Search Results (1,328)

Rare-earth elements (REEs), which include the entire lanthanide series together with scandium and yttrium, have unique electronic configurations and coordination chemical properties that provide them with special magnetic, optical, and redox abilities. Generally used for diagnostic imaging and theranostic applications, increasing evidence emphasizes their potential as direct anticancer agents. This review aims to present a thorough investigation of the studies published in the last ten years that focus on the intrinsic anticancer properties of REE-based molecular complexes and nanostructures, without discussing their recognized imaging functions. Rare-earth compounds exhibit selective cytotoxicity against malignant cells via mechanisms that mainly include modulations in the generation of reactive oxygen species, mitochondrial dysfunctions, interaction with DNA molecules, apoptosis, and ferroptosis induction, as well as radiosensitization. Molecular complexes that are based on the trivalent coordination chemistry of REEs enable them to target biomolecules like DNA and serum albumin. Nanostructured systems, on the other hand, render tumors more responsive to treatment by improving the cellular uptake, enabling surface functionalization, and controlling ROS generation. Terbium, thulium, yttrium, scandium, ytterbium, cerium, erbium, dysprosium, and europium show different levels of anticancer activity in both in vitro and in vivo cancer models. They often exert more toxicity in tumor cells than in normal tissues, thus exhibiting selective anticancer effects. The findings collectively underscore the therapeutic potential of REE-based compounds as novel metal-based anticancer agents and advocate for additional mechanistic and translational research to enhance their clinical applicability. Full article

Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive condition characterized by bone necrosis, impaired vascularization, and immune dysregulation, often resulting in femoral head collapse. Effective strategies to halt disease progression are limited. Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication and influence osteogenesis, angiogenesis, and immune responses. This review summarizes current evidence on EVs in ONFH and their translational potential. Methods: A structured narrative review of PubMed, Scopus, Web of Science, and Cochrane Central databases was conducted, including in vitro, preclinical, and clinical studies on EVs in ONFH. Data on EV sources, molecular cargo, signaling pathways, functional effects, and translational implications were qualitatively synthesized. No pooled statistical analysis was performed because the extracted data were heterogeneous. Bioinformatic analyses such as Gene Ontology, KEGG enrichment, and protein–protein interaction networks were also summarized. Results: In vitro, EVs from bone marrow mesenchymal stem cells, endothelial cells, and M2 macrophages modulate osteogenic differentiation, angiogenesis, and inflammation. Preclinical studies demonstrate that EV administration reduces femoral head necrosis, improves trabecular structure, and enhances neovascularization. Clinical studies have identified EV-associated molecules (SAA1, C4A, RPS8) linked to disease stage and the risk of femoral head collapse. Bioinformatic analyses connect EV cargo to pathways regulating bone formation, vascularization, immunity, and metabolism. Conclusions: EVs appear to play key roles in ONFH pathogenesis and may represent promising candidates for diagnostic and therapeutic applications. However, current clinical evidence remains limited and requires validation in larger studies. Nonetheless, heterogeneity and limited clinical data require standardized, longitudinal studies to validate their translational relevance. Full article

Background: Biodegradable magnesium-based alloys are increasingly explored as emerging biomaterials for dental and maxillofacial applications due to their osteoconductive properties and potential to reduce long-term implant-related complications. However, early-stage evaluation requires predictive diagnostic screening methods capable of assessing cytocompatibility and cellular response under clinically relevant extract conditions. Objectives: In this study, Mg–0.5Ca alloys modified with increasing strontium concentrations (0.5–3 wt.%) were investigated through an in vitro diagnostic framework using MG-63 osteoblast-like cells. Methods: Cell viability was quantitatively assessed via MTT assays after 24 and 72 h of exposure, while fluorescence-based live-cell imaging provided complementary morphological insights. Results: demonstrated a composition-associated cytocompatibility profile, with Sr-enriched compositions showing improved cellular metabolic activity and adhesion patterns compared to lower-Sr compositions. Conclusions: These findings support the role of strontium as a functional alloying element and highlight the importance of standardized diagnostic screening workflows for emerging dental biomaterials. Overall, this study proposes a simplified predictive platform for early biocompatibility diagnostics, contributing to the integration of biomaterial evaluation into future digitalized dental regeneration workflows. Full article

