Search Results (1,401)

Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers. Full article

The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed. Full article

The emergence of antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2) represents a potential paradigm shift in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), a setting historically characterized by limited therapeutic options following progression on EGFR tyrosine kinase inhibitors (TKIs). This review examines the biological rationale and clinical challenges underpinning the development of anti-TROP2 ADCs in EGFR-mutated NSCLC. From a mechanistic standpoint, TROP2 occupies a unique and dynamic role in EGFR-mutated NSCLC, providing strong biological rationale for clinical development of anti-TROP2 ADCs in this population. Three TROP2-directed ADCs are currently in clinical development in this setting. Available clinical data in previously treated EGFR-mutated patients are critically reviewed here, focusing on efficacy, toxicity profiles, clinical challenges and potential future perspectives. Full article

Bumped kinase inhibitor 1708 (BKI-1708), previously demonstrated to target apicomplexan kinases and CDPK1 and MAPKL1, exhibits remarkable activity against Toxoplasma gondii infection both in vitro and in vivo. Notably, BKI-1708 does not affect the viability of mammalian cells. Upon exposure to BKI-1708, T. gondii tachyzoites form large multinucleated complexes named baryzoites and remain trapped within host cells. In this study, proteins binding to BKI-1708 were identified in soluble extracts of T. gondii ME49 tachyzoites and human foreskin fibroblasts (HFF) using differential affinity chromatography coupled to mass spectrometry (DAC-MS). Beyond kinases, secondary interactions in T. gondii involved the binding of proteins associated with cell division, cytoskeleton, vesicular trafficking, secretory organelles, and transcriptional and translational regulators. In non-infected HFFs, BKI-1708 interactors included cytoskeletal regulators along with multiple RNA/DNA-binding proteins. Upon infection, this profile shifted, with cytoskeletal components no longer detected, while nucleic acid-binding proteins remained present, consistent with infection-induced chromatin and transcriptional remodeling. These results suggest that multi-target interference could contribute to the impaired cytokinesis and the formation of multinucleated baryzoites, aligning with the concept that antiprotozoal drugs exert efficacy through coordinated perturbation of multiple cellular processes rather than a single dominant target. Full article

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC. Full article

Lifespan is increasing throughout the world leading to a rise in non-communicable diseases in the global population that impacts over 800 million individuals with metabolic disorders, such as diabetes mellitus. Metabolic disease presents a significant challenge for clinical care since multi-organ disease progression ensues despite a broad array of treatment protocols. The pursuit of innovative strategies with mammalian forkhead transcription factors of the “O” class (FoxOs) and intimately related pathways of aging, cellular senescence, telomere integrity, oxidative stress, programmed cell death with apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis, Wnt/β-catenin signaling, Wnt1 inducible signaling pathway protein 1, and the gut microbiome becomes vital to address the clinical hurdles of metabolic disorders. Platforms incorporating novel diagnostics with artificial intelligence and machine learning can further address the underlying mechanisms tied to FoxOs that include the mechanistic target of rapamycin, AMP activated protein kinase, silent mating type information regulation 2 homolog 1 (S. cerevisiae), and glucagon-like peptide-1 receptor agonists that can markedly influence biological outcomes. Given the premise that it is essential to comprehend the intimate relationship that FoxO signaling pathways hold, FoxOs offer an exciting and promising approach to address the clinical aspects of disease onset, progression, and treatment with metabolic disorders. Full article

