Clinical and translational discovery最新文献

Sepsis is a syndrome of life-threatening organ dysfunction caused by a dysregulated immune response to infection.^{1, 2} It is a global health priority as recognised by the World Health Organisation³ and according to the Global Burden of Disease Study 2017, 11 million sepsis related fatalities and 48.9 million sepsis episodes occurred globally in 2017.⁴ Bloodstream infections (BSIs), defined by the presence of viable bacteria (or fungi) in the bloodstream, are an important cause of sepsis.^{5, 6} Early identification of a causative pathogen and its antimicrobial resistance (AMR) profile is essential for appropriate and timely treatment.^{7, 8} However, using the current gold standard of microbial identification through blood cultures (BCs), a causative pathogen is only detected in around 30% of cases.⁹ Although culture-based methods are inexpensive and simple, their turnaround time (TAT) can stretch to several days¹⁰ (Figure 1), delaying diagnoses and leading to inappropriate antimicrobial treatment.¹¹ Furthermore, BCs may fail due to slow-growing, fastidious or non-culturable microbes, low microbial load or prior antibiotic treatment.^12-14 Clinical metagenomic next-generation sequencing (mNGS) uses untargeted shotgun sequencing of all DNA or RNA in a sample to identify microbial genomes present in the sample^15-18 (Figure 1). mNGS provides a high-throughput pathogen detection method and is increasingly employed in various infectious syndromes, including BSI,^{19, 20} central nervous system,²¹ bone and joint,²² respiratory infections.²³ Although mNGS is pathogen agnostic and could be quicker than BC (Figure 1), sensitivity can be compromised due to high human DNA background (>99%) in blood samples and low microbial loads during BSI (1–10 colony-forming units [CFU]/mL).^24-27 Thus, a more sensitive approach for diagnosing BSI using NGS is urgently required.

Targeted NGS (tNGS) is an approach that selectively amplifies specific genomic regions or gene sequences, such as AMR determinants. This targeted enrichment enhances sensitivity and minimises host nucleic acid background, offering improved performance over untargeted shotgun mNGS.³² An example of tNGS is hybridisation-based probe-capture metagenomics. Short DNA/RNA oligonucleotide probes (or “baits”) are designed to be complementary to various pathogen sequences and can be designed to identify over 3,000 species.^33-35 This method enables greater genome coverage by using overlapping probes, ensuring more comprehensive target capture and reduced background or host DNA^{32, 36}

Neutrophil extracellular traps (NETs), once recognised solely as antimicrobial defenders, have emerged as key, yet paradoxical, players in the complex theatre of cancer. These intricate webs of DNA decorated with cytotoxic granule proteins, ejected by activated or dying neutrophils via NETosis, are now implicated in nearly every stage of tumour progression. Recent advances, as comprehensively reviewed by Wang et al. in Clinical and Translational Medicine, reveal that NETs are dynamically regulated by the tumour microenvironment (TME) and exhibit context-dependent pro- or anti-tumour effects.¹ Cytokines (IL-8, G-CSF, TNF-α), tumour-derived extracellular vesicles (EVs), platelets, complement factors, and even extracellular matrix (ECM) aberrations can trigger NETosis. Once formed, NETs wield a double-edged sword: their DNA scaffolds, proteases (NE, MPO), histones, and associated proteins can directly fuel tumour cell proliferation, invasion, epithelial–mesenchymal transition (EMT), and awakening of dormant cells, whilst simultaneously establishing physical traps for circulating tumour cells (CTCs) in distant organs, facilitating metastasis.² They contribute to a pro-thrombotic state, therapy resistance (particularly to chemotherapy and immunotherapy), and immunosuppression by excluding cytotoxic T cells. Conversely, under specific contexts, NETs may exert anti-tumour cytotoxicity. Clinically, NETs components (e.g., citrullinated histone H3 [CitH3], cell-free DNA [cfDNA]) serve as diagnostic/prognostic biomarkers, whilst therapeutic strategies targeting NET formation (e.g., PAD4 inhibitors) or degradation (e.g., DNase I) show promise in preclinical models. Despite progress, key challenges—including NETs heterogeneity, detection standardisation, and therapeutic specificity—remain unresolved.

