Search Results (4,813)

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8⁺ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article

Zinc-α2-glycoprotein (ZAG) is a novel adipokine with a plethora of functions meaningful for the regulation of adipose tissue and insulin sensitivity. Despite research, the role of ZAG in the course of childhood obesity is not fully understood. The aim of this study is to investigate whether the levels of ZAG can be used as a predictive or monitoring biomarker of adolescent obesity. Secondly, to determine the cut-off value of ZAG in blood serum in adolescents with obesity. The study included a group of 77 adolescent patients, including 59 obese patients, and 18 without obesity as healthy control subjects. All study participants had their biochemical parameters assessed by a certified medical laboratory. The recommendations of the Polish Society of Hypertensions were used to assess the blood pressure measurements in each group. ELISA enzyme immunoassays (R&D Systems, Minneapolis, MN, USA) were used to detect serum levels of ZAG. Our study showed that obese children and adolescents have significantly higher body mass, cholesterol, LDL-cholesterol, triglycerides (TG), systolic blood pressure (SBP) and diastolic blood pressure (DBP), but lower serum ZAG levels compared to the healthy control subjects. Furthermore, in our study, we found that median ZAG values were comparable between females and males within the same obesity category (median female ZAG level: 2.84, median male ZAG level: 2.89) and healthy control participants (median female ZAG level: 5.20, median male ZAG level: 4.99). Serum ZAG concentrations were significantly lower in obese participants (2.86 ± 0.40 mg/L) than in the control group (5.10 ± 0.74 mg/L; p < 0.001). The multivariable Firth’s logistic regression model, incorporating the selected factors, revealed a significant association between obesity and ZAG. ROC curve analysis indicated strong discriminatory ability of ZAG for identifying obesity, with a proposed cut-off value of 3.62 mg/L. Circulating ZAG level is significantly reduced in children and adolescents with obesity. An important finding of our study is the detection of a cutoff value for serum ZAG levels. Furthermore, the use of the Least Absolute Shrinkage and Selection Operator (LASSO) model can be considered a valuable contribution to defining ZAG as an independent factor associated with obesity. Full article

Henipaviruses (HNVs), including Nipah virus (NiV) and Hendra virus (HeV), are highly pathogenic and often lethal zoonotic viruses with broad species tropism and no approved human vaccines. The emergence of genetically divergent HNVs—including Ghana virus (GhV), Langya virus (LayV), and Mojiang virus (MojV)—emphasizes the need for broadly protective countermeasures. Here, we evaluated the antibody (Ab) responses to sequential mRNA vaccines encoding the membrane-bound attachment glycoprotein (gG) from NiV, GhV, and/or LayV in a pilot study with Indian rhesus macaques. Serum binding Ab responses were quantified by ELISA against five soluble gG antigens (NiV, HeV, GhV, LayV, MojV). Functional activity was assessed by neutralization assays using NiV, HeV, and GhV pseudoviruses, and by receptor-blocking ELISA. Sequential vaccination induced high-titer IgG binding against all five HNV gGs with increasing breadth after each dose. Pan-genus regimens elicited moderate neutralizing Ab titers against NiV, HeV, and GhV, whereas the NiV-only regimen elicited potent but narrow neutralization against NiV and HeV. Conversely, the GhV-LayV-GhV regimen elicited strong binding to GhV, LayV, and MojV gG and robust neutralization of GhV pseudovirus, but limited cross-reactivity to NiV and HeV. In this pilot study, we demonstrated that mRNA vaccination can elicit broadly reactive binding and neutralizing Ab responses across phylogenetically distant HNVs. Additionally, we show GhV pseudovirus neutralization for the first time. Collectively, these data provide a foundation for the development of next-generation pan-genus HNV vaccines capable of mitigating future HNV outbreaks. Full article