Non-small cell lung cancer (NSCLC) comprises a diverse group of malignancies driven by distinct molecular alterations that have become critical targets for precision oncology. Among these, EGFR exon 20 insertion mutations and HER2 dysregulation, including HER2 mutations, amplification, and overexpression, define clinically important subsets of NSCLC characterized by unique biological behavior and historically limited treatment options. Although these alterations account for a relatively small proportion of NSCLC cases, their identification has become increasingly relevant due to advances in molecular diagnostics and the development of novel targeted therapies. This review provides a comprehensive overview of the epidemiology, molecular biology, and clinical characteristics of EGFR exon 20 insertion-mutated and HER2-deregulated NSCLC. We discuss current diagnostic approaches, including the role of next-generation sequencing and biomarker testing, and summarize the evolving therapeutic landscape encompassing conventional chemotherapy, immunotherapy, and targeted agents. Particular attention is given to recently approved therapies and emerging treatment strategies, including tyrosine kinase inhibitors and antibody-based therapies that have demonstrated clinically meaningful activity in these patient populations. We also address the major challenges associated with treatment resistance, molecular heterogeneity, and optimal therapeutic sequencing. Finally, we highlight ongoing research efforts and future perspectives aimed at improving outcomes for patients with these rare but clinically significant molecular subtypes of NSCLC. Full article

Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive “smart” hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care. Full article

Safflower (Carthamus tinctorius L.) is an economically important crop, and heat stress has become a major environmental constraint that limits its growth and development under global climate change. However, the molecular mechanisms underlying its response to heat stress remain poorly understood. Here, transcriptome sequencing was performed on safflower leaves exposed to heat stress (42 °C) for 0, 1, 2, 4, 8, and 12 h, with three biological replicates per time point. Compared with the control (0 h), a total of 12,964 differentially expressed genes (DEGs) were identified across the five time points (1, 2, 4, 8, and 12 h) using criteria of |log₂ (fold change)| ≥ 1 and false discovery rate (FDR) < 0.05, of which 1097 were common to all comparisons. KEGG enrichment analysis of these DEGs across all five comparison groups consistently showed significant enrichment in plant hormone signal transduction and the MAPK signaling pathway. Furthermore, a total of 750 transcription factors (TFs) were identified as differentially expressed across the five comparison groups, of which 99 were common to all comparisons, with the bHLH, MYB, WRKY, and HSF families being the most abundant. Weighted Gene Co-expression Network Analysis (WGCNA) identified five modules that were significantly associated with different heat stress time points. Furthermore, 13 hub genes were identified as potential targets for future functional studies on heat tolerance in safflower. The reliability of the RNA-seq data was confirmed by qRT-PCR validation of selected hub genes. Notably, a non-specific serine/threonine protein kinase (CtAH03G0292100) from the MEred module, which is also involved in plant hormone signal transduction, emerged as a promising candidate gene for heat tolerance. Collectively, these findings provide candidate genes for future functional studies aimed at further elucidating the mechanisms of heat tolerance in safflower. Full article

Background and Objectives: Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is characterized by type 2 inflammation, marked eosinophil infiltration, and enhanced epithelial–mesenchymal transition (EMT). Although interleukin-5 (IL-5) is central to eosinophil differentiation and activation, its role in EMT in human nasal epithelial cells (HNECs) remains unclear. This study aimed to elucidate the contribution of IL-5Rα/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling in eosinophils in EMT in ECRSwNP. Materials and Methods: Nasal mucosal tissues from control and ECRSwNP or non-ECRSwNP group patients (n = 12 each) were analyzed for type 2 cytokine, EMT marker, and IL-5Rα/JAK2/STAT5 axis component levels using Western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. HL-60 cells were differentiated into eosinophil-like cells using butyric acid and stimulated with IL-5, and HNECs were co-cultured with undifferentiated, differentiated, or IL-5-activated differentiated HL-60 cells. EMT induction and migration were assessed using immunofluorescence, wound-healing assays, and Western blotting. IL-5RA, JAK2, or STAT5 was silenced using small interfering RNA to determine pathway dependency. Results: ECRSwNP tissues showed elevated type 2 cytokine and EMT marker expression and enhanced IL-5Rα/JAK2/STAT5 pathway activation. Co-culture with IL-5-activated differentiated HL-60 cells induced EMT in HNECs, evidenced by decreased E-cadherin and zonula occludens-1, increased N-cadherin and vimentin levels, and enhanced migration. Moreover, silencing IL-5RA, JAK2, or STAT5 significantly attenuated these effects. Conclusions: IL-5-activated IL-5Rα/JAK2/STAT5 signaling in eosinophils may contribute to EMT in HNECs. Thus, this pathway could be a potential therapeutic target for tissue remodeling and polyp formation in type 2 chronic rhinosinusitis. Full article