Background: Hepatocellular carcinoma (HCC) represents an extremely lethal malignancy on a global scale. The clinical significance and molecular mechanisms of the immune-related gene RFXANK in HCC remain unclear. This study seeks to elucidate the clinical implications and diagnostic utility of RFXANK in HCC, while further exploring its underlying molecular mechanisms. Methods: Expression differences of RFXANK in pan-cancer and HCC were analyzed using the TCGA and GEO (GSE45267) databases. Its diagnostic efficacy was evaluated by Cox regression, Kaplan–Meier survival curves, and ROC curves. Potential functional pathways were explored through GO, KEGG, and GSEA enrichment analyses. The correlation between RFXANK and immune cell infiltration, as well as immune checkpoint molecules, was analyzed using the ssGSEA algorithm and CIBERSORTx. In vitro, siRNA interference was employed to knock down RFXANK expression in Huh-7 and MHCC97H cells. The effects on cell proliferation and RAF1 protein levels were assessed using a CCK-8 assay and Western blot, respectively. Results: RFXANK was significantly overexpressed in HCC tissues and was closely associated with aggressive clinical features, including pathological T stage, histological grade, and AFP levels. Multivariate Cox regression analysis confirmed that RFXANK was an independent risk factor for survival in HCC patients (HR = 1.871). The area under the ROC curve (AUC) was 0.939, demonstrating excellent diagnostic predictive value. Enrichment analysis revealed a significant association with the cell cycle, PPAR signaling pathway, and lipid metabolism pathways. Immune infiltration analysis further revealed that RFXANK expression was significantly positively correlated with Th2 and TFH cells, as well as key immune checkpoint molecules such as PD-1, CTLA4, and LAG3, suggesting distinct features of immune polarization and an inhibitory microenvironment. In vitro cellular experiments demonstrated that knocking down RFXANK significantly inhibited the proliferative capacity of HCC cells and reduced RAF1 protein expression. Conclusions: RFXANK may promote HCC progression by driving a multidimensional proliferation–metabolism–immunity mechanism. RFXANK holds promise as a novel biomarker for diagnostic assessment and a potential therapeutic target for HCC patients. Full article

Nanomaterials (NMs) are increasingly utilized in drug delivery, diagnostic imaging, and therapeutic applications. However, their widespread use raises concerns regarding potential neurotoxicity, particularly for metal and metal oxide nanoparticles. Accumulating evidence indicates that these nanoparticles induce neurotoxicity through interconnected mechanisms, including excessive reactive oxygen species generation, activation of neuroinflammatory pathways, mitochondrial dysfunction, and disruption of blood–brain barrier integrity. These molecular events collectively lead to synaptic impairment, neuronal apoptosis, and progressive cognitive and behavioral deficits, with toxicity severity influenced by dose, exposure duration, and age. Given that in vitro models often fail to capture complex systemic interactions such as nanoparticle biodistribution, blood–brain barrier dynamics, and neuroimmune responses, this review places particular emphasis on in vivo studies to provide a more physiologically relevant understanding of nanoparticle-induced neurotoxicity. Importantly, a growing body of in vivo evidence demonstrates that natural bioactive compounds can mitigate these effects by targeting key pathogenic pathways, including oxidative stress, inflammation, and mitochondrial dysfunction, while preserving neuronal integrity. These findings highlight the therapeutic potential of natural bioactives as protective agents against nanoparticle-induced neurotoxicity and as candidates for broader neuroprotective strategies. This review summarizes the mechanistic basis of metal and metal oxide nanoparticle neurotoxicity and critically evaluates the protective role of natural bioactive compounds, with a focus on evidence derived from animal models. Full article

Background: The contribution of intronic variants to the etiology of Mendelian diseases is still underrecognized, impacting the diagnostic yield. Whole genome sequencing (WGS) detects intronic variants, but besides canonical splice-sites, intronic variants are frequently excluded from the interpretation step or are classified as variants of uncertain significance (VUS). In fact, assessing their clinical significance often requires validation via RNA-sequencing (RNA-seq) or in vitro studies. Methods: We studied a 31-year-old patient with spinocerebellar ataxia who lacked a molecular diagnosis after WGS analysis. We applied the Detection of RNA Outliers Pipeline (DROP) to analyze RNA-seq data from patient fibroblasts. DROP integrates OUTRIDER and FRASER 2.0 algorithms designed to identify aberrant gene expression and splicing, respectively. Results: DROP identified differential expression and aberrant splicing of SNX14. Retrospective WGS data analysis revealed a homozygous NM_153816.6(SNX14): c.867+288A>G deep intronic variant, which caused pseudo-exon activation and reduced transcript levels. Biallelic loss-of-function variants in SNX14 cause autosomal recessive spinocerebellar ataxia type 20 (SCAR20; OMIM 616354), consistent with the clinical presentation of this case. Conclusions: We identify a deep intronic SNX14 variant as the genetic basis of SCAR20. We demonstrate the utility of RNA-seq to increase the diagnostic yield by identifying and resolving the pathogenicity of deep intronic variants. Defining aberrant splicing events is therapeutically relevant, as these mechanisms are targets for antisense oligonucleotide (ASO) based interventions. Full article