Background/Objectives: Acute carotid tandem lesions (TLs), defined by concurrent cervical internal carotid artery (ICA) stenosis or occlusion and intracranial large vessel occlusion, occur in 10–20% of patients undergoing mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Optimal periprocedural antiplatelet management during emergent carotid artery stenting (eCAS) remains uncertain, particularly regarding the balance between preventing stent thrombosis and avoiding hemorrhagic complications. Methods: A narrative review was conducted using PubMed and Scopus (until 6 March 2026) to identify English-language studies evaluating antiplatelet therapies during eCAS for TLs. We included seven real-world studies and registry analyses. Data on study design, patient characteristics, procedural strategies, angiographic results, functional outcomes, and safety metrics were extracted. Results: No randomized controlled trials (RCTs) were identified. The available evidence is derived exclusively from observational studies. Across these cohorts, glycoprotein IIb/IIIa inhibitors (GPIs), particularly tirofiban, were generally associated with lower rates of in-stent thrombosis and higher reperfusion success, with symptomatic intracranial hemorrhage (sICH) rates that appeared comparable to or lower than those reported with acetylsalicylic acid (ASA). Cangrelor, an intravenous (IV) P2Y₁₂ inhibitor, was associated with improved stent patency and increased likelihood of complete reperfusion, although reported effects on clinical outcomes were inconsistent when compared with GPIs or ASA. Aside from abciximab, potent IV antiplatelet agents did not consistently show an increased sICH signal. Oral dual antiplatelet therapy was also associated with improved technical outcomes without a clear excess in bleeding complications. Conclusions: Current real-world observational data suggest that rapid-acting IV antiplatelet agents—particularly GPIs and, increasingly, cangrelor—may represent feasible periprocedural options during eCAS for TLs, with potential benefits for technical success and no consistent evidence of increased hemorrhagic risk. However, interpretation is limited by study heterogeneity and non-randomized designs. The absence of RCTs highlights the need for prospective comparative studies and standardized periprocedural antiplatelet protocols. Full article

Background/Objectives: Multidrug resistance (MDR) remains a major pathophysiological barrier to effective chemotherapy based on anthracyclines, including daunorubicin (DNR), in the treatment of leukemia. However, conventional population-level measurements of drug uptake do not resolve variability in uptake kinetics among individual leukemia cells, which may influence intracellular drug accumulation and therapeutic response. Methods: In this study, real-time DNR uptake was quantified at the single-cell level using a microfluidic biochip that enabled long-term cellular retention and continuous monitoring. Both wild-type drug-sensitive leukemia cells and a multidrug-resistant mutant overexpressing the P-glycoprotein (P-gp) efflux pump were examined. Results: Kinetic analysis revealed that DNR uptake in drug-sensitive cells was well described by a single dominant uptake process, whereas uptake in MDR cells required a model incorporating two kinetically distinct processes. In both cell populations, pronounced cell-to-cell variation was observed in uptake rates and intracellular drug retention, indicating substantial functional heterogeneity within phenotypically similar cells. This variability persisted following the treatment with an MDR inhibitor and obscured the differences between inhibitor-treated and untreated cells when the uptake was compared across different single cells. To overcome this limitation, a same-single-cell analysis (SASCA) approach was employed, enabling direct comparison of DNR uptake in the same individual cell before and after inhibitor exposure, thereby revealing enhanced intracellular DNR retention and accelerated uptake kinetics following inhibition. Conclusions: Together, these results demonstrate that real-time single-cell kinetic analysis reveals functionally relevant heterogeneity in multidrug-resistant leukemia cells and provides insight into the pathophysiology of MDR that cannot be obtained from population-averaged measurements. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by heterogeneous behavioral symptoms and systemic comorbidities, including immune and gastrointestinal dysfunctions. Emerging studies suggest that glycosylation—a fundamental post-translational modification regulating cellular communication and immune responses—may play a role in ASD pathophysiology, yet its contribution remains underexplored. Methods: In this study, we developed an integrative transcriptomic and network analysis framework to investigate glycosylation-related gene expression changes and their functional associations in ASD. Using publicly available datasets from bulk and single-cell RNA sequencing of brain and blood tissues, we focused on four prior-knowledge gene subsets: glycogenes, extracellular matrix glycoproteins, immune response genes, and autism risk genes. Results: Differential expression and pathway enrichment analyses revealed consistent dysregulation of glycosylation pathways, including mucin-type O-glycan biosynthesis, glycosaminoglycan metabolism, GPI-anchor formation, and sialylation, across ASD tissues. These transcriptional changes were functionally linked to altered immune signaling (e.g., IL-17, Toll-like receptor, and complement pathways) and synaptic development pathways, forming a distinct glyco-immune axis. Network analysis identified key glycogenes such as GALNT10, NEU1, LMAN2L, and CHST1 as central molecular nodes, interacting with immune and neuronal regulators. Linkage disequilibrium analysis further revealed ASD-associated SNPs influencing the expression of these glycogenes in both blood and brain tissues. Conclusions: Together, these findings support a model in which disrupted glycosylation contributes to ASD pathophysiology by mediating immune dysregulation and altered neuronal connectivity. This study offers a systems-level framework to understand the molecular complexity of ASD and highlights glycogenes as potential biomarkers and targets for future therapeutic exploration. Full article

