Search Results (5,851)

Compounds of plant origin have increasingly emerged as anticancer agents through direct cytotoxicity and sensitizing mechanisms. Melanoma remains the most aggressive form of skin cancer that exhibits a steadily increasing number of new cases globally each year, thus urgently requiring more effective therapeutic strategies. Therefore, phytochemicals can be considered promising candidates, particularly when used in combination with immune checkpoint inhibitors. Their ability to optimize therapeutic efficacy and strengthen antitumor immune responses is mediated through various mechanisms that include the stimulation of T cell activity, the regulation of the TME, the activation of intrinsic immune responses and cytokine signaling, and the regulation of immune checkpoints such as PD-1/PD-L1, CTLA-4, and LAG-3. Additionally, these compounds can alter key signaling pathways that control immune regulation. Nevertheless, the extrapolation of preclinical studies to clinical applications remains limited by insufficient clinical evidence, the lack of standardized therapeutic protocols, and poor pharmacokinetic behavior. Consequently, further studies are required in order to clarify their actual efficacy and to better define their role in modern oncology. This article aims to review the mechanisms that underlie the anticancer sensitizing activity of major classes of plant-derived compounds such as polyphenols, flavonoids, terpenoids, alkaloids, and isothiocyanates. The available preclinical and clinical evidence were reported together with their potential synergistic effects when combined with immune checkpoint inhibitors. An important aspect related to the anticancer effects of these compounds lies in their ability to simultaneously target multiple signaling pathways. Furthermore, advanced formulations such as nanoparticulated delivery systems are discussed as strategies to optimize their clinical application and therapeutic outcomes. Full article

Deep reinforcement learning often suffers from inefficient exploration, which is commonly addressed by introducing an auxiliary model that assigns intrinsic rewards when the agent encounters novel scenarios. However, such approaches increase training complexity and computational overhead. This paper proposes an Attribution-Guided Reinforcement Learning (AGRL) framework that exploits real-time attribution analysis to guide exploration in autonomous driving decision-making. The proposed method is built upon the Kolmogorov–Arnold-Network-based Interpretable Deep Reinforcement Learning (KAN-IDRL) framework. Specifically, action-wise attribution patterns are computed online, and perturbations are applied to the state inputs to measure attribution sensitivity. The resulting attribution-sensitivity signal identifies actions whose decision rationales are more locally responsive to state changes, and these actions are therefore preferentially explored. In addition, local attribution results collected from a pretrained interpretable policy are aggregated into global feature-importance scores, which are then used to initialize a trainable prior attention gate in a Prior-Attention-Enhanced Kolmogorov–Arnold Network (PAE-KAN). This design allows the policy to incorporate attribution-derived prior knowledge while maintaining sufficient adaptability for task-specific learning. Experiments across multiple autonomous driving scenarios demonstrate that the proposed AGRL framework achieves faster convergence and competitive final performance compared with representative baseline methods. These findings indicate that attribution information can be transformed from a post hoc interpretability tool into an effective guidance signal for improving reinforcement learning. Full article

Feline panleukopenia virus (FPLV) is the primary causative agent of a highly contagious and often fatal disease affecting domestic cats and other felids. The increasing isolation of species-specific FPLV variants from multiple host species has garnered considerable attention, highlighting the need to investigate their genetic diversity. In this study, three FPLV isolates were obtained and phylogenetically classified into two distinct FPLV-China groups within separate clusters. Compared to the prototype FPLV (M38246.1), these isolates exhibited seven amino acid substitutions in the NS1 (n = 6) and VP2 (n = 1) proteins. Further analysis of 157 NS1 sequences and 947 VP2 sequences retrieved from the NCBI database revealed 113 and 479 synonymous substitutions and 71 and 279 non-synonymous substitutions, respectively. Notably, the majority of these substitutions occurred as single events (57% in NS1, 40/71; 55% in VP2, 153/279) or were present in no more than five FPLV sequences (23% in NS1, 16/71; 32% in VP2, 89/279). However, three non-synonymous substitutions in the NS1 protein (Ile443Val, His595Gln, and Val596Leu) were detected in more than half of the 157 sequences analyzed. In the VP2 protein, six non-synonymous substitutions (Ala91Ser, Thr101Ile, Val232Ile, Lys93Asn, Asp323Asn, and Val562Leu) were each found in 20 to 40 FPLV sequences. Furthermore, ten sites in the NS protein and 224 sites in the VP2 protein exhibited both synonymous and non-synonymous substitutions simultaneously. Additionally, 75 sites in VP2 harbored multiple non-synonymous substitutions. These findings provide valuable insights for future research on the genetic determinants and vaccine development of FPLV. Full article

