Search Results (6,472)

Atherosclerosis is a chronic immune–inflammatory disease of the arterial wall in which antigen-presenting cells (dendritic cells, macrophages and B cells) present locally generated antigens, such as oxidized low-density lipoprotein, to plaque-infiltrating T cells. Full T-cell activation requires costimulation through the B7 family ligands CD80 (B7-1) and CD86 (B7-2), which engage CD28 to activate T cells and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to restrain them. Although long considered functionally redundant, CD80 and CD86 are now known to be structurally and mechanistically distinct, differing in receptor affinity, susceptibility to CTLA-4-mediated trans-endocytosis, capacity to cis-heterodimerize with programmed death-ligand 1, and dependence relationships with regulatory versus effector T cells. In atherosclerosis, CD80 is expressed by lesional dendritic cells, macrophages, foam cells, B cells and, under inflammatory conditions, vascular endothelial and smooth muscle cells, with expression levels correlating with plaque vulnerability in humans. Genetic deletion, CTLA-4-Ig-based pharmacological blockade and selective small-molecule antagonism in preclinical models generally converge on a proatherogenic role for CD80/CD86-dependent costimulation, although combined genetic deletion of CD80 and CD86 has also been reported to paradoxically enhance early lesion formation in some contexts, while augmented CTLA-4-mediated coinhibition is atheroprotective—a balance corroborated by the accelerated atherosclerosis and cardiovascular toxicity observed with checkpoint-inhibitor cancer immunotherapy. Molecular imaging agents targeting CD80/CD86, repurposed CTLA-4-Ig biologics such as abatacept, and antigen-specific tolerogenic dendritic cell strategies together constitute an emerging translational pipeline. To our knowledge, this is the first review to integrate CD80’s structural and receptor pharmacology with its cellular sources in the plaque, preclinical genetic and pharmacological evidence, human plaque and biomarker data, molecular imaging approaches, and checkpoint inhibitor-associated cardiovascular toxicity within a single translational framework. This review synthesizes the structural biology, cellular sources, preclinical genetics, human plaque and biomarker data, and therapeutic and diagnostic implications of CD80 as an immune mediator and candidate therapeutic target in atherosclerosis. Full article

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates within the intratumoral and peritumoral microenvironment. In hepatocellular carcinoma (HCC), the presence of TLSs was closely associated with immunotherapy response and prognostic outcomes. However, TLSs exhibit pronounced spatial heterogeneity within tumors and biopsy, being invasive and prone to sampling bias, may cause inaccurate assessments. Multi-parametric imaging techniques based on computed tomography (CT)/magnetic resonance imaging (MRI)CT/MRICT/MRI with the aid of artificial intelligence (AI) algorithms could effectively integrate anatomical structures with functional metabolic information, quantifying and visualizing key pathological molecular features of tumor treatment response across multiple dimensions. This review summarizes the biological characteristics and clinical significance of TLSs in hepatocellular carcinoma. Furthermore, it focuses on the latest advances in non-invasive TLS assessment using multi-parametric imaging techniques, integrating these technologies with large-scale artificial intelligence models to explore their application value in prognosis prediction and immunotherapy benefit evaluation. Full article

Transient receptor potential vanilloid channel 3 (TRPV3) is a keratinocyte-expressed ion channel that regulates calcium signaling and thymic stromal lymphopoietin (TSLP) production, contributing to pruritic inflammatory skin diseases. Although avicularin (AVC), a flavonoid from Polygonum aviculare L., and senegenin (SNG), the bioactive aglycone of Polygala tenuifolia Willd., possess anti-inflammatory properties, their effects on TRPV3-associated signaling remain unknown. A natural product library was screened for nitric oxide (NO) production in carvacrol-stimulated human keratinocytes. Following primary screening and secondary evaluation of TRPV3 and TSLP expression, AVC and SNG were selected for further study and subsequently evaluated by molecular docking, calcium imaging, quantitative real-time PCR, immunocytochemistry, and pathway inhibition assays. AVC and SNG showed favorable predicted docking poses at both TRPV3 docking sites and significantly attenuated carvacrol-induced calcium-dependent fluorescence responses in TRPV3-expressing cells. Both compounds reduced TRPV3 and TSLP expression at the mRNA and protein levels and attenuated the nuclear translocation of phospho-Nuclear Factor of Activated T Cells 2 (NFATC2) and phospho-p50. Co-treatment with NFAT or Nuclear Factor Kappa B (NF-κB) inhibitors produced no additional suppression, consistent with convergence of AVC/SNG-associated effects with NFAT/NF-κB signaling. Collectively, these findings support further investigation of AVC and SNG as candidate modulators of TRPV3-associated inflammatory signaling in keratinocytes. Full article