Chronic myeloid leukaemia (CML) is driven by the t(9;22) forming the BCR::ABL1 fusion gene, leading to the development of hyper-myeloid proliferation. This led to development of tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, and Ponatinib. However, resistance or intolerance to ATP-competitive TKIs remains a challenge for some patients. asciminib (ABL001), a novel TKI, targets the myristoyl pocket of ABL1 instead of the ATP-binding site, reducing resistance to mutations. As asciminib is linked to thrombocytopenia, its effects on platelet activation, endothelial function, and inflammation must be studied to assess its potential to promote thrombosis. The main objective of this study is to determine the potential of asciminib as a monotherapy in inducing pathological responses to platelets and endothelium over time within the vasculature. This study assessed the effects of TKIs including asciminib on platelets and thrombotic biomarkers. Washed platelets were used to measure granule secretion, thrombus formation, surface expression of glycoproteins, apoptosis, and viability. Plasma from chronically Asciminib-treated CML patients was analysed using sandwich ELISA for inflammatory and platelet–endothelial biomarkers, and thrombin generation assays were performed to study coagulation. This approach combined in vitro and ex vivo methods to explore the impact of asciminib on platelet function and thrombotic potential. The study shows that acute treatment with asciminib does not promote platelet activation or thrombus formation. Instead, it exhibits an inhibitory effect on thrombus formation in vitro and is associated with reduced thrombo-inflammatory biomarkers ex vivo in chronically treated CML patients. Asciminib was associated with increased thrombin generation over time, suggesting an effect on secondary haemostasis. Asciminib does not appear to induce a prothrombotic or proinflammatory state under the conditions studied, which may be advantageous for CML patients. However, the observed increase in thrombin generation over time suggests a potential effect on secondary haemostasis that warrants further investigation in controlled studies. Full article

Breast carcinoma is a major cause of cancer-related mortality among women worldwide. Identifying novel molecular targets remains essential, particularly for aggressive triple-negative breast cancer (TNBC). Leucine-rich alpha-2-glycoprotein 1 (LRG1) has been linked to tumor progression and angiogenesis, but its molecular mechanisms in breast cancer are poorly defined. We evaluated the effects of recombinant human LRG1 (rhLRG1) on cell viability and migration in MDA-MB-231 TNBC cells and performed transcriptomic profiling followed by functional enrichment analyses using GenArise, Cytoscape, and R-based tools. RhLRG1 treatment significantly increased cell viability and migration. Transcriptomic analysis revealed activation of key oncogenic cascades, including the PI3K/AKT, MAPK, and RAS signaling pathways. Hub-gene analysis identified upregulated genes involved in proliferation (NRAS, STAT5B, IGF2), angiogenesis (PGF, ANGPT2), and apoptosis (CASP8, BAD), whereas downregulated genes were associated with apoptotic resistance (BCL2, MCL1) and adhesion (LAMB1, ITGB4). Functional enrichment highlighted LRG1’s role in the bioinformatic analysis of differentially expressed genes that were obtained from microarray assays. LRG1 remodels the tumor microenvironment by promoting proliferation, angiogenesis, and apoptotic sensitivity while repressing resistance-related genes. These findings position LRG1 as a potential diagnostic biomarker and therapeutic target for advanced breast carcinoma. Full article