Advances in regenerative medicine increasingly rely on human-relevant in vitro systems to model the multistage process of wound healing. However, the translation of research into effective therapies remains limited by the inability of traditional 2D cultures and animal models to faithfully replicate the structural and biochemical complexity of human skin. While existing reviews often focus on the structural composition of static skin equivalents, this review addresses a critical knowledge gap: the need for dynamic, time-dependent methodologies that can capture the spatiotemporal evolution of healing, from inflammation to remodeling, in both physiological and pathological conditions. To this end, we critically evaluate next-generation platforms, including 3D bioprinting, organ-on-chip systems, organoids, and iPSC-based models, highlighting their comparative advantages and technical hurdles like vascularization and scalability. The unique contribution of this work lies in providing a forward-looking framework that advocates for the convergence of bioengineering and computational modeling to move beyond “steady-state” snapshots toward predictive, high-resolution dynamic models. We conclude that the future of wound healing research depends on integrating vascular and immune components within these platforms to achieve truly human-relevant, personalized diagnostic and therapeutic tools. Full article

European armillarioid fungi (Armillaria and Desarmillaria) are white-rot fungi with soilborne pathogenic potential on woody hosts and clear relevance to forest pathology. This structured narrative review synthesizes the reported chemical composition of European armillarioid taxa across wild basidiocarps, infected host material, and laboratory-derived matrices, with emphasis on metabolites and biochemical traits that can be interpreted in a forestry context. The available evidence is taxonomically and methodologically uneven and is dominated by A. mellea and A. ostoyae, whereas infected host material remains less well characterized than culture-derived and basidiocarp-derived material. Protoilludene-derived aryl esters provide the clearest compound-resolved evidence for antifungal and phytotoxic activity across controlled assay systems, but these data derive from distinct experimental formats that are not directly comparable as a single potency scale, while lipid profiling offers the strongest support for chemistry-based diagnosis from infected material. Overall, current evidence supports forestry interpretation, diagnostic profiling, and selective screening of culture-derived metabolites, but practical application remains constrained by matrix dependence, taxonomic gaps, and the limited transferability of in vitro findings to forest conditions. Full article

Background/Objectives: Early embryonic arrest during the cleavage stage (days 2–4) accounts for a substantial proportion of developmental failure in in vitro fertilization. This phenomenon remains poorly understood at the molecular level, even in chromosomally normal embryos identified by preimplantation genetic testing. This review aims to redefine cleavage-stage arrest from a passive energy deficit to a checkpoint-regulated endpoint caused by inadequate coordination among metabolism, transcriptome integrity, and stress-response pathways. Methods: We integrate evidence from long-read transcriptomics, metabolomics, epigenetics, and immunobiology relevant to pre-blastocyst development. These data are assembled into a unifying mechanistic framework and a clinically oriented stratification model, together with candidate multimodal readouts for early classification. Results: We propose a three-axis model linking: (i) metabolic–epigenetic insufficiency, including defective histone lactylation and impaired alpha-ketoglutarate-dependent DNA demethylation; (ii) isoform-level abnormalities, including intron retention and retrotransposon activation within a hidden transcriptomic landscape better resolved by long-read sequencing; and (iii) stress-related immune signaling, in which NLRP7 links alternative splicing and DNA-damage-response dysfunction with mitochondrial stress and p53-associated arrest. Within this framework, we distinguish three molecular arrest states: an early transition failure marked by defective maternal-to-embryonic reprogramming and severe splicing disruption; a metabolically quiescent state that may retain a limited rescue window; and a later stress-associated state characterized by senescence-like features, oxidative stress, and broad transcriptomic and genomic instability. Conclusions: Early embryo arrest should no longer be viewed as a nonspecific developmental failure, but as a mechanistically stratifiable condition with distinct metabolic, transcriptomic, and stress-associated trajectories. A diagnostic platform combining fluorescence lifetime imaging microscopy, long-read sequencing, and digital polymerase chain reaction may improve early mechanistic classification, help identify embryos with possible reversibility, and reduce uncertainty in embryo selection during in vitro fertilization. Full article