Maxillary expansion combines sutural skeletal displacement with variable alveolar, dental, and periodontal responses. Because these effects are often reported as a single transverse outcome, their biological contributions are difficult to separate. We reviewed clinical, histological, and experimental evidence on midpalatal and circummaxillary sutural remodeling, alveolar deformation, anchorage-related periodontal loading, and used this evidence to formulate a three-compartment model. The sutural skeletal domain is the intended orthopedic target; the alveolar and dentoalveolar domain describes adaptive load transfer; and the anchorage-related periodontal domain captures non-target tissue responses. These labels describe treatment roles and do not imply a fixed sequence or biological independence. Experimental studies report overlapping mechanosensing, cellular recruitment, osteoclast-related margin turnover, immune and vascular activity, and osteogenesis within expanded sutures. Direct longitudinal molecular data in humans remain scarce, and the order of these events is unresolved. Clinical imaging also shows that comparable transverse corrections can contain different proportions of sutural opening, alveolar bending, dental tipping, and buccal cortical change. The model distinguishes skeletal correction from accompanying dentoalveolar and periodontal effects and yields testable predictions for multimodal imaging, tissue-specific biological measurements, histology, and patient-specific computational modeling. We present it as a provisional analytic model, not as a validated biological classification or clinical prediction rule. Full article

Background/Objectives: Glycogen synthase kinase-3β (GSK-3β) serves as a crucial molecular target for Alzheimer’s disease and other neurological disorders. Positron emission tomography (PET) enables non-invasive quantification of GSK-3β in vivo, offering value for early diagnosis and mechanistic studies. However, despite two decades of effort, no GSK-3β PET tracer has yet entered clinical trials. Methods: This review systematically summarizes the radiochemical synthesis and preclinical evaluation of major GSK-3β tracer classes, comparing synthetic accessibility, target affinity, brain uptake, P-gp efflux, metabolic stability, radiometabolite profiles, and blocking experiments. The literature was systematically searched in PubMed and Web of Science databases (2005–2026). Several key obstacles impeding clinical progression of GSK-3β PET radiotracers are identified. Results: First, P-gp efflux markedly reduces brain tracer accumulation, rendering even sub-nanomolar high-affinity ligands ineffective for brain imaging. Second, interfering factors such as brain-penetrant radiometabolites of [¹¹C]OCM-44 and the extremely low plasma free fraction of [¹⁸F]OCM-50 greatly impair the quantitative accuracy of tracer uptake. Third, the paradoxical increase in brain uptake of isonicotinamide tracers upon blocking remains an unresolved confounding factor. Moreover, rodent data fail to reliably predict tracer performance in higher species, and to date, no tracer has been directly validated against GSK-3β expression in patient brain tissue. Conclusions: This review proposes a tiered validation framework comprising four levels: assessment of P-gp efflux, metabolite-corrected arterial input function, low-affinity enantiomer controls, and human brain autoradiography. The framework provides a rigorous basis for screening candidates and a systematic reference for developing next-generation GSK-3β PET tracers. Full article