Magnetic resonance techniques have evolved beyond conventional proton-based imaging, enabling access to a broader range of nuclei that provide complementary structural, functional, and molecular information. This review presents a comprehensive overview of multinuclear NMR and MRI in solid and soft materials as well as in biomedical applications, with particular emphasis on ¹H, ¹³C, ³¹P, ²³Na, and ¹⁹F nuclei. Proton-based methods remain the foundation of magnetic resonance due to their high sensitivity and widespread applicability, offering insights into molecular mobility, hydration, and microstructural heterogeneity. In contrast, heteronuclear approaches enable more specific characterization of chemical structure (¹³C), phosphorus-containing functional groups and membranes (³¹P), ionic homeostasis and transport (²³Na), and exogenous tracers with negligible biological background (¹⁹F). Together, these techniques extend magnetic resonance from primarily anatomical imaging toward functional, metabolic, and molecular-level analysis. The review further discusses key hardware aspects, including magnetic field strength and radiofrequency coil design, highlighting the trade-offs between low- and high-field systems and the growing importance of multinuclear coil architectures. For example, because ¹H, ²³Na, ³¹P, and ¹⁹F resonate at different Larmor frequencies, multinuclear experiments require dedicated or multi-tuned RF coils that balance sensitivity, field homogeneity, and decoupling between channels. Mechanisms of contrast generation are examined in detail, distinguishing between endogenous sources—such as water, ions, and metabolites—and exogenous contrast agents, including gadolinium-, manganese-, and fluorine-based compounds, as well as targeted and theranostic platforms. A comparative framework of endogenous and exogenous signals is presented, emphasizing their complementary roles in balancing safety, specificity, and sensitivity. Finally, the opportunities and challenges of multinuclear magnetic resonance are critically evaluated, including limitations in sensitivity, signal-to-noise ratio, data interpretation in heterogeneous systems, and technical complexity. Emerging directions such as ultrahigh-field imaging, advanced RF technologies, hyperpolarization, and artificial intelligence-assisted reconstruction are discussed as key drivers for future development. Overall, multinuclear NMR and MRI represent a powerful and expanding toolbox for probing complex material and biological systems, with the potential to significantly enhance diagnostic capabilities and deepen our understanding of structure–function relationships across multiple scales. Full article

Decidualization in the human endometrium is not merely a hormone-dependent differentiation process; rather, it represents a multilayered adaptive program characterized by the tight integration of immune regulation, metabolic reprogramming, and cellular stress responses. In this review, endoplasmic reticulum (ER) stress and the associated unfolded protein response (UPR) are proposed as central regulatory mechanisms governing this process. Triggered by increased protein synthesis and secretory demand, UPR activation under physiological conditions preserves proteostasis and supports the secretory capacity of stromal cells. In contrast, chronic or dysregulated activation leads to a maladaptive response characterized by apoptosis, inflammation, and metabolic dysfunction. UPR signaling pathways shape immune tolerance through their effects on macrophage polarization, uterine natural killer (uNK) cell function, and T cell balance. At the metabolic level, adenosine monophosphate-activated protein kinase (AMPK) regulates cellular adaptation through bidirectional interactions with mitochondrial function and redox homeostasis. Within this framework, the ER stress–immune–metabolic axis operates not as a linear pathway but as a dynamic network incorporating multiple feedback loops, thereby constituting a critical threshold mechanism that determines the success of decidualization. Disruption of this axis provides a shared mechanistic basis for pathologies such as recurrent implantation failure, pregnancy loss, and preeclampsia. From a therapeutic perspective, agents including chemical chaperones, UPR modulators, AMPK activators, and anti-inflammatory compounds hold translational potential by targeting these pathological feedback circuits. However, key knowledge gaps remain, particularly regarding the cell type-specific and temporal regulation of ER stress, the molecular boundaries defining the transition from adaptive to pathological states, and interspecies differences. Future studies employing single-cell omics approaches and functional in vivo models will be essential to elucidate the dynamic organization of this axis and to enable the development of targeted and personalized therapeutic strategies. Full article

