Search Results (3,532)

The catheter is among the most commonly used blood-contacting medical devices, but its use can induce surface-mediated coagulation activation, leading to catheter-related thrombosis (CRT). The occurrence of CRT causes venous thromboembolism and catheter malfunction, but current antithrombotic strategies have unsatisfactory efficacy and safety profiles. Here, we review recent advances in the understanding of the pathology of CRT, particularly the roles of the contact pathway factors, and promising novel therapeutic options. Recent studies using genetically modified animals, factor-deficient plasmas, specific inhibitors and purified systems demonstrated an important contribution of contact pathway factors XII and XI to catheter-related blood clotting. Accordingly, contact pathway inhibition has efficacy comparable to that of heparins in mitigating catheter-related coagulation or intraluminal occlusion in various in vitro and animal models, while having lower bleeding risk. Early human studies suggest potential thromboprotective effects of FXI inhibition in catheter placement and hemodialysis settings. However, inhibition of factors XII or XI may impair the defense against infection or disturb normal cardiac function, respectively. Larger human trials are needed to further confirm the efficacy and safety of these contact pathway inhibitors, and to explore whether low-dose combinations of contact pathway inhibitors with heparins are more effective for CRT protection. Full article

Cardiovascular–kidney–metabolic (CKM) syndrome encompasses the convergent pathophysiology of obesity, insulin resistance, type 2 diabetes, chronic kidney disease, and cardiovascular disease, conditions whose interactions account for a substantial proportion of cardiovascular morbidity and mortality despite contemporary guideline-directed therapy. Nitric oxide (NO) pathway dysfunction constitutes a unifying mechanism across this continuum, linking endothelial dysfunction, impaired insulin signaling, and multiorgan injury through endothelial NO synthase (eNOS) uncoupling, increased arginase activity, asymmetric dimethylarginine (ADMA) accumulation, and paradoxical inducible NO synthase (iNOS)-driven nitrosative stress. Established cardiometabolic therapies—sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), renin–angiotensin–aldosterone system (RAAS) inhibitors, statins, and metformin—improve NO signaling indirectly through reductions in oxidative stress and inflammation yet fail to fully restore NO bioavailability and leave substantial residual cardiovascular and renal risk unaddressed. Direct NO-restoring strategies, including soluble guanylate cyclase (sGC) modulators, arginase inhibition, ADMA-lowering approaches, and microbiome-targeted interventions, demonstrate mechanistic promise in preclinical and early translational studies but currently lack outcome-level evidence. Biomarkers of NO pathway dysfunction—ADMA, flow-mediated dilation (FMD), the tetrahydrobiopterin–dihydrobiopterin (BH4/BH2) ratio, cyclic guanosine monophosphate (cGMP), and endothelial microparticles (EMPs)—offer a foundation for patient phenotyping but remain insufficiently standardized for clinical use. A NO-centered framework provides a biologically coherent model for understanding residual cardiometabolic risk; its translation into personalized therapy will require validated biomarker panels and biomarker-guided outcome trials. Full article

The heart–kidney axis has emerged as a central framework for understanding the bidirectional interactions that drive cardiorenal syndrome and broader cardiovascular–kidney–metabolic (CKM) disease. However, existing interpretations have often emphasized hemodynamic and neurohormonal mechanisms without fully integrating the growing evidence for endocrine, inflammatory, and metabolic mediators that coordinate injury across organs. This Review was therefore undertaken to provide an updated and clinically relevant synthesis of the physiological basis of heart–kidney communication, the mechanisms underlying its disruption, and the therapeutic implications of these insights. To achieve this aim, we performed a systematic narrative review of the literature using PubMed, Embase, Web of Science, and Scopus for studies, supplemented by manual screening of reference lists. Priority was given to original studies, large cohort analyses, randomized controlled trials, meta-analyses, and authoritative reviews. We integrated evidence spanning physiological regulation, maladaptive signaling pathways, emerging mediators, experimental models, and evolving treatment strategies. The reviewed evidence indicates that heart–kidney crosstalk is driven not only by altered perfusion and venous congestion, but also by sustained activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), inflammation, oxidative stress, mitochondrial dysfunction, anemia, uremic toxins, and disordered mineral metabolism. Among novel mediators, fibroblast growth factor 23 (FGF23) emerges as a major bone-derived, chronic kidney disease (CKD)-associated endocrine mediator linking renal injury to cardiac hypertrophy, fibrosis, calcium mishandling, and diastolic dysfunction, whereas Klotho appears to exert counter-regulatory protective effects. Heart-derived natriuretic peptides, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), remain important modulators of renal blood flow, natriuresis, and volume homeostasis. We further highlight the translational relevance of newer biomarkers and therapies, including sodium–glucose cotransporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists), and mineralocorticoid receptor antagonists (MRAs), which may help address cardiac and renal dysfunction in parallel. Overall, this Review supports a revised conceptual model in which the heart–kidney axis is governed by multidirectional hemodynamic, neurohormonal, immune, and endocrine signaling networks. A more integrated understanding of these mechanisms may improve biomarker discovery, refine risk stratification, and promote therapies that target both organs simultaneously. Full article