The rapid global spread of antimicrobial resistance among pathogenic microorganisms poses a serious challenge to both human and animal health, underscoring the urgent need for new strategies to combat resistance. Antimicrobial peptides (AMPs), key components of the innate immune system, are promising candidates because they disrupt the membranes of bacteria, fungi, and viruses, thereby reducing the risk of resistance development. Lactoferrin (LF), a multifunctional iron-binding glycoprotein abundant in mammalian milk, is a rich source of AMPs. Cationic peptide fragments such as lactoferricin and lactoferrampin exhibit more potent direct antimicrobial activity than the intact protein. Our previous studies have shown that peptides derived from Equine milk lactoferrin exhibit antihypertensive, anti-inflammatory, and anti-oncogenic activity in silico, highlighting their multifunctional bioactive potential. Building on these results, the present study aims to investigate the antimicrobial properties of these peptides. We used an integrated approach combining computer modeling and in vitro studies to identify and validate novel antimicrobial peptides from equine milk lactoferrin. Bioinformatics tools, including AMPScanner and CAMP, were used to predict antimicrobial domains, followed by experimental testing against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The results showed that equine milk lactoferrin peptides possess potent and selective antimicrobial activity, with efficacy varying across bacterial species. These data expand the functional profile of lactoferrin-derived peptides, demonstrating their multifunctionality, and suggest that equine milk lactoferrin represents a promising natural source of antimicrobial agents, supporting alternative strategies to reduce antibiotic use in human and veterinary medicine. Full article

Kidney Injury Molecule-1 (KIM-1), a type I transmembrane glycoprotein, is emerging as a promising biomarker in the landscape of genitourinary malignancies. Initially it was described for its role in renal tubular injury, but it is currently being studied for its expression in various neoplasms, particularly renal cell carcinoma, where it correlates with tumor grade, stage and prognosis. Recent studies have demonstrated its potential usefulness as a non-invasive diagnostic tool through urinary and plasma/serum studies, offering a valuable adjunct to imaging and pathology studies. KIM-1 may also play a role in urothelial cancer, although its specificity and relevance in this context are not clearly established yet. The following review presents our current knowledge on the biology of KIM-1, its expression patterns across various genitourinary tumors and its clinical implications in early detection, prognosis and treatment monitoring. We also explore the limitations and future directions regarding the integration of KIM-1 into precision oncology approaches. Full article

Drug resistance remains a major challenge in epilepsy, and overexpression of ATP-binding cassette transporters, particularly P-glycoprotein (P-gp), at the blood–brain barrier (BBB) has been consistently implicated in limiting central nervous system drug exposure. Genetic experimental models suitable for investigating molecular regulation and functional alterations of P-gp in epilepsy remain scarce. This study evaluated P-gp expression and functional alterations in the Wistar Audiogenic Rat (WAR), a genetic model of epilepsy exhibiting phenotypic heterogeneity. WAR animals were classified into refractory epilepsy (WAR-RE) or temporal lobe epilepsy (WAR-TLE) phenotypes and compared with non-epileptic Wistar controls. Fexofenadine, a well-established in vivo P-gp probe substrate, was administered orally, and plasma pharmacokinetic parameters were determined. P-gp expression at the BBB was assessed by immunohistochemistry in hippocampal regions. WAR-RE animals exhibited significantly increased systemic exposure to fexofenadine, characterized by higher area under the curve and prolonged half-life, alongside reduced apparent clearance, compared with control animals (p < 0.05). In contrast, WAR-TLE animals showed greater interindividual variability without statistically significant differences. Immunohistochemical analysis revealed increased P-gp expression in hippocampal microvessels in both WAR phenotypes. These findings demonstrate that the WAR model displays molecular upregulation of P-gp at the BBB, accompanied by functional alterations in the disposition of a prototypical P-gp substrate. Although direct brain drug concentrations were not assessed, the integration of systemic pharmacokinetics with transporter expression supports the use of WAR as a genetic proof-of-concept model for studying P-gp regulation and transporter-mediated drug disposition in epilepsy. This model provides a valuable molecular framework for future investigations addressing transporter modulation and mechanisms underlying pharmacoresistance. Full article