Background and Clinical Significance: Mixed-phenotype acute leukemia (MPAL) is a rare hematologic malignancy characterized by the co-expression of myeloid and lymphoid markers and is associated with poor prognosis. Myeloid sarcoma (MS), particularly in the mediastinum, is an uncommon extramedullary manifestation and is rarely reported in association with MPAL. Case Presentation: We report a rare case of mediastinal MS with biphenotypic features and pericardial extension occurring concurrently with MPAL, highlighting diagnostic challenges, therapeutic strategies, and long-term outcomes. We describe the clinical course, diagnostic workup, treatment, and follow-up of a 21-year-old woman who presented with cardiac tamponade secondary to a mediastinal mass. Histopathology and immunophenotyping established the diagnosis of mediastinal MS associated with MPAL (B/myeloid, NOS). Management included surgical cytoreduction, intensive induction chemotherapy, and consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. Fertility preservation with oocyte retrieval, in vitro fertilization (IVF), and embryo cryopreservation was performed prior to conditioning. A focused literature review of MPAL cases with extramedullary involvement was conducted. The patient achieved complete remission following induction therapy and underwent allo-HSCT. Despite the historically poor prognosis of mediastinal MS and MPAL, she remains in sustained complete remission 13 years after diagnosis. A literature review identified only eight reported cases of MPAL with extramedullary disease, with mediastinal involvement described in a single case and allo-HSCT performed in only two patients. Conclusions: This case illustrates a rare presentation of MPAL with mediastinal myeloid sarcoma and cardiac tamponade, demonstrating that aggressive multimodal therapy including allo-HSCT may achieve durable remission even in high-risk presentations. Early multidisciplinary management and consideration of fertility preservation are essential in young patients. Full article

As surgery is the first-line paradigm for many solid tumors, precision in preoperative diagnosis and intraoperative imaging is of significant importance. Dual MRI and NIR-II fluorescence imaging could fulfill precision imaging requirements in treating cancers, because of its deep penetration and real-time high spatiotemporal resolution. Thus, the design of dual MRI/NIR-II fluorescence contrast agents is crucial for the diagnosis and surgery of cancers. Herein, we developed optically transparent NaGdF4 matrix-based downshifting nanoparticles (DSNPs) co-doped with Nd³⁺, Yb³⁺, and Er³⁺ as a single nanoplatform for dual NIR-II fluorescence and T1-weighted MRI. Systematic dopant engineering reveals that optimal Nd³⁺ loading enhances cascade Nd → Yb → Er energy transfer and yields intense NIR-II emission at 1334 and 1521 nm upon 808 nm excitation with a relative quantum yield of 1.55, while the presence of Gd³⁺ in the optically transparent matrix imparts strong T1 contrast (4.98 s⁻¹ mM⁻¹). The Pluronic F-127 surface coating confers colloidal stability and biocompatibility. In vitro assays confirm negligible cytotoxicity and efficient cellular uptake. In vivo studies in subcutaneous 4T1 tumor-bearing mice demonstrate robust accumulation, high tumor-to-background contrast in both MRI/NIR-II fluorescence and enable precise NIR-II fluorescence imaging-guided surgery with real-time margin visualization. Therefore, dopant-engineered DSNPs represent a promising dual-modal imaging agent for deep-tissue diagnostic and real-time surgical guidance in precision oncology. Full article

Background: Partial ceramic veneers in the esthetic zone are a novel, conservative alternative to traditional veneer preparations intended to preserve maximum tooth structure. This narrative review summarizes the available clinical case reports on partial ceramic veneers and includes a case illustration demonstrating a step-by-step approach to closing a space between the maxillary left lateral incisor and canine. Methods: The review synthesizes the limited case-report evidence, focusing on patient selection, treatment planning, and clinical execution. The case illustration details each step, including a diagnostic digital wax-up to preview the proposed outcome and a minimally invasive preparation limited to rounding sharp areas and optimizing the path of insertion. Results: Published reports emphasize that careful case selection and a well-executed plan are essential. In the case illustration, hand-crafted partial veneers achieved a natural appearance, with a high esthetic outcome confirmed using the White Esthetic Score (WES) system. Conclusions: Although evidence remains limited, partial ceramic veneers can be predictable in appropriately selected cases. More long-term clinical data are needed, and the case illustration may help guide early-career clinicians. The case illustration is limited in that it does not provide quantifiable outcomes like in vitro studies; however, qualitatively, it fulfilled the patient’s esthetic and functional demands. Full article

