Biomarker Research最新文献

Gliomas constitute a major category of primary brain malignancies, characterized by limited therapeutic options and generally poor prognoses. Despite the promising outcomes of immunotherapies, particularly immune checkpoint inhibitors (ICIs), in various cancers, their clinical efficacy in gliomas has remained modest. This limited efficacy is largely attributed to the brain's immune-privileged status and the profoundly immunosuppressive nature of the glioma tumor microenvironment (TME). These challenges underscore the urgent need to improve understanding of the glioma TME and to develop innovative strategies that enhance the effectiveness of immunotherapies. This review provides a comprehensive overview of recent advances in glioma immunobiology and immunotherapy, with emphasis on ongoing clinical trials and emerging combinatorial strategies. Current efforts to combine ICIs with modalities such as radiotherapy and chemotherapy are highlighted, aiming to remodel the TME, improve antigen presentation, and stimulate more robust antitumor immune responses. The evolving landscape of glioma immunotherapy offers renewed hope for enhanced patient outcomes.Clinical trial registration Not applicable.

The blood biomarker hPG₈₀ is linked to multiple solid tumors, including lung cancer. This study examined blood hPG₈₀ levels of asymptomatic individuals and patients with non-small cell lung cancer (NSCLC), categorized by their smoking and chronic obstructive pulmonary disease (COPD) status. Plasma hPG₈₀ levels were measured across five cohorts of patients, including 396 NSCLC patients, 200 NSCLC cancer-free COPD patients, 369 asymptomatic never smokers, 278 asymptomatic current smokers, and 235 asymptomatic former smokers. Receiver operating characteristic (ROC) curves assessed diagnostic accuracy. In asymptomatic current smokers, hPG₈₀ levels were significantly higher (6.70 pM (IQR: 5.13-11.29)) than those in gender- and age-matched never smokers (2.50 pM (IQR: 1.70-3.70; p < 0.0001). In contrast, gender- and age-matched former smokers showed a return to normal hPG₈₀ levels (2.29 pM (IQR: 1.61-2.97)). In multivariate analysis, age and smoking status were significantly associated with elevated levels of hPG₈₀ (p-values of 0.0319 and < 0.0001, respectively). Levels of hPG₈₀ in current smokers were not different from levels found in age-matched patients with NSCLC or COPD (6.60 pM (IQR: 4.36-11.22) and 6.07 pM (IQR: 3.99-11.69), respectively). In NSCLC and COPD patients, hPG₈₀ levels were independent of the smoking status. When comparing asymptomatic and NSCLC-diagnosed former smokers, the AUC was 0.85 (95% CI:0.80-0.90, p < 0.0001). The AUC was equal to 0.53 (95% CI: 0.45-0.60, p = 0.4436) for current smokers. Our findings identify hPG₈₀ as both a reversible marker of active smoking and a diagnostic biomarker of NSCLC. This dual role supports its potential use in risk stratification and early detection, particularly among non-COPD former smokers.

Premature ovarian insufficiency (POI) is associated with an increased risk of neurodegenerative diseases, but the underlying mechanisms remain unclear. Here, we integrated DNA methylome profiling of peripheral blood leukocytes and circulating steroid hormone analysis to identify potential mechanism linking POI to neurogenerative risk. Methylome analysis revealed distinct epigenetic signatures in POI patients, including hypomethylation at the SOAT1 promoter, a gene critical for cholesterol homeostasis. Gene set enrichment analysis (GSEA) implicated suppressed steroid biosynthesis, supported by significantly reduced circulating levels of steroids, including androstenedione, dehydroepiandrosterone (DHEA), aldosterone, cortisol, and cortisone in POI patients. Notably, neuroprotective steroids DHEA and pregnenolone exhibited an age-dependent decline exclusively in the POI group. Our findings suggest that SOAT1-mediated cholesterol dysmetabolism leads to steroidogenesis suppression and depletion of neuroprotective steroids. Epigenetic dysregulation of SOAT1 and steroidogenic genes, coupled with depletion of DHEA and pregnenolone might contribute to the elevated neurodegenerative risk in POI.

