Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform’s migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies.

Age-related changes in neurotransmitter systems contribute to declines in cognitive, emotional, and motor function, yet the biological mechanisms linking these changes to aging are not completely understood. Epigenetic regulation offers a promising framework to bridge this gap. DNA methylation-based biomarkers of biological aging (i.e., epigenetic clocks) capture cumulative and dynamic aspects of biological aging that may reflect vulnerability in neural systems beyond chronological age. However, whether these indices track with the integrity of neurotransmitter systems has not been systematically examined. This scoping review synthesizes evidence across human studies to evaluate how epigenetic aging processes influence neurotransmitter gene regulation and system function across the lifespan. We included 109 studies spanning 2005–2026. GABAergic genes (GAD1, GABRA2) showed the most consistent and reproducible age-related promoter hypermethylation across the cortex, inversely correlated with mRNA expression and corroborated by MRS evidence of cortical GABA decline. Dopaminergic and serotonergic evidence during normative aging was sparse; most epigenetic data in these systems came from disease cohorts. Histone modifications converged on neurotransmission and synaptic-plasticity loci, predominantly in Alzheimer’s disease tissue. Subcortical and brainstem nuclei central to monoaminergic and cholinergic systems remain under-investigated for normative aging epigenetic processes. Environmental and social determinants, socioeconomic status, childhood adversity, and chronic stress, were consistently associated with accelerated peripheral epigenetic aging, but brain-specific data are scarce.

Background: Hepatocellular carcinoma (HCC) develops predominantly from chronic liver injury, with diet representing a clinically actionable yet mechanistically complex modulator of hepatic carcinogenesis. Despite advances in immunotherapy, long-term survival remains poor, underscoring the need for complementary preventive and adjunctive strategies. Methods: We conducted a narrative review of epidemiological, experimental, and clinical literature on dietary patterns, polyphenols, and non-polyphenol nutraceuticals for HCC prevention and management, with a focus on underlying molecular and cellular mechanisms. Results: Dietary polyphenols and selected nutraceuticals exert pleiotropic effects on signaling pathways implicated in HCC, including NF-κB, STAT3, TGF-β/SMAD, PI3K/AKT, and Wnt/β-catenin, while modulating hepatic stellate cell activation, immune cell polarization, and microbiome-derived metabolites. Preclinical studies suggest that some compounds may enhance antitumor immunity and sensitize tumors to systemic therapies; however, clinical translation is constrained by limited bioavailability, pharmacokinetic variability, formulation heterogeneity, and a lack of high-quality trials. Conclusions: This review highlights the potential of dietary patterns and nutraceuticals in HCC prevention and as adjunctive therapies. It outlines key translational priorities, including etiologic stratification, biomarker-driven trial design, and rigorous safety evaluation.

Glioblastoma is the deadliest primary brain tumor, and fewer than 7% of patients survive 5 years even after surgery, radiation, and chemotherapy. Several features make it difficult to treat: the tumor heterogeneity, it adapts quickly to resist drugs, and the blood-brain barrier keeps most agents from reaching it. These obstacles have renewed interest in adjuncts to standard care. Dietary polyphenols and certain nutritional compounds are among the candidates, since they can influence oxidative stress, inflammation, tumor metabolism, and the glioblastoma stem cells that drive recurrence. This review weighs the mechanistic, preclinical, and early clinical evidence for major polyphenols (curcumin, resveratrol, EGCG, quercetin, apigenin), non-polyphenol agents (omega-3 fatty acids, vitamin D, melatonin), and dietary patterns such as ketogenic, anti-inflammatory, and caloric restriction approaches. Across models these agents act on familiar oncogenic and stress pathways, including NF-κB, STAT3, PI3K/AKT/mTOR, and MAPK, curbing proliferation and invasion, triggering apoptosis, and sensitizing tumors to temozolomide and radiation. What the laboratory shows has rarely reached patients. Poor oral absorption, inconsistent brain penetration, heavy first-pass metabolism, individual variability, and a shortage of biomarker-guided trials stand in the way. We do not propose these agents as substitutes for treatment. Instead, we connect their biological promise to the pharmacokinetic, delivery, and trial design problems that decide whether they can ever help, treating them strictly as experimental adjuncts. By covering polyphenols, other nutritional agents, and whole dietary patterns together, the review offers a translational picture that earlier reviews have missed.

Neuropeptide Y [NPY; encoded by the NPY gene] is a widely expressed 36-amino-acid neuropeptide that regulates neuronal function, vascular regulation, and immune regulation; its role in glioblastoma [GBM] remains incompletely characterized. We performed an integrative in silico multi-scale transcriptomic analysis combining bulk RNA-sequencing of IDH-wildtype GBM [n = 169] and lower-grade glioma [n = 510] surgical resections from TCGA, normal cortical tissue from GTEx [n = 207], and four independent GEO validation cohorts of surgical GBM and non-tumor brain specimens [GSE4290, GSE50161, GSE131928 scRNA-seq of ~20,426 cells from 28 patients, and GSE194329 10X Visium spatial transcriptomics from five patients], along with survival modeling, pathway enrichment, single-cell RNA sequencing, spatial transcriptomics, and cell–cell communication analysis. NPY and its principal receptor, NPY1R, were significantly downregulated in GBM, while genes associated with hypoxia, angiogenesis, invasion, and immune suppression were upregulated. Single-cell analysis showed that NPY-axis transcript expression was elevated in neural progenitor-like populations. In contrast, hypoxia and metabolic programs were concentrated in mesenchymal tumors and stromal compartments, indicating distinct cellular contexts. Spatial analysis revealed a weak and heterogeneous relationship between NPY and hypoxia signatures, with substantial inter-patient variability and no significant global spatial cross-correlation. These findings indicate that loss of NPY signaling is a consistent feature of GBM and is associated with hypoxia-driven tumor states, while the spatial relationship between NPY and hypoxia appears weak, heterogeneous, and patient-specific.