Brown adipose tissue (BAT) is increasingly recognized as a metabolically active organ in adult humans that contributes to systemic energy homeostasis and represents a potential therapeutic target for obesity-associated metabolic diseases. However, effective strategies to increase BAT mass or thermogenic activity in humans have not yet been established. Although β-adrenergic receptors have traditionally been viewed as the principal drivers of adaptive thermogenesis and adipocyte browning, β-adrenergic stimulation alone may be insufficient to safely enhance BAT thermogenic capacity due to systemic adverse effects. Emerging evidence suggests that alternative receptor-mediated signaling pathways contribute to the regulation of brown adipocyte function, including both UCP1-dependent and UCP1-independent thermogenic mechanisms, and systemic metabolic homeostasis. These pathways include G protein-coupled receptors, receptor tyrosine kinases, and nuclear receptors, which enable brown adipocytes to integrate endocrine, immune, nutritional, and thermal cues. In this review, we discuss recently characterized non-adrenergic receptor signaling pathways and their potential roles in regulating adipocyte browning and thermogenic activity in human adipose tissues. This review highlights the concept of selective modulation of non-adrenergic receptor signaling as a strategy to enhance adipocyte browning and thermogenic capacity while minimizing systemic adverse effects. Understanding these integrated signaling networks may facilitate the development of safer and more selective therapeutic strategies targeting brown adipocyte function in metabolic disease. Full article

The treatment landscape of oncogene-driven non-small-cell lung cancer (NSCLC) has evolved substantially with the development of targeted therapies directed against actionable molecular alterations. Tyrosine kinase inhibitors (TKIs) remain the cornerstone of treatment for many driver-defined subsets; however, acquired resistance, central nervous system progression, and tumor heterogeneity continue to limit long-term disease control. This review examines the mechanistic foundations, clinical evidence, resistance patterns, and emerging therapeutic roles of TKIs, antibody–drug conjugates (ADCs), and bispecific antibodies (bsAbs) in oncogene-driven NSCLC. Relevant preclinical studies, clinical trials, and recent therapeutic advances across major actionable driver alterations were reviewed and compared. TKIs provide potent and selective inhibition of oncogenic signaling and remain the preferred frontline therapy in most molecular subgroups, whereas ADCs offer targeted payload delivery that may overcome diverse resistance mechanisms, and bsAbs provide dual-target blockade and immune-mediated antitumor activity. Emerging evidence supports the expanding role of ADCs and bsAbs in post-TKI settings and selected biomarker-defined populations. Resistance mechanisms differ across therapeutic classes and include secondary target alterations, bypass pathway activation, antigen loss, payload resistance, and receptor adaptation. Collectively, these modalities are increasingly being integrated into biomarker-guided treatment strategies, with future management likely to rely on rational sequencing and combination approaches tailored to resistance mechanisms, target expression, central nervous system involvement, and tumor heterogeneity. Full article

Ferroptosis is an iron-dependent regulated form of cell death characterized by lethal lipid peroxidation and is increasingly implicated in cancer, neurodegenerative diseases, cardiovascular injury, and metabolic disorders. Metformin, a widely prescribed antidiabetic biguanide, exerts pleiotropic effects beyond glucose lowering and has emerged as a context-dependent regulator of ferroptosis. In malignant cells, metformin may enhance ferroptotic susceptibility through activation of AMP-activated protein kinase (AMPK), suppression of mechanistic target of rapamycin (mTOR) signaling and SLC7A11, induction of ferritinophagy, mitochondrial complex I stress, and promotion of lipid peroxidation. Conversely, in normal or stressed non-malignant tissues, metformin may limit ferroptotic injury by activating nuclear factor erythroid 2-related factor 2 (NRF2), supporting glutathione peroxidase 4 (GPX4) and SLC7A11-dependent antioxidant defenses, improving mitochondrial quality control, and stabilizing iron homeostasis. This review synthesizes the molecular basis of this duality, evaluates therapeutic opportunities in oncology and cytoprotection, and outlines biomarker-driven and clinical trial strategies required for translation. Overall, metformin should not be regarded as a universal ferroptosis inducer or inhibitor, but rather as a context-dependent metabolic regulator whose effects are shaped by cell type, dose, exposure duration, transporter expression, iron status, and antioxidant capacity. Full article

