Molecular Diagnosis & Therapy最新文献

Background: Activating epidermal growth factor receptor (EGFR) mutations are key drivers in non-small cell lung cancer (NSCLC) and other solid tumours, predicting responses to tyrosine kinase inhibitors (TKIs). Tumour heterogeneity alongside sampling and technical factors may contribute to discordant EGFR status across biopsies, complicating treatment decisions. However, systematic evidence on prevalence and drivers of discordance remains limited.

Methods: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in PROSPERO (CRD42024615727). MEDLINE, Embase, and Scopus (2004-2024) were searched for studies reporting EGFR mutation discordance in adult solid tumours. Eligible studies compared primary and metastatic tumours (tissue-tissue), tissue and liquid biopsies (tissue-liquid), or different liquid biopsies. Data extraction and QUADAS-2 risk of bias assessment were performed independently. Discordance proportions were analysed on the logit scale with Haldane-Anscombe correction when needed. Random-effects meta-analysis was conducted using the Paule-Mandel estimator with Hartung-Knapp-Sidik-Jonkman confidence intervals. Subgroup analyses and meta-regression were used to estimate pooled discordance and explore potential predictors.

Results: A total of 154 studies (15,560 patients) predominantly involving NSCLC were included. The pooled discordance rate was 16.1% (95% confidence interval 14.2-18.2). Rates were similar for tissue-tissue (16.8%) and tissue-liquid (15.5%), but higher for liquid-liquid (34.0%). Plasma was the most-studied liquid source (16.5%), while cerebrospinal fluid showed the highest discordance (35.5%). Prior TKI exposure was associated with higher discordance (25.8%) compared with treatment-naive patients (14.6%; p = 0.003). Patients who later developed resistance also had higher baseline discordance (21.0% vs 15.0%; p = 0.042). Discordance varied by metastatic site, from 15.1% in lymph nodes to 17.9% in brain/central nervous system. Meta-regression identified TKI exposure, resistance, and mutation prevalence as predictors.

Conclusions: EGFR mutation discordance is common and clinically relevant, particularly in NSCLC, but varies substantially by sampling strategy, biofluid, treatment context, and metastatic site. Given the high between-study heterogeneity and the predominance of NSCLC and Asian cohorts, pooled estimates should be interpreted as descriptive summaries rather than universally generalisable benchmarks. These findings support integrated and context-aware sampling strategies for EGFR-targeted therapy and resistance monitoring.

Sarcopenia is a progressive loss of skeletal muscle mass and strength that significantly contributes to frailty and disability in older adults. Traditionally considered a consequence of myofiber atrophy and impaired protein turnover, recent evidence highlights neuromuscular junction (NMJ) degeneration as an early and critical event in the pathogenesis of this condition. Structural and functional changes at the NMJ, including fragmentation of acetylcholine receptor clusters, motor neuron loss, and disruption of agrin-muscle-specific kinase (MuSK) signaling, impair neuromuscular transmission and accelerate muscle decline. This review synthesizes current understanding of NMJ biology, its age-related deterioration, and emerging therapeutic strategies aimed at preserving synaptic integrity. We discuss pharmacological approaches that target presynaptic neurotransmitter synthesis, stabilize the synaptic cleft, and enhance postsynaptic receptor clustering, as well as interventions that activate Schwann and satellite cells to restore regenerative capacity. Adjunctive therapies such as antioxidants, mitochondrial protectants, and metabolic modulators complement NMJ-specific drugs by mitigating oxidative stress and inflammation. Translational insights underscore the importance of NMJ-specific biomarkers, such as circulating c-terminal agrin fragment-22 (CAF22), and advanced imaging modalities to facilitate early detection and personalized interventions. Future directions focus on multimodal regimens that combine NMJ-targeted agents with exercise, nutrition, and digital health tools, supported by computational analytics for precision care. By integrating molecular, systemic, and lifestyle strategies, NMJ-focused therapies offer a promising approach to delaying the progression of sarcopenia and improving functional independence in aging populations. Continued interdisciplinary research and mechanistically informed clinical trials are crucial for translating these advances into effective treatments.