Background: Gliomas are characterized by a high degree of molecular heterogeneity, which impairs the reproducibility of predictive biomarkers derived from bulk-based molecular profiling due to immune/stromal contamination of tumors and the high prevalence of the IDH mutation signature. Methods: In this study, we used MOFA+ to derive intrinsic molecular signatures from transcriptional, methylation, and genomic profiles of a cohort of 667 diffuse gliomas in the Cancer Genome Atlas database. Thereafter, factor scores were derived for two separate Chinese Glioma Genome Atlas batches (Batch 1, n = 325; Batch 2, n = 693) without any retraining on the model. The prognostic independence of identified molecular signatures was assessed using multivariable Cox regression adjusted for IDH mutation status and tumor purity; purity-residualized survival analyses; IDH-stratified Cox regression in each cohort; validation by concordance index against established molecular signatures; and survival extreme profiling. To characterize the biological significance of factor signatures, we projected gene set signatures corresponding to each factor signature onto a single-cell RNA-seq dataset of GBM (GSE131928). Results: MOFA+ identified 12 latent factors, of which a vascular–extracellular matrix (ECM) remodeling axis (Factor 1) explained the highest multi-omics variance (24.9%) and was the strongest independent prognostic factor. In multivariable Cox regression adjusting for IDH status and tumor purity, Factor 1 remained independently prognostic (HR = 1.67, 95% CI 1.27–2.20, p = 0.0002); in a fully-adjusted model additionally including age, WHO grade, MGMT methylation, and 1p/19q codeletion (plus radiotherapy and chemotherapy status in the CGGA cohorts), Factor 1 remained prognostic in both CGGA cohorts (CGGA1: HR = 1.50, p = 3.8 × 10⁻⁵; CGGA2: HR = 1.18, p = 0.003) but lost significance in TCGA (HR = 1.04, p = 0.83), consistent with the cohort-dependent magnitude reported in the IDH-stratified and meta-regression analyses below. Purity-residualized survival analysis showed negligible attenuation of the Factor 1 signal (raw HR = 3.57 vs. residualized HR = 3.72; concordance 96.5%). Within IDH-wildtype gliomas, Factor 1 was significant in both external validation cohorts (CGGA1: HR = 1.64, FDR = 4.6 × 10⁻⁶; CGGA2: HR = 1.20, FDR = 0.02), though the TCGA IDH-wildtype subgroup showed a trend that did not survive FDR correction (FDR = 0.060). All validation was performed without model retraining. Within IDH-mutant gliomas, Factor 1 was strongly prognostic in both CGGA cohorts but was not significant in TCGA (HR = 1.17, FDR = 0.33). These findings should therefore be interpreted as consistent in directionality across cohorts but not uniformly replicated at the FDR-adjusted significance threshold in the TCGA discovery dataset. Concordance index benchmarking on a matched subset (n = 503) showed Factor 1 achieved discrimination comparable to the Mesenchymal signature (C = 0.797 vs. 0.801; ΔC = −0.004) while outperforming four other established classifiers. Factor 1 consistently separated patients with extreme survival phenotypes (OS < 6 vs. >15 months) across all three cohorts (all log-rank p < 0.001). Projection onto a single-cell GBM atlas (GSE131928), supported by inferCNV-based malignant-cell classification, localized the Vascular–ECM program to malignant cells and the Immune–ECM axis to myeloid compartments. Conclusions: The Vascular–ECM axis is a consistent, prognostic program robust to purity adjustment for diffuse gliomas that remains relevant across IDH-defined subgroups in three independent datasets comprising 1685 patients. The Vascular–ECM axis is a reproducible, purity-robust prognostic program in diffuse glioma, with directionally consistent adverse effects across TCGA, CGGA Batch 1, and CGGA Batch 2 (pooled n = 1685). Given the strong co-loading of endothelial, ECM, and myeloid genes observed in the single-cell projection, Factor 1 is best interpreted as a vascular/ECM-associated tumor–microenvironment ecosystem program rather than a malignant-cell-autonomous signature. Its FDR-adjusted significance within IDH-stratified subgroups is cohort-dependent and robust in both CGGA cohorts but attenuated in the TCGA IDH-wildtype (FDR = 0.060) and TCGA IDH-mutant (FDR = 0.33) strata. The pooled signal should therefore be interpreted as evidence of a generalizable biological program rather than a uniformly replicated subgroup-specific biomarker. It is possible to calculate factor scores based on RNA sequencing alone using fixed loadings (Z = XWᵀ), which may have implications for future translational applications. All findings are correlative; a causal role for the Vascular–ECM program in glioma progression, invasion, or therapy resistance remains to be established through functional perturbation experiments.