Macrobrachium nipponense holds significant economic importance in freshwater aquaculture in China, where larger body weight and longer body length are directly associated with higher market demand and improved commercial value. Consequently, identifying genes associated with growth traits is a priority for enhancing economic returns. Previous studies have predicted that the cAMP-dependent protein kinase type I regulatory subunit-like (PKA-R1) may be involved in the growth regulation of M. nipponense. In this study, we functionally characterized the Mn-PKA-R1 gene to investigate its potential involvement in growth and molting regulation in M. nipponense through qPCR analysis and RNA interference (RNAi). The open reading frame of Mn-PKA-R1 spanned 3345 base pairs, encoding a protein of 1114 amino acids. The Mn-PKA-R1 amino acid sequence showed the highest identity with that of Macrobrachium rosenbergii, followed by Penaeus vannamei. Tissue distribution analysis revealed that Mn-PKA-R1 was ubiquitously expressed across all examined tissues, with the highest transcript level detected in the testis, suggesting a potential association with testis-related physiological functions. Functional validation via RNA interference showed that repeated dsPKA-R1 treatment was associated with reduced molting frequency and relative body weight compared with the non-targeting dsRNA control group. From day 14 to day 42, the relative body weight compared with day 0 in the non-targeting dsRNA control group was significantly higher than that in the dsPKA-R1-injected group. Additionally, the molting frequency in the non-targeting dsRNA control group was significantly higher than that in the dsPKA-R1-injected group at days 7, 14, 21, 28, and 35. These findings suggest that Mn-PKA-R1 may participate in the regulation of growth and molting in M. nipponense under the tested experimental conditions. This study provides preliminary functional evidence for the involvement of Mn-PKA-R1 in growth-related traits in M. nipponense. Full article

Bispecific antibodies (bsAbs) have emerged as a novel therapeutic class in oncogene-driven non-small-cell lung cancer (NSCLC), designed to simultaneously target multiple signaling pathways and overcome resistance mechanisms associated with tyrosine kinase inhibitors (TKIs). Unlike small-molecule TKIs, bsAbs enable dual receptor blockade and immune effector engagement, offering a mechanistically distinct advantage in the context of tumor heterogeneity and bypass signaling. This review summarizes the structural and biological principles underlying bsAb design, with a focus on clinically approved agents such as amivantamab (EGFR/MET) and zenocutuzumab (HER2/HER3) and a growing pipeline of investigational agents. We evaluate key clinical evidence from Phase I-III trials including CHRYSALIS, PAPILLON, MARIPOSA, MARIPOSA-2 and eNRGy, and compare the efficacy, toxicity, and CNS penetration profile of bsAbs relative to TKIs and antibody–drug conjugates (ADCs). While bsAbs demonstrate meaningful clinical activity, particularly in TKI-resistant disease and molecularly defined subsets such as EGFR exon 20 insertions and NRG1 fusions, their limitations, including intravenous administration, increased immune-mediated and thromboembolic toxicity, currently preclude replacement of TKIs in most settings. Collectively, available evidence supports a complementary role for bsAbs within evolving multimodal treatment paradigms, particularly in combination strategies. Future directions include biomarker-driven patient selection, improved drug engineering and integration into adaptive therapeutic sequencing frameworks. Full article