L-type amino acid transporter 1 (LAT1), which controls the neutral amino acid uptake across the cell membranes, has been frequently overexpressed in various human cancers. Overexpression of LAT1 is associated with higher proliferation and shorter patient survival in tumors. Here, upregulated LAT1 expression was observed in patient-derived canine bladder cancers (BCs), and a small-molecule LAT1 inhibitor (JPH203) successfully reduced BC tumor growth both in vitro and in vivo. Patient-derived cancer cells were collected from dogs with naturally occurring tumors at veterinary clinics in Japan, and the 2.5D cancer organoid culture system was generated following our previous studies. Compared with other canine cancers or normal bladder cells, the increased LAT1 expression was observed in 2 strains of BC organoids. JPH203 inhibited boronophenylalanine (BPA) uptake activity by more than 90% and suppressed cell proliferation dose-dependently. Deprivation of BPA uptake activity by JPH203 also regulated the phosphorylation of mTOR-related proteins. Furthermore, intraperitoneal administration of JPH203 decreased the growth and tumor weight of BC organoid-derived xenograft in immunodeficient mice with an induction of apoptosis and a decrease in LAT1 expression compared to vehicle-administered mice. Therefore, the present study demonstrates that JPH203 exerts anti-tumor effects in canine BC through modulation of the mTOR signaling pathway and supports further investigation of LAT1-targeted therapy for canine BC. Full article

Epithelial ovarian cancer (EOC) comprises biologically and immunologically distinct histotypes and frequently develops within a chronically inflamed tumor microenvironment, particularly in advanced disease with malignant ascites. This narrative review revisits translational observations from the 1990s–2000s showing impaired lymphomonocyte proliferation, altered Fas/CD25 signaling, and abundant cytokine release in ovarian cancer effusions. These findings are interpreted as direct evidence of dysfunctional immune activation, but not as retrospective proof of T-cell exhaustion according to contemporary molecular, transcriptional, epigenetic, or functional definitions. Modern single-cell and spatial studies provide independent evidence that malignant ascites is a dynamic ecosystem containing heterogeneous T-cell and macrophage states and that immune architecture differs across anatomical compartments and histotypes. Within this framework, cytokine signaling, macrophage plasticity, iron/redox biology, ferroptosis susceptibility, adipocyte–tumor crosstalk, and systemic metabolic dysfunction are considered at different levels of evidentiary strength, with ovarian cancer-specific data distinguished from pan-cancer or preclinical extrapolation. Clinical experience with immune-checkpoint inhibitors further illustrates the distinction between immune-cell presence and effective immunity: single-agent activity has generally been modest, whereas the phase III ENGOT-ov65/KEYNOTE-B96 trial demonstrates that clinically meaningful benefit can emerge in an appropriate therapeutic and biomarker-selected context. We propose that “inflammation without effective immunity” is best viewed as an overarching, histotype- and context-dependent immunometabolic framework rather than a uniform ovarian cancer phenotype. The concept remains hypothesis-generating and requires prospective validation before biomarker or therapeutic implementation. Full article

The urokinase plasminogen activator or urokinase is a highly specific extracellular protease involved in numerous physiological and pathological processes. Its activity is a consequence of its interplay with its inhibitor, PAI1, and receptor, uPAR, and is finely regulated at several levels. The aim of the work was to investigate whether endoplasmic reticulum stress can modulate urokinase activity. Two tumor cell lines grown in cell culture were treated with Thapsigargin and sodium salicylate, inducers of ER stress response. Urokinase activity was determined in the conditioned media, and expression of uPA system molecules and molecules involved in response to ER stress in cell lysates was measured. ER stress influenced urokinase activity: while in the glioblastoma line its activity was increased, in breast cancer cells it was decreased. Differences in activity were a consequence of urokinase and PAI1 expression at the protein and RNA level. However, ER stress decreased cell migration, invasion, and proliferation regardless of the changes in urokinase activity. Gene expression analysis indicated that cell specific activation of some transcription factors and pathways could be responsible for different urokinase activity regulation. Full article