Cutaneous melanoma remains a global health challenge. Although BRAF/MEK-targeted therapies and immune checkpoint inhibitors (ICIs) have improved outcomes in advanced disease, durable responses remain difficult to achieve for most patients. Therapeutic resistance represents the central barrier to long-term disease control. This review comprehensively examines the molecular and immunologic mechanisms underlying melanoma resistance and integrates these insights with emerging pharmaceutical strategies designed to overcome them. We explore the genetic landscape of melanoma, including oncogenic alterations in BRAF, NRAS, NF1, CDKN2A, and PTEN, and explain how dysregulation of the MAPK and PI3K/AKT/mTOR signaling axes drives therapeutic escape. Phenotypic plasticity is discussed as a critical epigenetic driver of drug tolerance. The tumor microenvironment (TME) is examined as an active co-conspirator in resistance, encompassing immunosuppressive cell populations, cancer-associated fibroblasts, and metabolic competition. Resistance mechanisms to targeted therapy, including MAPK reactivation, bypass signaling, transcriptional reprogramming, and metabolic rewiring, are reviewed alongside tumor-intrinsic and tumor-extrinsic mechanisms of ICI resistance. Emerging therapeutic strategies are surveyed, including next-generation RAF and ERK inhibitors, dual-pathway blockade, and metabolic therapies targeting oxidative phosphorylation. Innovations in molecular imaging, liquid biopsy, and artificial intelligence-driven biomarker discovery are highlighted as pivotal tools for real-time resistance monitoring and adaptive treatment. By linking mechanistic insights with translational advances, this review advocates for combination strategies and adaptive clinical frameworks to achieve more durable disease control in melanoma. Full article

Background/Objectives: The accelerating integration of machine learning (ML) with molecular, imaging, and physiological data is transforming Alzheimer’s disease (AD) research. Methods & Results: Recent studies demonstrate that multimodal, AI-assisted platforms can enhance early diagnosis, predict biomarker trajectories, and identify novel therapeutic targets. This mini-review covers the evolving AD diagnostic and biomarker frameworks, current therapeutic strategies including recently approved anti-amyloid immunotherapies, and advances from contemporary studies employing ML across diverse data streams, ranging from cerebrospinal fluid (CSF) and plasma proteomics to Raman spectroscopy, neuroimaging, transcriptomics, and microbiome signatures. Conclusions: Collectively, they illustrate how artificial intelligence (AI) has shifted A biomarker discovery from univariate to network-based inference, achieving clinically relevant accuracy while emphasizing model interpretability. We discuss biological insights, translational implications, and persisting challenges related to validation, bias, and regulatory integration. Full article

Background: Prostate cancer (PCa) remains a significant health challenge, requiring innovative treatments. Here, we evaluated the efficacy of Talazoparib-loaded liposomes incorporating a targeting moiety, in combination with BI 2536, in PCa. This study develops lipid nanoparticles (LIPOs) targeting prostate-specific membrane antigen (PSMA) for better drug delivery. Methods: Two new PSMA-targeting agents, DUPA-DSPE and DUPA-PEG-DSPE, were created and incorporated into LIPOs via thin-film hydration. LIPOs’ size and morphology were characterized using Dynamic light scattering, and structural analysis was done via TEM imaging. In vitro cytotoxicity and cell viability were assessed using an MTT assay, while in vivo radioactivity was evaluated by PET imaging, and radioactive activity was quantified using a γ-counter. Results: These LIPOs demonstrated excellent stability and specific binding to PSMA-expressing prostate cancer cells in vitro. In vivo, mouse model studies showed that PSMA-targeted LIPOs accumulated preferentially at tumor sites. Talazoparib, a PARP inhibitor with low solubility and cytotoxicity, has limited use in PCa. Conclusions: These findings provide proof-of-concept evidence that PSMA-targeted DUPA-PEG LIPOs can facilitate Talazoparib delivery and, particularly in combination with BI 2536, may enhance antitumor activity in PCa models. Further studies with expanded control groups and larger cohorts are warranted to validate the therapeutic efficacy of this combination strategy and support its further development for PCa treatment. Full article

