Biomarker Research最新文献

Background: Splenomegaly is an event occurring in a variable range between 10-40% of de novo acute myeloid leukemia (AML), recently linked to poorer prognosis. Studies in murine models have shown that loss of the additional sex combs-like 1 (ASXL1) gene function leads to a significantly enlarged spleen volume, due to an increased infiltration of myeloid cells into the spleen.

Methods: In 58 de novo AML patients presenting with splenomegaly at diagnosis, we evaluated the occurrence of ASXL1 somatic mutations, deepened the molecular profile and conducted high-throughput RNA sequencing, with the aim of unveiling possible peculiar aspects of this rare clinical scenario.

Results: ASXL1 mutations (ASXL1mut) were detected in 23/58 (40%) patients, being the most frequently mutated gene, followed by TET2 and NRAS. ASXL1mut cases were significantly older than ASXL1wt (71 vs 64 years old, p = 0.003), showed a significantly higher white blood cells count (31,970/uL vs 17,810/uL, p = 0.044) and a higher platelet count (177,700/uL vs 67,700/uL, p = 0.0006). In contrast, the median bone marrow blasts percentage was lower in the ASXL1mut subset compared to ASXL1wt (36.4% vs 72,1%, p = 0.002). Comparing the gene expression profile of the ASXL1mut and ASXL1wt groups, we found the upregulation of PCDHB2 and LURAP1L/LURAP1L-AS1 (all involved in mechanisms of cellular interaction and migration) genes in the former group, unveiling a role in the splenic infiltration of ASXL1mut leukemic cells.

Conclusions: Overall, our data paves the way for further studies of an AML subgroup with a distinctive phenotype, whose prompt identification could improve patient management and therapeutic decision making.

The molecular features of coronary atherosclerosis progression remain incompletely understood. A comprehensive characterization of coronary proteome dynamics during atherosclerosis progression could facilitate the identification of novel biomarkers for early detection of plaque initiation and risk assessment of plaque destabilization. We performed proteomics on human coronary artery specimens representing five progressive histopathologic stages of atherosclerosis according to the modified AHA classification, including adaptive intimal thickening (AIT), pathological intimal thickening (PIT), fibroatheroma (FA), thin cap fibroatheroma (TCFA), and ruptured plaque (RP). The results revealed progressive dysregulation of complement and coagulation cascades and extracellular matrix (ECM) organization during histopathologic progression, particularly in plaque initiation and destabilization. Integrated single-cell RNA sequencing data showed that complement and coagulation pathways were predominantly upregulated in fibroblasts and macrophages, while ECM organization was elevated in fibroblasts and smooth muscle cells. Plasma proteomics in a discovery cohort identified THBS1, ECM2, and C1R proteins as robust diagnostic biomarkers from among the overlapping complement and ECM proteins found in the tissue proteomics. The combination of these biomarkers achieved area under the curve (AUC) values of 0.831 in the training set and 0.764 in the test set for identifying coronary artery disease (CAD). In both the discovery cohort and the external validation cohort, this biomarker panel distinguished stable CAD from non-stenosis controls (AUC: 0.765 and 0.841, respectively) and identified ACS patients (AUC: 0.786 and 0.822, respectively). These findings elucidate the proteomic landscape of atherosclerosis progression and establish a three-protein biomarker panel with potential for CAD diagnosis.

Background: A certain degree of self-repair is initiated following spinal cord injury (SCI). Although intraneuronal regeneration and a supportive growth environment are limited, they serve as the foundation for functional recovery after SCI.

Methods: In this study, we conducted single-cell RNA sequencing combined with spatial transcriptomics and spatial metabolomics to reveal the spatial molecular characteristics of self-repair processes after SCI at single-cell resolution.

Results: We identified three cell subsets-Mic2 (a microglia subset), Mac4 (a macrophage subset), and Fib4 (a fibroblast subset)-that express markers associated with spinal cord repair. Mic2 and Mac4 exhibit clustered spatial distribution patterns, whereas Fib4 is predominantly located around the injured spinal cord. Additionally, Mic2 is predominantly distributed in the white matter, particularly in the dorsal region of the injured spinal cord, and exhibits high expression of taurine. Mac4 and Fib4 exhibit high expression of copalic acid and uridine, respectively.

Conclusions: In this study, we have identified three distinct cell subsets that express markers associated with wound healing and may promote regenerative processes, and we have determined their spatial transcriptional and metabolic features enriched within these regions. Our dataset represents a valuable resource that offers novel mechanistic insights into the pathobiology of spinal cord injury.