Olfactory receptors (ORs), once considered peripheral to sensory biology, are now recognized as functionally important components of precision medicine. This review synthesizes genomic, structural, and translational evidence demonstrating that ORs act as context-dependent molecular sensors influencing metabolism, immunity, neurological function, cardiovascular regulation, and cancer. Extensive genomic diversity within the OR gene family, including single nucleotide variants, copy number variation (CNV), and pseudogenization, drives interindividual differences in receptor function and signaling, providing a mechanistic basis for personalized chemosensory and physiological phenotypes. Beyond the olfactory epithelium, ORs are ectopically expressed across diverse tissues, including the gut, brain, skin, vasculature, immune system, and tumors. In these settings, ORs engage canonical and non-canonical G-protein-coupled receptor (GPCR) signaling pathways to regulate processes such as wound repair, vascular tone, cell proliferation, apoptosis, immune modulation, and barrier function. Collectively, these observations establish ectopic ORs as active signaling components rather than passive expression markers, supporting their potential utility as functional biomarkers and therapeutic targets. Despite growing biological and clinical relevance, translational progress remains limited by incomplete receptor annotation, a large proportion of orphan receptors, and the complexity of mapping ligand-receptor relationships across tissues. This review also highlights emerging strategies addressing these challenges, including high-throughput functional assays, multi-omic and spatial transcriptomic profiling, and artificial intelligence (AI)-enabled models that accelerate ligand prediction, receptor deorphanization, and genotype-phenotype mapping. The development of OR-based biosensor platforms capable of real-time chemical detection further underscores their diagnostic and translational potential. At the population level, substantial variation in OR allele frequencies across ancestries introduces both opportunities and challenges for precision medicine. Accordingly, ethical considerations related to population stratification, data privacy, and equitable implementation are discussed. Together, the evidence reviewed positions ORs as a tractable and clinically promising receptor family that bridges chemosensory biology with individualized diagnostics, therapeutic targeting, and biosensor-guided interventions in precision medicine.

In recent years, fibroblast activation protein (FAP) has demonstrated significant potential in oncology, and the development of FAP-targeted therapeutic agents has increasingly become a key research focus in the fields of molecular imaging and radionuclide therapy. Among these, FAP inhibitor (FAPI)-based small molecules have demonstrated favorable pharmacokinetics and imaging potential, showing promising potential in the diagnosis and treatment of tumors. As a peptide-based radiopharmaceutical derived from structural optimization of FAPI, FAP-2286 consists of a FAP-specific binding peptide conjugated to a DOTA chelator. It not only preserves the high affinity and favorable imaging characteristics of small-molecule FAPI tracers but also markedly prolongs tumor retention, thereby enabling both diagnostic and therapeutic applications. Preclinical and early clinical studies have shown encouraging results, characterized by prolonged in vivo retention and a favorable safety profile, supporting its use as a theranostic agent. This review provides a comprehensive overview of the current literature on FAP-2286, from preclinical development to clinical translation, highlighting its diagnostic value, the status of FAP-targeted radionuclide therapy, and the challenges and opportunities in advancing FAP-based theranostics.

Introduction: High-grade vulvar intraepithelial neoplasia (VIN), the precursor lesion to vulvar cancer, comprises human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent VIN (HPVi-VIN), differing in pathogenesis and cancer risk. HSIL typically develops from low-grade squamous intraepithelial lesion (LSIL), and HPVi-VIN from lichen sclerosus (LS). The PreCursor-M AnoGYN Methylation test, targeting ASCL1/ZNF582, may improve diagnostic accuracy and risk stratification in high-grade VIN patients. This study assessed its diagnostic performance to detect high-grade VIN and cancer.

Methods: ASCL1/ZNF582 methylation was analyzed in 170 vulvar formalin-fixed paraffin-embedded (FFPE) tissue samples from healthy controls, LS, LSIL, HSIL, HPVi-VIN and vulvar cancer patients by quantitative methylation-specific polymerase chain reaction (qMSP). Logistic regression analysis was used to evaluate its diagnostic performance and compare it to the previously established ZNF582/SST/miR124-2 marker panel.

Results: Methylation levels increased with disease severity, from low in controls, LS and LSIL to high in HSIL, HPVi-VIN and vulvar cancer. The ASCL1/ZNF582 marker panel detected 92% and 84% of HSIL at 70% and 80% specificity, respectively, and 96% of HPVi-VIN and 100% of vulvar cancer at both specificities. Both marker panels (ASCL1/ZNF582 and ZNF582/SST/miR124-2) showed comparable excellent diagnostic performance for high-grade VIN detection, with an area under the curve (AUC) of 0.93 (95% confidence interval [CI] 0.88-0.98) and AUC 0.91 (95% CI 0.86-0.97), respectively.

Conclusions: In conclusion, the ASCL1/ZNF582 methylation assay accurately detects high-grade VIN and vulvar cancer, while minimizing the detection of benign and low-grade lesions, indicating its clinical value.