Background: Obesity is a major health challenge and fat accumulation in visceral depots is more strongly associated with metabolic comorbidities than deposition in subcutaneous depots. Epitranscriptomic regulation of gene expression by N⁶-methyladenosine (m⁶A) influences various aspects of RNA metabolism, however the m⁶A methylome in human adipose tissue and its relationship with fat distribution has not yet been investigated in detail.

Methods: In this study, we performed epitranscriptomic mapping of m⁶A in intra-individually paired samples of subcutaneous (SAT) and omental visceral adipose tissue (OVAT) from women with normal weight (BMI ≤25, n = 3) and obesity (BMI ≥35, n = 10) using meRIP-seq (discovery cohort). We further investigated differential m⁶A methylation for specific target genes in a larger cohort of individuals with obesity (n = 72, validation cohort) using meRIP-qPCR. meRIP-seq was performed for primary adipocytes from a subset of the patients (n = 4) to account for cell type specific differences.

Results: We here provide the first global map of m⁶A in human adipose tissue in paired samples of SAT and OVAT. We show an overall high overlap in m⁶A sites between individuals and depots, but also distinct depot-specific differences. We identify 339 target genes showing depot-specific m⁶A methylation. Depot-specific methylation was validated for selected sites in SEMA3A, SNAP47 and PPP1R9A in a larger validation cohort. We additionally identify differentially methylated targets between lean individuals and individuals with obesity, including TSC22D1, FMNL2 and IL1R1. By combining data from primary adipocytes with data from corresponding bulk adipose tissue, we identified a higher number of genes containing m⁶A in non-adipocyte cells in OVAT compared to SAT. Mechanistically, we show for selected targets that m⁶A affects RNA lifetime in pre-adipocyte cell culture models. Importantly, m⁶A methylation in selected targets correlates with clinically important variables related to obesity, fat distribution and glucose metabolism.

Conclusions: We identify a catalogue of novel targets showing adipose tissue depot specific m⁶A methylation, with potential as biomarkers in metabolic disease. Our findings underscore the regulatory role of m⁶A in obesity and provide valuable insights for future research. The datasets generated represent a significant resource for further insight in adipose tissue biology and its implications for metabolic health.

The development of brain metastasis is a major cause of significantly reduced survival in breast cancer patients. The initiation and progression of breast cancer brain metastasis (BCBM) involve multiple distinct molecular pathways and reprogramming of the tumor microenvironment (TME). This review systematically summarizes key mechanisms underlying BCBM, including epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and the spatiotemporal dynamics of metabolic reprogramming regulated by critical signaling pathways during brain colonization. In particular, we highlight emerging mechanisms of breaching the specialized brain multifunctional barriers. Furthermore, this review provides an in-depth analysis of the cooperative immune-suppressive network within the BCBM TME, emphasizing the crosstalk among various immune cell components (such as T cells, B cells, macrophages, neutrophils, NK cells, MDSCs) and intracranial-specific cellular elements (including astrocytes, microglia, brain metastasis-associated fibroblasts). Through the complex interplay, these cells collectively facilitate immune evasion and metastatic outgrowth. Accordingly, we discuss the current clinical management of BCBM and potential future directions. Deeper mechanistic insights are expected to offer novel biomarkers and reveal new targets for developing precision therapeutic strategies against BCBM.

Metabolic rewiring is a defining feature of malignant cells, enabling them to dynamically exploit nutrient resources to meet bioenergetic problems at different growth stages. Beyond the classical Warburg effect, recent studies have shown that neoplasms demonstrate a marked dependency on lipid metabolism, using free fatty acids to support cellular proliferation and regeneration via fatty acid oxidation (FAO). As a central component of lipid metabolism, FAO exerts dual immunomodulatory functions within tumors. Although numerous studies have described the enzymatic reactions of the FAO pathway in different malignancies, relatively few have investigated the pharmacological disruption of these enzymatic checkpoints and the resulting immunological consequences. Moreover, existing therapeutic strategies have failed to achieve a risk-benefit balance, limiting the clinical translation of FAO-directed approaches. To better understand the therapeutic implications of FAO, we investigated the mechanistic pathways mediated by mitochondrial rate-limiting enzymes, with a particular focus on the carnitine palmitoyltransferase 1 enzyme family-the critical gatekeeper controlling the entry of fatty acids into mitochondrial oxidation instead of CPT2. We comprehensively evaluated its role in tumor biology and also highlight future research directions to inform rational intervention strategies.