Shigellosis remains a significant global cause of infectious colitis, increasingly complicated by multidrug-resistant strains and the microbiota-disrupting effects of broad-spectrum antibiotics. Although conventional antimicrobial therapy can reduce symptom duration and bacterial shedding, it also contributes to gut dysbiosis, loss of colonization resistance, and further selection for antimicrobial resistance. These challenges have renewed interest in precision antimicrobial strategies, particularly bacteriophage therapy, which provides strain-level specificity and preserves the gut microbiota. This narrative review evaluates the biological rationale, preclinical and early clinical evidence, safety considerations, and translational challenges associated with bacteriophage therapy targeting Shigella spp. The historical development and mechanistic basis of phage therapy are summarized, with emphasis on the advantages of obligately lytic phages, receptor-specific targeting, self-amplification at infection sites, and activity against both planktonic and biofilm-associated bacteria. Recent microbiota research indicates that shigellosis is closely associated with early and persistent disruption of gut ecology, including depletion of short-chain fatty acids-producing taxa and reduced microbial resilience. Phage-based approaches may reduce pathogen burden while preserving beneficial microbial communities. Evidence from in vitro systems, animal models, human intestinal organoids, and a Phase 1 clinical trial demonstrates targeted efficacy and favorable safety profiles for Shigella-specific phages and phage cocktails. Major barriers to clinical adoption include immune interactions, phage resistance dynamics, genomic safety screening, regulatory classification, and the need for standardized susceptibility testing. Future directions emphasize the development of personalized phage therapy platforms that integrate rapid diagnostics, phage libraries, metagenomics, and artificial intelligence-assisted matching to enable scalable, precision treatment. Full article

Functional analysis of SLC22A5 variants can improve diagnostic accuracy in patients with primary carnitine deficiency (PCD). Herein, we performed a genetic analysis of three neonates with PCD. Two of the patients harbored a novel synonymous SLC22A5 variant that has not been previously reported, and the other patient harbored a classical splice site variant. The splicing patterns of the two SLC22A5 variants were evaluated using three in silico tools, and in vitro minigene analysis was performed to verify the impact of variants on RNA splicing mechanisms. All three in silico tools predicted that both SLC22A5 variants could alter normal RNA splicing. Functional studies using minigene assays demonstrated that the c.450C>T (p.F150=) leads to partial exon 2 skipping, and c.394-1G>A leads to intron 1 retention and exon 2 skipping. Intron 1 retention of 65 nucleotides and exon 2 skipping were confirmed by sequencing cDNA amplification products. These results, along with functional evidence, led to reclassification of c.450C>T (p.F150=) and c.394-1G>A as likely pathogenic and pathogenic, respectively. This is the first reported synonymous variant in the SLC22A5 gene that has been functionally validated to affect RNA splicing, thus enriching the variant spectrum of SLC22A5 and aiding accurate PCD diagnosis. Full article

Background: Cone-beam computed tomography (CBCT) is increasingly applied for the assessment of periodontal bone levels. However, its measurement reliability and consistency depend strongly on image quality parameters such as voxel size, noise, and reconstruction sharpness. With the growing use of CBCT datasets for artificial intelligence (AI)-based diagnostics, it is essential to understand how image degradation conditions affect examiner-derived measurement outcomes and the reliability of reference data used for AI training. Methods: An anonymized CBCT dataset containing one periodontally healthy tooth (31) and one tooth with pronounced periodontal bone loss (41) was analyzed. The original DICOM data were systematically degraded using controlled voxel enlargement (double and triple voxel size) and simulated image blur (Gaussian and median filtering). Six dentists (n = 6) independently performed standardized linear bone-level measurements, with three repeated measurements per tooth and image condition. Data were analyzed using the Shapiro–Wilk test for normality assessment, the Kruskal–Wallis H test for group comparisons, Bonferroni-adjusted Mann–Whitney U tests for post hoc pairwise comparisons, and intraclass correlation coefficients (ICC (2,1)) for inter-examiner reliability assessment. Results: A total of 180 measurements were evaluated. Image degradation conditions were associated with statistically significant differences in bone-level measurements for both teeth (tooth 31: p = 0.017; tooth 41: p = 0.0049). Significant pairwise differences were primarily observed between the original dataset and specific degraded conditions involving blur and reduced spatial resolution, while several comparisons remained non-significant. Inter-examiner reliability varied across image groups and decreased notably with pronounced voxel enlargement, particularly in the periodontally compromised tooth. Conclusions: Controlled image degradation conditions of CBCT image quality significantly affect measurement outcomes and inter-examiner reproducibility of periodontal bone measurements. These findings demonstrate that image quality is a critical determinant of measurement reliability and examiner-dependent interpretation. From both a clinical and AI-development perspective, maintaining adequate CBCT resolution may contribute to more consistent measurement behavior and more reliable training datasets. Full article