Alterations in propanoate metabolism are increasingly recognized as significant biomarkers for various liver disorders, notably hepatocellular carcinoma (HCC). To enhance diagnostic specificity for HCC, we conducted integrated binary omics and targeted metabolomics analyses, identifying liver-specific propanoate metabolism (LPM) gene signatures and associated metabolites. Leveraging data from 40 tissues and 81 cell subclasses, hepatocytes showed the highest metabolic specificity. Clinical validation using the TCGA-LIHC cohort highlighted LPM genes, notably ALDH2 and ABAT, as robust prognostic markers significantly associated with poor survival outcomes. Serum metabolomic profiling of 273 patients demonstrated that elevated toluene and xylene isomers and significantly reduced 2-ethylhexanol distinctly characterize HCC, distinguishing it from liver cirrhosis, hepatitis, and other cancers. These findings emphasize the potential of LPM-based metabolic profiling as a precise diagnostic and prognostic tool, with potential implications in targeted therapeutic development for HCC.

Aging is associated with enhanced platelet activation and inflammatory responses, contributing to an increased risk of thrombotic and cardiovascular events. However, how megakaryocytes (Mk) change with age or between sexes is still unclear.We performed single-cell RNA sequencing to profile bone marrow from young (3-month-old) and old (> 24-month-old) C57BL/6 mice, as well as from young and middle-aged human donors. In parallel, platelet activation was assessed by CD62P expression using flow cytometry in isolated and washed mouse platelets from young and old donors. Single-cell clustering in mouse bone marrow revealed five distinct Mk subpopulations. The age-dependent shift was more pronounced for subpopulations associated with platelet activation (mMk3) and immune/inflammatory responses (mMk4). mMk3 cells were more abundant in females, whereas mMk4 predominated in males. An increased platelet activation phenotype in old mice was confirmed in both sexes by CD62P expression analyses. Differential gene expression analyses showed that aging alters gene expression patterns related to platelet activation and aggregation via receptor signaling, granule formation, and inflammation. Aged males exhibited enrichment in genes linked to mitochondrial function, oxidative stress, lipid metabolism and membrane dynamics, whereas aged females showed upregulation of serotonin receptor genes. Human transcriptomic data support our murine findings, exhibiting increased expression of genes involved in mitochondrial electron transport and immune signaling in middle-aged individuals. Our study reveals a complex, sex-specific remodeling of Mk subpopulations in the aging organisms, characterized by distinct pro-thrombotic and pro-inflammatory transcriptional profiles. These observations suggest potential targets for developing age- and sex-tailored antithrombotic therapies.

The role of innervation in the pathogenesis of malignancies has been documented in many investigations. Recent studies have revealed that neurotransmitters act as mediators in nerve-stimulated cancer progression by directly influencing tumor cells and modulating the tumor microenvironment, including immune cells, angiogenesis, and surrounding stromal cells. Notably, psychological stress has been identified as a contributing factor to oncogenesis, primarily mediated by neurotransmitters. However, the complex interplay between neurotransmitters and tumor cells remains only partially understood. In this review, we explore newly identified mechanisms through which neurotransmitters (acetylcholine, glutamate, serotonin, dopamine, adrenaline, noradrenaline, γ-aminobutyric acid, neurotensin, and neuropeptide Y) regulate cancer initiation and progression, along with potential therapeutic strategies derived from these findings.

Background: Detecting and treating precancerous lesions can lower the incidence of esophageal squamous cell carcinoma (ESCC), making it a key preventive strategy. Although endoscopic screening and intervention can significantly reduce mortality associated with ESCC, they have certain shortcomings. We aimed to develop three predictive models: the motif, eight-protein, and combined motif-protein models to identify ESCC and its precancerous lesions.

Methods: Plasma samples were collected for cfDNA sequencing, and nine commonly used clinical protein biomarkers related to the digestive system were measured. Using a total cohort of 199 patients with ESCC, 91 patients with esophageal squamous precancerous lesions (ESPL), and 201 controls, we developed an integrative model based on selected multi-omics biomarkers.

Results: The motif-protein model, integrating 20 principal components of cfDNA terminal motifs with six protein features, outperformed both the motif model and the eight-protein model in distinguishing patients with ESCC and ESPL (area under the curve = 0·90). It achieved an overall sensitivity of 88·5% and a specificity of 75·4%. Notably, it successfully identified 90·9% of high-grade intraepithelial neoplasia cases, 86·8% of stage I ESCC cases, and 87·8% of HGIN or T1aN0 stage ESCC (subset of Stage I) cases who were eligible for endoscopic treatment, highlighting its potential as an effective tool for early diagnosis.

