L8 triple combination. Molecular dynamics simulations revealed non-redundant membrane interaction behaviors, with smaller peptides exhibiting deeper membrane insertion and the dimeric form favoring interfacial membrane engagement. Conclusions: These findings support a cooperative formulation strategy in which structurally related SET-M33 oligomers contribute complementary antibacterial functions while reducing the predicted cytotoxic burden. Further experimental validation using direct cytotoxicity assays of complete peptide mixtures will be necessary to confirm the therapeutic potential of these formulations. Full article