Essential oils (EOs) and their bioactive constituents have attracted growing interest as potential anticancer agents because they can target multiple pathways involved in tumor progression. However, the literature on their anticancer activity is highly heterogeneous and often limited by methodological weaknesses that reduce the reliability and translational value of the reported findings. This systematic review critically assessed the anticancer activity of EOs and EO-derived compounds by considering only studies that met defined methodological criteria. A PubMed search identified 872 articles published between 2015 and 2026, of which 97 were retained after screening based on EO chemical characterization, evaluation of cancer selectivity using non-tumoral control cells, and direct assessment of EO-driven anticancer effects. Across different tumor models, EOs and their constituents consistently showed selective cytotoxic or antiproliferative activity, commonly associated with oxidative stress, mitochondrial dysfunction, apoptosis, cell-cycle arrest, and modulation of oncogenic pathways. Some studies also reported reduced migration, invasion, and tumor-promoting signaling, while nanoformulation improved stability and efficacy in selected models. Overall, despite encouraging preclinical evidence, the translational potential of EO-based anticancer strategies remains limited by recurrent methodological shortcomings and insufficient in vivo validation. Standardized experimental criteria will be essential to improve reproducibility and support future clinical development. Full article

To prevent the spread of antibiotic resistance, bacteriophages have gradually become the most promising alternative to antibiotics for treating bacterial infectious diseases. In this study, using E. coli DC1 as the host strain, we isolated a bacteriophage named Escherichia coli phage XJA18 from farm sewage. We conducted morphological identification, host range determination, biological characteristic analysis, genomic feature analysis, and evaluation of in vitro and in vivo antibacterial effects. Electron microscopy revealed that phage XJA18 belongs to the class Caudoviricetes, with an icosahedral head and a non-contractile long tail. Whole-genome sequencing revealed that the phage has dsDNA with a length of 50,572 bp, with a GC content of 45.33%. The genome does not contain any antibiotic resistance genes or virulence genes, indicating good safety. XJA18 showed lytic activity against 24% of clinically isolated E. coli strains. The optimal multiplicity of infection (MOI) was 0.001, with a latent period of 10 min, a burst period of 30 min, and a burst size of 2.22 × 10² PFU/cell. It remained stable at 4–50 °C and pH 4–12. In vitro antibacterial results revealed that XJA18 had the most pronounced initial bacterial growth suppression at MOI = 0.001 during the first 4 h. In vivo experiments demonstrated that both prophylactic and therapeutic administration of XJA18 could protect against E. coli infection, significantly reducing inflammatory cytokine levels and bacterial loads in the livers and spleens of mice (p < 0.001), significantly increasing body weight (p < 0.05), and reducing histopathological damage to the colon, liver, and lungs. In summary, phage XJA18 can effectively inhibit E. coli and is safe and stable. These characteristics indicate that phage XJA18 has great potential as a novel biological agent to replace antibiotics for treating bacterial infectious diarrhea in calves. Full article

The pursuit of sustainable winter road maintenance has intensified the need for deicers that balance functional effectiveness, economic viability, and minimal environmental impact. However, the absence of a systematic, multi-dimensional evaluation framework has hindered informed product selection and green procurement. This study develops and validates the Comprehensive Deicer Multi-criteria Evaluation System (CDMES)—a structured assessment framework that integrates economic, functional, environmental, and infrastructural sustainability dimensions. The evaluation index system was constructed for deicers, consisting of 18 indicators including preparation cost, engineering maintenance cost, operability of agent preparation, application difficulty, asphalt binder adhesion loss, minimum application concentration, proportion of active ingredients, effective time, ambient temperature, freezing point, solid dissolution rate, relative snow/ice-melting capacity, seed damage rate, chlorophyll attenuation, soil pH, aqueous solution pH, steel–carbon corrosion rate, and pavement friction attenuation rate. Subsequently, the analytic hierarchy process (AHP) was employed to determine the weight of each indicator, and evaluation criteria were established in accordance with relevant standards and literature. Finally, this weight determination method, combined with the simple additive weighting (SAW) method for index aggregation, forms a quantitative evaluation model. These elements together constitute a comprehensive deicer evaluation system, designated as the Comprehensive Deicer Multi-criteria Evaluation System (CDMES). Validation using three representative deicers—sodium chloride, a composite chloride-based formulation, and an organic acetate-based product—demonstrated that the CDMES can effectively discriminate product performance across multiple sustainability dimensions and identify critical weaknesses that may be obscured by purely compensatory scoring. The framework offers a transparent and reproducible decision-support tool for winter maintenance managers seeking to align deicer selection with sustainability objectives. Full article