Juvenile idiopathic arthritis (JIA) represents the most common cause of chronic arthritis in childhood; however, not all early-onset arthropathies are inflammatory in origin. We report the case of a 4-year-old girl initially diagnosed with oligoarticular JIA and treated with methotrexate followed by a tumor necrosis factor inhibitor, without significant clinical improvement and despite persistently normal inflammatory markers. Clinical reassessment raised suspicion of a non-inflammatory arthropathy, supported by characteristic radiographic findings including metaphyseal flaring of the distal femora and proximal tibiae. Genetic analysis identified compound heterozygous pathogenic variants in the PRG4 gene, confirming the diagnosis of camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome (OMIM #208250). PRG4 encodes lubricin, a mucin-like glycoprotein essential for boundary lubrication of articular cartilage and maintenance of synovial joint homeostasis. Loss-of-function variants disrupt joint lubrication, leading to mechanical synovial hyperplasia and chronic non-inflammatory joint effusion. This case highlights common diagnostic pitfalls in pediatric rheumatology and underscores the importance of considering genetic causes of chronic arthropathy when clinical and laboratory features are atypical for inflammatory disease. Early molecular diagnosis prevents unnecessary immunosuppressive therapy and enables appropriate multidisciplinary management. Full article

Background: Influenza A(H3N2) continues to evolve rapidly, frequently eroding population immunity and challenging seasonal vaccine strain selection. During the 2025/26 season, the A(H3N2) subclade K (J.2.4.1) expanded quickly across multiple regions and showed evidence of antigenic divergence in standard assays. Methods: In this study, we combined phylogenetic analyses of hemagglutinin (HA) and neuraminidase (NA) sequences with a systematic synthesis of recent peer-reviewed studies and official surveillance reports to comprehensively define the molecular profile and early epidemiological dynamics of subclade K. Results: Our phylogenetic reconstructions of HA and NA genes confirmed the emergence of a coherent and recently diversified lineage characterized by coordinated evolution of surface glycoproteins and broad geographic representation during 2025. Integration of molecular, temporal, and surveillance evidence further supported rapid expansion with limited early regional structuring. Antigenic analyses reported in peer-reviewed studies described reduced haemagglutination inhibition reactivity to vaccine reference antisera for many subclade K viruses, whereas vaccine effectiveness (VE) estimates from multiple settings remained moderate. Conclusions: Overall, the available genetic, antigenic, and epidemiological evidence indicates that subclade K represents a recently diversified A(H3N2) lineage associated with rapid international spread during the 2025/26 season, highlighting the importance of integrated HA/NA genomic surveillance and timely antigenic characterization to support evidence-based vaccine strain selection. Full article

Located on the traditional and ancestral homelands of the Arapaho, Cheyenne, and Ute Nations, Colorado State University’s Mountain Campus hosted the 25th Annual Rocky Mountain Virology Association meeting. The three-day event, held from 26 September to 28 September 2025, welcomed 152 participants focused on the following topics: viruses, prions, immunology, transmission, structural biology, and vector biology. This year’s Randall Jay Cohrs Keynote Presentation summarized ongoing research on viral glycoproteins in relation to viral entry and assembly. Understanding the role of viral glycoproteins is essential in vaccine and antiviral development for enveloped RNA viruses. Alongside rigorous scientific discourse and networking, attendees made the most of their time by hiking amidst beautiful fall colors, wildlife, and young aspens starting the forest anew. On behalf of the Rocky Mountain Virology Association, this report summarizes select presentations from the 25th annual meeting. Full article