Background/Objectives: Direct oral factor Xa inhibitors (DOACs) show substantial interindividual exposure variability in real-world practice, yet interpretation of plasma drug concentrations remains challenging because routine monitoring is not standardized. This study evaluated dosing appropriateness, plasma drug exposure measured by chromogenic anti-factor Xa assays, inter-platform comparability, and associations with routine coagulation tests. Methods: This single-center retrospective study included 392 plasma samples from 292 patients with atrial fibrillation treated with apixaban (n = 207), edoxaban (n = 147), or rivaroxaban (n = 38). Post-dose outpatient spot samples were analyzed using Sysmex CS-5100 and CN-6000 analyzers with two chromogenic anti-factor Xa assay systems (BIOPHEN™ DiXaI and BIOPHEN™ Heparin LRT) and drug-specific calibrators. Correlations between routine assays (prothrombin time [PT]/international normalized ratio [INR], activated partial thromboplastin time [aPTT]) and DOAC concentrations, as well as inter-platform agreement, were assessed using Spearman’s rank correlation and Passing-Bablok regression. Dosing appropriateness was determined according to Food and Drug Administration-approved labeling. Results: Overall dosing appropriateness was 69.2% (edoxaban 73.3%, apixaban 70.5%, rivaroxaban 45.5%), whereas inappropriate underdosing was the predominant prescribing pattern (26.9%), particularly among patients without formal dose-reduction criteria. PT/INR demonstrated the strongest correlation with edoxaban concentrations (rs = 0.83, p < 0.001). Inter-analyzer correlation between the CS-5100 and CN-6000 was excellent (r = 0.885–0.996), with LRT reagents providing highly consistent results across platforms. Conclusions: Real-world outpatient DOAC concentrations demonstrated substantial variability and frequent off-label underdosing. Chromogenic anti-factor Xa assays showed strong inter-platform agreement, particularly with LRT reagents, supporting their analytical reliability for laboratory assessment of DOAC exposure. Because exact dosing times were unavailable, these concentrations should be interpreted as heterogeneous spot samples rather than standardized pharmacokinetic reference intervals; these findings may nonetheless support individualized interpretation of outpatient spot sample DOAC concentrations in selected clinical settings. Full article

Colorectal cancer therapy requires drug delivery systems that improve treatment efficacy and minimize systemic toxicity. In this study, chitosan-based nanoparticles were fabricated and functionalized with folic acid (FA), phenylalanine (PA), and butyric acid (BA) to enhance the delivery of curcumin to Caco-2 cancer cells. The nanoparticles were prepared using an ionic gelation method, and their physicochemical properties, cellular uptake efficiency, and cytotoxicity—including safety evaluation against normal HIEC-6 cells—were investigated. Results showed that ligand conjugation significantly influenced the physicochemical properties of the nanoparticles. CRFANP (FA-modified) exhibited the largest particle size (263.5 nm) due to its rigid aromatic structure, while CRPANP (PA-modified) showed an intermediate size (138.0 nm) and the lowest surface charge (15.59 mV). In contrast, CRBANP (BA-modified) presented the smallest particle size (128.2 nm) and the highest positive surface charge (23.27 mV). These distinct physicochemical properties directly influenced their cellular interactions; CRBANP and CRFANP showed higher uptake than CRPANP, with CRBANP yielding the maximum accumulation of curcumin in Caco-2 (21.92 nM/mg protein) and HT-29 cells (22.09 nM/mg protein). Correlating with the uptake data, cytotoxicity assays revealed that CRBANP was the most potent formulation, exhibiting the lowest IC₅₀ of 1.30 µM in Caco-2 cells, which was significantly lower than that of CRFANP (3.49 µM) and CRPANP (7.40 µM), while demonstrating high selectivity against Caco-2 cells with an SI of 46.5 and no apparent toxicity toward normal HIEC-6 cells. This enhanced efficacy is attributed to the synergistic action of butyric acid as a histone deacetylase inhibitor (HDACi), which complements curcumin’s anticancer activity. These findings indicate that integrating butyric acid into chitosan nanoparticles provides an effective and selective strategy for targeted colorectal cancer therapy. Full article