Nipah virus (NiV) is an animal-borne RNA virus of the genus Henipavirus that poses a significant global health threat. This threat is driven by the virus’s high mortality rate, its capacity to cause epidemics, and the lack of licensed therapeutic interventions or vaccines. Since its initial identification during the 1998–1999 outbreak in Malaysia and Singapore, recurrent episodes have occurred primarily in Bangladesh and India, with mortality rates frequently exceeding 70%. Fruit bats of the genus Pteropus serve as the biological host for the virus. Transmission to humans occurs via contact with infected wildlife, consumption of contaminated products, such as freshly harvested date palm sap, or direct person-to-person exposure. Other modes of transmission, such as transplacentally or via breast milk, are still under investigation. The clinical presentation of NiV infection varies widely, from mild flu-like symptoms to life-threatening respiratory disease and acute encephalitis. It frequently attacks the nervous system, which can lead to coma, permanent neurological damage, or relapsing encephalitis. The virus enters host cells via ephrin-B2/B3 receptors, enabling systemic dissemination and infiltration of the central nervous system. Diagnosis relies primarily on RT-PCR and serological assays, and virus isolation requires high-containment laboratories. Management remains largely supportive, as no approved antiviral therapy exists. Experimental agents, such as remdesivir, favipiravir, and monoclonal antibodies such as m102.4, have shown promise in preclinical studies. Multiple vaccine platforms—including subunit, viral vector, mRNA, and nanoparticle-based approaches—are under development, though none is yet licensed for human use. Strengthened surveillance, infection control measures, and continued research are essential to mitigate the threat posed by this emerging pathogen. This review summarizes current knowledge on NiV, including its virology, epidemiology, pathogenesis, transmission, and recent progress in therapeutic and vaccine development. Full article

Plant hormones and their synthetic analogueues offer sustainable alternatives for crop protection, yet the direct antifungal activity of strigolactone (SL) and its analogues against necrotrophic pathogens remain largely unexplored. Here, we screened eight phytohormones and related analogues for treatments of Botrytis cinerea and identified the SL analogue rac-GR24 (racemic GR24) as a concentration-dependent growth inhibitor active at low micromolar concentrations. Given the stereochemical complexity of SLs and their analogues, we evaluated multiple enantiopure isomers and found that ent-5DS and GR24^ent-5DS, which differ in configuration from natural SLs, exhibited the strongest inhibitory activity. This stereospecific response was further validated using another filamentous fungus, Sclerotinia sclerotiorum, which displayed an identical susceptibility profile. Combinatorial treatments with enantiopure isomers and double-concentration rac-GR24 revealed that the antifungal effect of the racemate is primarily attributable to the GR24^ent-5DS enantiomer, whereas the opposite enantiomer GR24^5DS is almost inactive. Collectively, our findings uncover a stereospecific response in fungal pathogens, demonstrating that B. cinerea and S. sclerotiorum respond to exogenous SL analogues in a chirally selective manner. This work establishes a stereochemically defined framework for developing enantioselective fungicidal agents with potential applications in sustainable agriculture. Full article

Background: Diabetic peripheral neuropathy (DPN) affects up to 50% of diabetes patients and is driven by hyperglycemia-induced oxidative stress, mitochondrial dysfunction, polyol pathway activation, advanced glycation end-product formation, and inflammation. Current management is largely symptomatic, prompting interest in metabolic/nutritional therapies. This review critically evaluates the mechanistic rationale and clinical evidence for alpha-lipoic acid (ALA) and benfotiamine as adjunctive treatments for DPN. Methods: A structured narrative review of PubMed/MEDLINE was conducted using predefined keywords for DPN, oxidative stress, metabolic therapy, and thiamine derivatives. Randomized controlled trials, clinical studies, systematic reviews, and relevant experimental studies were included. Evidence was synthesized qualitatively with emphasis on mechanistic plausibility, clinical efficacy, intervention duration, and methodological rigor. Results: ALA consistently improves short-term symptoms across multiple randomized trials. The long-term NATHAN 1 trial reported a marginal, borderline significant effect on the primary composite endpoint (NIS-LL, p = 0.05) without significant improvements in nerve conduction studies; therefore, evidence for functional stabilization is very limited and inconclusive. ALA’s effects are attributed to antioxidant activity, mitochondrial protection, and improved microvascular function. Benfotiamine has a strong biochemical rationale (transketolase activation, diversion of glycolytic intermediates from damaging pathways), but clinical evidence remains limited to short-duration, symptom-based studies, with no large-scale, long-term trials published. Conclusions: Both agents target key pathways in DPN pathogenesis. ALA is the most established adjunctive metabolic therapy for symptomatic DPN, although no study has demonstrated structural nerve regeneration or a definitive disease-modifying effect. Benfotiamine is biologically plausible but requires further validation in long-term randomized trials with structural and biomarker-based endpoints. Outside of documented thiamine deficiency, its routine use cannot be recommended based on current evidence. Full article