Adenomyosis and uterine fibroids are among the most common benign uterine disorders in women of reproductive age and represent major causes of abnormal uterine bleeding, pelvic pain, and infertility. Despite their distinct histopathological features, they frequently coexist and share several hormonal and molecular mechanisms, making diagnosis and treatment challenging. This narrative review examines the current evidence on their epidemiology, pathophysiology, clinical presentation, imaging characteristics, reproductive impact, and therapeutic management, with particular attention to the role of imaging in the differential diagnosis and management of coexisting disease. A non-systematic narrative review of the literature was conducted using PubMed/MEDLINE and Scopus. Relevant original studies, systematic reviews, meta-analyses, consensus statements, and clinical guidelines addressing adenomyosis, uterine fibroids, imaging, fertility, and treatment were considered. Additional references were identified through manual screening of the bibliographies of the retrieved articles. Although adenomyosis and uterine fibroids differ in their biological origin and morphological appearance, they commonly present with overlapping symptoms, including heavy menstrual bleeding, dysmenorrhea, chronic pelvic pain, and reproductive dysfunction. Transvaginal ultrasound remains the first-line imaging modality, whereas magnetic resonance imaging is particularly valuable in complex cases, lesion characterization, and preoperative assessment. Accurate imaging phenotyping may help distinguish isolated from coexisting disease and support individualized medical, surgical, or minimally invasive treatment planning. A structured imaging-based approach integrated with clinical findings and reproductive goals may improve disease characterization and support individualized management of adenomyosis and uterine fibroids. Further standardization of imaging criteria and validation of emerging diagnostic technologies may improve patient stratification and treatment selection. Full article

The incidental discovery of focal liver lesions (FLLs) has reached unprecedented levels due to the widespread use of high-resolution imaging, yet unenhanced ultrasound often lacks the specificity required for definitive characterization. This review identifies Contrast-Enhanced Ultrasound (CEUS) as a transformative diagnostic pillar for common benign focal liver lesions (BFLLs). By utilizing strictly intravascular second-generation microbubble agents, CEUS enables continuous, real-time visualization of microvascular hemodynamics. This high temporal resolution allows clinicians to identify pathognomonic vascular signatures, such as the “iris-diaphragm” centripetal fill-in of hemangiomas and the rapid centrifugal “spoke-wheel” hyperperfusion characteristic of focal nodular hyperplasia (FNH). Critically, this review highlights the unparalleled safety profile of CEUS. Because microbubbles are not excreted by the kidneys and carry no risk of nephrotoxicity, CEUS is an essential diagnostic option for patients with renal failure. Furthermore, the lack of ionizing radiation and the ability to perform examinations bedside provide a safe and versatile solution for pregnant patients and those with contraindications to traditional cross-sectional imaging. This review serves as a comprehensive informational framework, equipping clinicians with detailed pathological, clinical, and radiological insights into common entities like hemangiomas, FNH, and hepatocellular adenomas (HCA). It correlates fundamental histological features—such as the “map-like” glutamine synthetase staining in FNH—with essential clinical management strategies. While multiparametric MRI remains the premier tool for complex subtyping and molecular mapping—particularly for differentiating hepatocellular adenoma variants—CEUS is established as a cost-effective and radiation-free initial diagnostic solution. This review equips clinicians with a comprehensive framework of pathological, clinical, and radiological insights to optimize the management of common benign hepatic incidentalomas Full article