Combination therapy, which involves the simultaneous use of two or more drugs within the same formulation, aims to broaden therapeutic activity, reduce the risk of resistance, and achieve synergistic or additive effects. This approach has gained prominence across diverse clinical settings, offering benefits such as enhanced efficacy, reduced side effects, and improved treatment outcomes in complex or chronic diseases. Despite these advantages, combination therapy faces challenges that must be overcome to fully realize its potential. To address these limitations, researchers have increasingly focused on nanosystems, particularly solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), which are especially effective in improving the bioavailability of poorly water-soluble drugs. This review highlights the key advantages of co-encapsulation strategies in combination therapy, emphasizing the roles of SLN and NLC. Published studies have shown that co-encapsulation within these nanosystems enhances drug stability, bioavailability, therapeutic efficacy, and provides controlled release, positioning them as promising tools for effective drug delivery. Current challenges and future perspectives for the clinical translation of SLN and NLC in combination therapies are also discussed, as these nanosystems, given their many advantages, remain at the forefront of research into innovative therapeutic strategies. Nonetheless, further investigation is needed to explore their full potential, particularly their underutilized capacity to support combination therapy. Although their application in this context has been limited to date, the therapeutic promise of SLN and NLC co-encapsulation continues to drive ongoing research.

Medulloblastomas are the most common malignant pediatric brain tumors, representing approximately 20% of the central nervous system cancers in children. These tumors are highly heterogeneous and classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic and epigenetic profiles that influence tumor behavior, therapeutic response, and patient outcomes. Advances in molecular diagnostics have improved the subclassification of medulloblastomas, yet treatment outcomes for high-risk subtypes, particularly Group 3, remain poor, with current modalities often associated with severe long-term neurocognitive and systemic toxicities. Effective drug delivery across the blood-brain barrier remains a major hurdle, limiting the clinical efficacy of targeted therapies. Drug repurposing offers a promising strategy to accelerate treatment availability by utilizing US Food and Drug Administration-approved agents, including niclosamide, itraconazole, and arsenic trioxide, to target critical oncogenic pathways and overcome therapeutic resistance. However, challenges such as limited blood-brain barrier penetration and the lack of pediatric-specific pharmacokinetic data persist. Future research should focus on integrating comprehensive molecular profiling to guide personalized therapy selection, optimizing drug-delivery systems, and exploring rational drug combinations. Emerging technologies, including nanotechnology-based delivery systems, CRISPR-mediated gene editing, and chimeric antigen receptor-T cell therapies, hold significant potential for transforming medulloblastoma treatment paradigms but require further refinement to address toxicity, off-target effects, and biomarker development. Advancing innovative, less toxic therapeutic strategies through the integration of molecular diagnostics and precision therapies is essential to improving survival outcomes and quality of life for children with medulloblastomas.

Background: Glaucoma is a leading cause of irreversible blindness worldwide. Current diagnostic methods often fail to detect disease at early stages. MicroRNAs (miRNAs), owing to their regulatory role in gene expression, have been investigated as potential biomarkers, although their diagnostic utility and clinical feasibility remain under evaluation.

Objectives: The aim of this work is to systematically review and synthesize evidence on the diagnostic significance of microRNAs and related genetic markers in glaucoma and its subtypes.

Methods: A systematic review and meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including 16 studies with 17,300 participants. Odds ratios (ORs) and log ORs with 95% confidence intervals (CIs) were pooled using fixed-effects models. Subgroup analyses were performed by sample type, glaucoma subtype, and molecular pathway.

Results: Specific miRNAs (e.g., miR-143-3p, miR-182) were significantly associated with glaucoma (OR 6.32, 95% CI 5.31-7.54, p < 0.001). Stronger correlations were observed in aqueous humor samples (OR 13.79, 95% CI 6.81-27.94, p < 0.001). Dysregulation of miRNAs was linked to increased retinal ganglion cell apoptosis and altered aqueous humor osmolality. Genetic analysis showed that common alleles in ATOH7 (OR 1.55, 95% CI 1.40-1.72) and CDKN2B (OR 1.66, 95% CI 1.55-1.78) significantly increased glaucoma risk, while miR182 variants also showed strong associations. The autotaxin (ATX)-lysophosphatidic acid (LPA) pathway was consistently implicated (OR 3.94, 95% CI 2.46-6.32).

Conclusions: MiRNAs, particularly in blood samples, show promise as feasible biomarkers for early glaucoma detection, while aqueous-humor-based testing remains clinically limited owing to invasiveness. Genetic variants such as ATOH7, CDKN2B, and miR182 modestly but consistently contribute to glaucoma susceptibility. Large-scale longitudinal studies are warranted to validate these findings and translate them into routine clinical practice.