Truck–multiple-drone routing problems involve conflicting operational criteria and are therefore naturally suited to multiobjective analysis. In practical settings, however, decision makers may also specify aspiration levels for the considered criteria, which call for a target-oriented perspective. This paper studies a bi-criterion truck–multiple-drone routing problem through a goal-induced deviation framework in which the original objectives are transformed to normalized positive deviations with respect to prescribed targets. First, a general mathematical framework is introduced, and several structural properties are established, including dominance preservation, invariance under positive weighting, equivalence with the original Pareto structure when all the targets are violated, and the loss of discrimination when the targets are attainable. To address this latter effect, an enhanced goal-programming scalarization is proposed and shown to preserve consistency with the Pareto efficiency. The framework is then specialized to a truck–multiple-drone routing problem with truck time and makespan as criteria and evaluated on representative benchmark instances together with a broader attainable-target benchmark battery, using a common agent-based metaheuristic search framework adapted from literature. This search framework is employed both to estimate a reference Pareto frontier and to solve the GP and EGP scalarizations under the same computational scheme. The computational results illustrate two target regimes: When the targets are unattainable, both formulations are mainly driven by the minimization of positive deviations; when they are attainable, classical goal programming may return satisfactory but dominated solutions, whereas the enhanced formulation preserves discrimination and selects Pareto-efficient alternatives. Full article

Background: This study examines the clinical efficacy of daratumumab when combined with other therapeutic agents in patients with multiple myeloma, with a focus on key outcomes including overall response, progression-free survival (PFS), and stringent complete response (sCR). Methods: A systematic literature search was conducted using PubMed, Web of Science, Scopus, and the Cochrane Library. Statistical analyses were performed with R software (version 4.2.2). Between-study heterogeneity was assessed using the Cochrane Q test and the I² statistic, while potential publication bias was evaluated through Egger’s regression test and visual inspection of funnel plots. Results: The meta-analysis revealed that daratumumab-containing regimens were associated with a 54.4% reduction in the risk of disease progression or death (hazard ratio[HR] 0.4558; 95% confidence-interval [CI]: 0.4031–0.5154). Similar results were observed using a random-effects model (HR 0.4667; 95% CI: 0.3771–0.5776), despite moderate heterogeneity (I² = 66.7%). Moreover, patients treated with daratumumab were approximately 2.4 times more likely to achieve a stringent complete response (odds-ratio[OR] 2.38; 95% CI: 1.80–3.15), with moderate heterogeneity across studies (I² = 58.2%). Conclusions: Incorporating daratumumab into standard therapy for multiple myeloma significantly enhances progression-free survival and the rate of stringent complete response. Despite some heterogeneity, the consistent positive outcomes support its use as an effective treatment option in clinical practice. Full article

Despite transformative therapeutic advances, multiple myeloma (MM) remains an incurable malignancy characterized by sequential relapses and progressive treatment resistance. Patients with heavily pretreated relapsed or refractory MM continue to face limited therapeutic options and poor outcomes. Melflufen (melphalan flufenamide) is a peptide–drug conjugate that enhances intracellular delivery of alkylating agents via aminopeptidase-mediated activation. Early clinical studies demonstrated encouraging activity in advanced MM, leading to accelerated approval by the U.S. Food and Drug Administration in 2021. However, results from the phase III OCEAN trial raised concerns regarding overall survival, ultimately resulting in withdrawal of the drug from the U.S. market. In this review, we examine the biological rationale, clinical development, and regulatory trajectory of melflufen, and critically reassess its role within the evolving therapeutic landscape of MM. While the negative survival findings observed in the phase III OCEAN trial substantially limited the clinical development of melflufen, the biological principles underlying enzyme-targeted intracellular drug delivery may still provide relevant insights for biomarker-driven therapeutic strategies and future peptide–drug conjugate development in MM. Full article

Cancer is one of the leading causes of death globally. Conventional treatments such as surgery, radiotherapy, and chemotherapy are associated with several side effects, including chemoresistance and cancer relapse. As a result, there is a critical demand for new therapeutic agents to support the current therapeutic options. Recently, research started to focus on the possible positive interaction(s) between melatonin and many phytochemicals as a combination therapy to target altered metabolism in cancer. Such a combination has many advantages, including low toxicity, the possibility of having multiple synergistic anticancer effects, and low cost. This review comprehensively examines the current literature regarding combining melatonin with phytochemicals as a potential strategy to target cancer metabolism. It aims to contribute to the evolving landscape of cancer therapeutics by highlighting the potential benefits and future directions of melatonin–phytochemical combinations as an area of active research. Full article