Background: Bicuspid aortic valve disease (BAVD) is the most frequent congenital heart disease, occurring either as an isolated lesion or in association with other congenital cardiovascular malformations, with variable patterns of progression and risk of valvular and vascular complications. Studies addressing pediatric bicuspid aortopathy are still in their infancy. This narrative review aims to provide a comprehensive perspective on the current scientific evidence regarding BAVD-associated aortopathy in pediatric patients, underscoring multiple challenges in initial diagnosis, long-term surveillance, and therapeutic decision-making, and focusing on the potential roles of circulating biomarkers and advanced multimodal imaging tools that may improve individualized risk stratification. Methods: Despite the narrative design of this review, a structured search of the current available literature was performed to identify studies addressing pediatric BAV, associated aortopathy, biomarkers, vascular remodeling, and multimodal imaging. Priority was given to pediatric cohorts, longitudinal studies, consensus documents, and contemporary guidelines. The search was conducted in the online databases PubMed/Medline and Web of Science for English-language original articles published in the last 10 years, up to May 2026. We used the following main terms: “Bicuspid Aortic Valve Disease” [MeSH], “Aorta” [MeSH], “Infant” [MeSH], “Child” [MeSH], “Adolescent” [MeSH], combined by Boolean operators with secondary keywords: “pathogenesis”, “mechanism”, “progression”, “multimodal imaging”, “echocardiography”, “cardiovascular magnetic resonance imaging”, “computed tomography”, “circulating biomarkers”. The retrieved studies were screened for eligibility using previously established inclusion and exclusion criteria. A total of 63 studies were included in the analysis for this narrative review. Results: Two main theories underpin the etiopathogenesis of aortopathy associated with the bicuspid aortic valve, positing that genetic factors predispose the aortic wall to remodeling in an abnormal hemodynamic environment. Embryological development and dysregulation of molecular and cellular structures are also intertwined during the formation and progression of the aortic valve with two semilunar cusps, resulting in consequent alterations in the aortic wall’s architectural organization. Advances in molecular studies have highlighted circulating biomarkers with potential utility in predicting aortopathy, as they are involved in extracellular matrix remodeling, endothelial dysfunction, and aortic valve calcification, including matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), transforming growth factor-β (TGF-β), and microRNAs. In addition, multimodal imaging techniques have emerged as essential tools for assessing the morphology and function of cardiovascular structures, particularly aortic biomechanical properties and hemodynamic abnormalities, at the time of initial diagnosis and during regular monitoring. Taken together, blood biomarkers and imaging parameters of aortic remodeling and flow disturbances might gain increasing prognostic value in pediatric BAVD-associated aortopathy. However, larger longitudinal studies are required for clinical validation beyond research settings. Although guidelines on the management of BAVD are available for adults, they are not entirely applicable to children, who are undergoing continuous somatic growth that affects diagnostic possibilities and therapeutic options. Conclusions: Despite growing literature in the realm of BAVD and related conditions, the management of pediatric patients remains challenging in daily clinical practice, as adult guidelines cannot be completely applied to children. Given the heterogeneity and complexity of pathogenic mechanisms, clinical presentations, natural history, and outcomes, future research is warranted to explore the progression profiles of valvular and vascular disorders associated with BAV in children and to achieve an optimal approach to pediatric bicuspid aortopathy. Full article

Ryanodine receptor 2 (RyR2) has been increasingly recognized as an important regulator in cancer biology. Previous studies demonstrate that RyR2 expression is associated with patient survival, although its precise role in tumorigenesis remains unclear. Elevated RyR2 expression has been linked to poorer survival outcomes, while gene silencing or pharmacological inhibition (e.g., with S107) has been shown to reduce cancer cell metastasis in both in vitro and in vivo models. Cytokeratin 18 (CK18), a key epithelial marker, is associated with tumor differentiation, hormonal phenotype, and clinical behavior in pituitary neuroendocrine tumors (PitNETs), reflecting underlying cytoskeletal organization. Variations in CK18 expression have been linked to distinct adenoma subtypes and may provide insight into tumor aggressiveness. This exploratory study investigated associations between RyR2 expression, CK18 status, and conventional MRI findings of pituitary tumors. Quantitative T2-weighted signal intensity and radiomic features were not assessed. This exploratory observational study used prospective patient recruitment between January 2017 and January 2026, after ethics approval was obtained in December 2016. RyR2 expression in immunohistological samples was quantified using QuPath v0.6.0. CK18 immunostaining was performed with the Dako Omnis system according to the manufacturer’s protocols. Conventional MRI findings were available for 24 patients and were retrospectively reviewed. Statistical analysis was conducted using SPSS/W 31.0. No statistically significant associations were observed between RyR2 expression and sex, hormonal activity, tumor size, invasiveness, recurrence, or the evaluated conventional MRI findings (all p > 0.05). The only statistically significant finding was higher RyR2 expression in CK18-negative than in CK18-positive tumors (median (IQR): 2.49% (18.36%) vs. 0.06% (0.39%); p = 0.006; r = 0.47). Higher RyR2 expression was observed in CK18-negative tumors. Given the exploratory design and limited sample size, this association should be considered hypothesis-generating and requires validation in larger independent cohorts. Full article