Conclusions: The motif-protein model may serve as an effective tool for the early diagnosis of esophageal lesions. Our findings underscore the clinical potential of the multi-omics liquid biopsy test as a non-invasive method for detecting early esophageal lesions.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by dysregulated differentiation and uncontrolled proliferation of myeloid precursor cells. AML is the second most common type of leukemia after acute lymphoblastic leukemia, yet it has the lower survival rates, with only approximately 30% of adult patients surviving five years post-diagnosis. Standard treatment regimens typically include intensive chemotherapy, advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) have significantly improved outcomes in the treatment of AML. Advances in molecular profiling technologies have significantly enhanced our understanding of the genetic and epigenetic alterations that drive AML, revealing numerous novel therapeutic targets. Consequently, targeted molecular therapies and epigenetic treatments are becoming increasingly important. Moreover, immunotherapy represents a promising therapeutic strategy that has demonstrated considerable potential in the context of AML. This review summarizes new strategies and emerging therapeutic targets in AML, with a particular focus on recent advancements in immunotherapy. It also explores the feasibility of integrating these therapeutic approaches into current treatment paradigms and their potential impact on future clinical practices.

Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major cause of cancer-related mortality worldwide, with rising incidence and limited treatment options, especially for patients diagnosed at advanced stages. In recent years, metabolic reprogramming has emerged as a hallmark of cancer that enables HCC cells to survive, proliferate, and resist therapy under hostile conditions. HCC cells undergo profound remodeling of glucose, lipid, and amino acid metabolism to adapt to hypoxia and nutrient deprivation. These processes are orchestrated by key signaling cascades, including the PI3K/AKT/mTOR, Ras-Raf-MEK-ERK-cMYC, and LKB1-AMPK pathways, forming a dynamic and integrated metabolic-signaling network. This review comprehensively integrates recent advances in the understanding of metabolic pathways in HCC, with a particular focus on glycolysis, de novo lipogenesis, and glutamine metabolism. We delineate the regulatory mechanisms underlying these pathways and construct an interaction map linking metabolic circuits to clinical phenotypes such as tumor heterogeneity, metastatic potential, and immune modulation. Furthermore, we systematically evaluate the biomarker potential of metabolic intermediates, rate-limiting enzymes, and key regulators in the context of early detection, molecular classification, prognosis prediction, and therapeutic response in HCC. We also highlight cutting-edge technologies, including metabolic imaging, liquid biopsy-based biomarker detection, and metabolism-targeted therapies. The review explores their potential synergy with immunotherapy, chemotherapy, and radiotherapy, aiming to provide a comprehensive framework for individualized HCC management. Our discussion underscores the translational relevance of metabolic biomarkers and offers insights for future research and clinical innovation.

Background: The advent of poly (ADP-ribose) polymerase inhibitors (PARPi) over the past decade has significantly altered the management of epithelial ovarian cancer (EOC). We proposed that the etiology of homologous recombination deficiency (HRD) might underlie the variable responses to PARPi observed across patient populations.

Methods: As part of the phase 2 study of the Chinese HRD Harmonization Project, we developed a genomic methylation sequencing (GM-seq) pipeline facilitated by the TET enzyme for the simultaneous identification of methylated modifications and genetic variations in EOC tumor samples, and compared with established DNA sequencing-based HRD assays.

Results: Somatic mutation and HRD scores were confounded by low tumor purity in our cohort of 98 locally advanced/advanced EOC patients. In samples with tumor purity ≥ 30% (n = 45), the GM-seq pipeline showed high consistency with DNA sequencing-based HRD assay, identifying genetic variations in homologous recombination repair (HRR) genes and HRD score with 92.6% (25/27) and 97.1% (33/34) consistency respectively, in addition to conducting methylation profiling. Moreover, different underlying mechanisms of HRD were associated with varying degrees of PARPi efficacy, with BRCA1/2 LOH group having the best efficacy (median PFS, undefined), followed by BRCA1 methylation group (median PFS, 23.4 months), and those with unknown etiology of HRD having the worst efficacy (median PFS, 8.8 months, p < 0.001).

Conclusion: Our findings underscore the importance of considering HRD etiology when evaluating PARPi efficacy in EOC patients. The GM-seq pipeline, represents a significant advancement in HRD detection, enabling more accurate predictions of PARPi response.