With immune checkpoint inhibitors becoming the mainstay of systemic therapy in both metastatic and early-stage settings across many cancer types, the management of immune-related adverse events has emerged as a central priority of modern oncological supportive care. These toxicities can substantially impair the quality of life of cancer patients, including those who achieve long-term survival. Consequently, there is a pressing need to develop reliable predictive biomarkers to better tailor immune checkpoint inhibitor treatment and optimize patient selection. This review summarizes several of the most promising predictive biomarkers currently under investigation, including genetic factors; peripheral blood parameters and their ratios; autoantibodies; cytokines and chemokines; cytomegalovirus serostatus; gut microbiome characteristics; body composition metrics; molecular imaging features; and tumour- and patient-related factors such as cancer type, gender, and physical activity. Because single biomarkers have limited predictive value, multi-omics prediction models and composite immune-cell scores are increasingly demonstrating greater potential. However, none of these candidate biomarkers have yet undergone sufficient validation to support their incorporation into routine clinical practice. Full article

Leucine-rich repeat kinase 2 (LRRK2) has emerged as a central molecular node linking genetic risk, membrane trafficking, lysosomal homeostasis, and immune signalling in Parkinson’s disease (PD). Rather than functioning as a conventional protein kinase, LRRK2 operates as a conformationally regulated, Rab-directed signalling machine whose activity is governed by long-range interdomain communication, membrane recruitment, and cooperative interactions with small GTPases. Converging advances in cryo-electron microscopy, quantitative phosphoproteomics, and human genetics indicate that pathogenic mutations, lysosomal stress, and pharmacological inhibitors do not simply alter catalytic output, but reshape the conformational landscape of LRRK2, biasing it toward distinct structural states with divergent cellular consequences. A defining feature of this system is the selective phosphorylation of Rab GTPases at low stoichiometry—most prominently Rab8 and Rab10—yet with disproportionate functional impact on vesicle trafficking, ciliogenesis, autophagy, and organelle positioning. The identification of Rab-directed phosphatases, particularly PPM1H, further establishes that LRRK2 signalling is governed by a dynamically balanced kinase–phosphatase circuit operating in space and time. These observations, together with emerging evidence linking LRRK2 activation to lysosomal damage and immune pathways, support a unifying hypothesis: PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis, rather than from kinase hyperactivity alone. In this review, we integrate structural, biochemical, and cellular evidence to advance this framework and discuss its implications for disease mechanisms and therapy. We highlight key unresolved challenges—including conformation-selective drug targeting, spatial control of Rab phosphorylation, and context-dependent immune–neuronal crosstalk—and propose that restoring physiological regulation of LRRK2, rather than simply inhibiting its activity, will be essential for achieving mechanism-based disease modification in Parkinson’s disease. Full article

Chronic kidney disease (CKD) is sustained by a network of sterile inflammation, oxidative and metabolic stress, uremic toxin retention, gut barrier dysfunction, and maladaptive immune activation. These processes contribute to kidney fibrosis, cardiovascular injury, wasting, and excess mortality, but inflammatory biomarkers do not by themselves establish therapeutic causality. This narrative review integrates mechanistic and therapeutic evidence using an explicit three-layer translational hierarchy. Renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, finerenone, and glucagon-like peptide-1 receptor agonists improve cardiorenal outcomes and have plausible anti-inflammatory actions, although inflammatory mediation remains unproven. Interleukin-1 blockade provides cardiovascular proof of principle and small dialysis feasibility data. Interleukin-6 ligand inhibition produces marked human target engagement; however, headline results from the completed phase 3 ZEUS trial showed no reduction in three-point major adverse cardiovascular events with ziltivekimab despite biomarker suppression, while serious infections were more frequent. POSIBIL6ESKD continues to test clazakizumab in inflamed dialysis patients. Direct NLRP3 inhibition has entered early human CKD development, whereas senescence-directed and microbiota-based approaches remain less mature. Future progress requires inflammatory endotyping, repeated biomarker assessment, mechanistically aligned outcomes, and rigorous infection surveillance. ZEUS underscores that pathway suppression must deliver clinical benefit beyond contemporary standard therapy. Full article