Shrimp shell–derived chitosan and protein hydrolysate–epigallocatechin gallate conjugates (SEC) were used to fabricate hybrid particles (C-SEC) at mass ratios of 1:1, 1:5, and 1:10 using an alkali precipitation method. SEC incorporation significantly enhanced the antioxidant capacity of chitosan particles (p < 0.05). Among the formulations, C-SEC prepared at a ratio of 1:5 (C–SEC–1:5) exhibited the highest antioxidant activities, including DPPH (14.55 mM TE/g) or ABTS (9.80 mM TE/g), or hydroxyl (70.29%) radical scavenging activities, ferric reducing antioxidant power (10.59 mM TE/g), and metal chelating activity (6.37 mM EE/g). The particle size was markedly reduced from 738 nm for chitosan particles (CP) to 112 nm following incorporation of SEC, indicating the formation of finely dispersed hybrid particles. ¹H NMR analysis confirmed successful molecular integration of SEC into the chitosan matrix through non-covalent interactions. Thermal analyses revealed altered degradation and transition behavior of the hybrid particles. TGA showed that the principal degradation stages shifted to higher temperatures, whereas DSC showed an increase in transition enthalpy from 370.74 to 2449.60 J/g. SEM and TEM images revealed that the C–SEC–1:5 formed porous, interconnected particle networks with rough surfaces. The selected hybrid particles also showed superior inhibition of Cu²⁺–induced lecithin liposome oxidation and β-carotene bleaching compared with CP, demonstrating concentration-dependent protection against lipid oxidation. Overall, these findings indicate the potential of C–SEC–1:5 as an antioxidant-based functional ingredient and bioactive delivery vehicle in food and nutraceutical formulations. Full article

Controlling dimensional fidelity and line-edge roughness is important in chemically amplified negative-tone imaging. In this study, two three-arm random terpolymers containing different acid-labile protecting groups were synthesized via core-first reversible addition–fragmentation chain-transfer (RAFT) polymerization to examine the influence of protecting-group structure within a common star-polymer framework. HTT 334 contained tert-butyl methacrylate (t-BMA), whereas HTM 334 contained 2-methyl-2-adamantyl methacrylate (MAMA). The two polymers exhibited comparable molecular weights and compositions, with narrow dispersities of 1.14 and 1.16. Thermal analysis showed that HTM 334 had a slightly higher glass-transition temperature than HTT 334 (77 and 73 °C, respectively). Fourier transform infrared (FT-IR) spectroscopy revealed spectral changes after exposure and post-exposure baking (PEB) that were consistent with acid-catalyzed deprotection and possible intermolecular reactions involving the hydroxyethyl methacrylate units. Negative-tone patterns were formed using an n-butyl acetate developer under the selected PEB conditions of 70 °C for HTT 334 and 90 °C for HTM 334. Across nominal mask dimensions of 10–80 μm, HTM 334 exhibited printed-to-mask critical-dimension ratios of 0.990–1.039, compared with 0.915–1.003 for HTT 334. HTM 334 also showed lower measured line-edge roughness values of 0.22–0.39 μm than HTT 334, which showed values of 0.52–1.27 μm. At the nominal 10 μm dimension, HTM 334 exhibited a line-edge roughness of 0.27 μm and an LER/CD ratio of 2.60%. These results indicate that an acid-labile protecting-group structure can influence thermal behavior and micrometer-scale pattern fidelity within the investigated three-arm RAFT polymer platform. Full article

NOS1AP (CAPON) is a signaling adaptor implicated in glioblastoma (GBM) proliferation, but its chemical tractability remains largely unexplored. Here, affinity selection–mass spectrometry screening of 10,000 drug-like compounds identified NGM1, a small molecule scaffold that directly binds NOS1AP. Binding was confirmed by microscale thermophoresis (MST), yielding a dissociation constant of 11.9 ± 7.0 μM. Focused structure–activity analysis and molecular modeling identified structural features associated with NOS1AP recognition and provided a framework for compound optimization. In living cells, NGM1 produced a concentration-dependent reduction in the NanoBRET signal generated by the NOS1AP-NOS1 reporter pair, consistent with perturbation of the complex. NGM1 reduced viability in U87 and U251 GBM cells, with IC₅₀ values of 12.7 ± 0.91 and 17.3 ± 1.04 μM, respectively, while normal human astrocyte viability remained above 50% at 150 μM. Mechanistic studies in U87 cells demonstrated reduced DNA synthesis, G₀/G₁ cell-cycle accumulation, and induction of apoptosis, accompanied by increased p53 and CDKN1A and decreased CDK6. Collectively, these findings establish the initial chemical tractability of NOS1AP and identify NGM1 as a chemical scaffold for investigating NOS1AP-associated signaling in GBM. The findings also provide a foundation for optimizing NOS1AP-directed compounds. Full article