Aortopathies in autoimmune rheumatic diseases (ARD) include a spectrum of aortic pathologies—including aortitis, aneurysms, dissections, and insufficiency—primarily caused by systemic inflammation. This comprehensive review investigates the clinical manifestations, pathophysiology, diagnostic modalities, and management strategies across various rheumatic diseases associated with aortopathies such as large vessel vasculitis (e.g., Takayasu arteritis, giant cell arteritis), connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis) and less common conditions (e.g., relapsing polychondritis, Cogan’s syndrome, Behçet’s disease, IgG4-related disease). Disease-specific pathophysiologic mechanisms of aortic wall inflammation and remodeling, including granulomatous and lymphoplasmacytic patterns and mixed inflammatory infiltrates, are described. Diagnostic imaging modalities—such as CTA, MRI, and PET/CT—are evaluated for their roles in detecting active inflammation, assessing structural complications, and guiding clinical decision-making. Histopathological findings provide insight into disease-specific vascular changes. Management strategies focus on the use of glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics, including IL-6 and TNF-α inhibitors, with an emphasis on patient-centered approaches, multidisciplinary care, and timely surgical intervention for complications. Evidence gaps include optimal screening intervals and the role of novel biomarkers in risk stratification and in monitoring disease progression, highlighting the need for early recognition, frequent monitoring, and aggressive management of aortic involvement in rheumatic diseases to prevent life-threatening complications. Full article

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer deaths worldwide. Mutations of the RAS and BRAF genes and the location of the primary tumor determine the choice of systemic therapy. Panitumumab—a fully human anti-EGFR monoclonal antibody—is well-established in the treatment of patients with wild-type RAS and BRAF and left-sided tumor localization. The aim of this review is to summarize the role and potential of targeted therapies for colorectal cancer with monoclonal antibodies such as panitumumab or cetuximab, to provide current evidence on the position of panitumumab in the treatment of mCRC, and to discuss biomarkers and qualification strategies for targeted therapy, including the role of ctDNA in disease monitoring and rechallenge. The work is based on a narrative review of literature from the PubMed, Scopus, Web of Science and Google Scholar databases, including publications available until May 2026. The efficacy of panitumumab was confirmed in phase III studies: first-line (PRIME: prolongation of OS by 5.6 months) and second-line treatment. A key condition for eligibility is complete RAS and BRAF genotyping, assessment of MSI/dMMR status, HER2 amplification, and tumor location. ctDNA analysis enables monitoring of tumor clonal evolution and qualification for rechallenge—the CHRONOS study showed 30% objective responses with liquid biopsy-based selection. Associations with BRAF/MEK and KRAS G12C inhibitors and modulation of the immune microenvironment via the CCL5/CCR5 axis remain promising directions. Panitumumab occupies an important position in the treatment of patients with mCRC, but increasingly precise molecular stratification and dynamic monitoring of disease with ctDNA are becoming the basis for the effective and rational use of the drug. Unlike reviews that selectively focus on individual aspects of anti-EGFR therapy, the following work integrates all aspects: from molecular biology and biomarkers used to qualify patients to clinical data on panitumumab and new strategies in the fight against mCRC. Further development of next-generation sequencing methods and standardization of ctDNA panels will be crucial for the widespread deployment of targeted therapies in everyday clinical practice. The role of panitumumab is well established in appropriately selected patients with RAS wild-type, particularly left-sided, metastatic colorectal cancer (mCRC). Combining panitumumab with immune checkpoint inhibitors warrants further investigation, particularly in patients with MSS/pMMR mCRC. The observed activity of panitumumab in combination with nivolumab and ipilimumab provides a rationale for further clinical evaluation and monitoring. Full article

The global emergence of multidrug-resistant fungal pathogens, including Candida auris, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Pneumocystis jirovecii, poses a growing threat to public health, particularly among immunocompromised individuals. The limited number of available antifungal drug classes and the rapid evolution of resistance mechanisms, including target-site mutations, efflux pump activation, biofilm formation, metabolic adaptation, and stress-response signaling, have substantially reduced treatment efficacy. This review provides a comprehensive overview of current antifungal therapies, their limitations, and emerging molecular targets for next-generation antifungal drug discovery. We highlight promising targets involved in fungal cell wall biosynthesis, membrane integrity, mitochondrial metabolism, virulence regulation, and host–pathogen interactions, emphasizing their interconnected roles within adaptive resistance networks. Attention is given to small-molecule isothiazolone-based inhibitors, including phosphoglucomutase-targeting compounds, as novel candidates capable of disrupting multiple fungal survival pathways. We further discuss advances in combination therapies, anti-virulence approaches, nanotechnology-based delivery systems, and artificial intelligence-driven drug discovery pipelines that integrate multi-omics data, structural modeling, molecular docking, and virtual screening to accelerate therapeutic development. These advances support a transition from conventional single-target strategies toward systems-level, precision-guided antifungal therapies, providing a framework for overcoming multidrug resistance and improving clinical outcomes in invasive fungal infections. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article