The burgeoning field of NETs in oncology holds immense potential, but significant challenges and exciting opportunities lie ahead. Future studies should prioritise (Figure 1).

The intricate dance between NETs and cancer is far from fully choreographed. Whilst their detrimental roles in promoting metastasis, thrombosis, immunosuppression, and therapy resistance are increasingly clear, harnessing their biology offers unprecedented opportunities. The future lies in moving beyond broad inhibition towards precision targeting—understanding the nuances of NET heterogeneity, context-specific functions, and their intricate interactions within the TME. Overcoming technical hurdles in detection and drug delivery, rigorously validating biomarkers, and designing intelligent clinical trials combining NET-targeting strategies with established and emerging therapies are critical next steps. Success in this endeavour promises not only deeper biological insights but also the development of novel diagnostic tools and therapeutic arsenals to disrupt the dark side of NETs, ultimately improving outcomes for cancer p

RNA modifications have recently garnered significant attention as key players in epigenetic regulation,¹ such as N6-methyladenosine (m6A), pseudouridine (ψ), N1-methyladenosine (m1A), N4-acetylcytidine (ac4C), 5-methylcytosine (m5C) and its oxidised product 5-hydroxymethylcytosine (hm5C). N-acetyltransferase 10 (NAT10), the sole enzyme identified for ac4C acetylation, modulates RNA stability, translation efficiency and metabolic reprogramming, thereby impacting cellular homeostasis and disease progression. This commentary highlights the multifaceted roles of NAT10 in health and disease, emphasising its potential as a therapeutic target.

NAT10 is a multifunctional enzyme belonging to the GCN5-related N-acetyltransferase (GNAT) family. The NAT10 gene is located on chromosome 11p13 and comprises 29 exons and 28 introns, encoding a 1025-amino acid protein. NAT10 is highly conserved from bacteria to humans, featuring both an acetyltransferase domain and an RNA-binding domain.² It catalyses the acetylation of specific RNA transcripts using acetyl-CoA as a substrate, primarily modifying tRNAs, rRNAs and mRNAs at specific sites. These modifications alter the structure and function of these RNA molecules, mainly to maintain mRNA stability and to enhance translation efficiency.³ However, the precise molecular mechanisms by which NAT10 increases mRNA stability through ac4C modification remain to be fully elucidated, requiring further in-depth research.

NAT10 plays diverse roles in cellular metabolism, cancer progression, cardiac injury, viral replication and other physiological and pathological processes. It directly regulates mRNA stability and translation efficiency through ac4C modification (e.g., SLC30A9, Mybbp1a) and interacts with other proteins to modulate key signalling pathways.^{4, 5} Additionally, NAT10 possesses biological functions independent of its classical RNA acetyltransferase activity (i.e., ac4C modification). These include roles in DNA repair, cytoskeletal regulation and epigenetic regulation via distinct molecular mechanisms.⁶ NAT10 is emerging as a potential therapeutic target in diseases such as cancer, cardiac injury and viral infections. Inhibiting its acetyltransferase activity or blocking its downstream signalling may provide novel therapeutic strategies.

NAT10-mediated ac4C modification of mRNA plays a significant role in various tumour-related processes. NAT10 enhances p53 stability and transcriptional activity by acetylating specific lysine residues on p53, thereby contributing significantly to tumour suppression.⁷ Conversely, upregulated NAT10 expression can promote the development of certain cancers by enhancing the stability and translation efficiency of target mRNA through ac4C modification. For instance, in bladder cancer, downregulation of NAT10 reduces ac4C mod

With continuous development of biotechnology, our understanding of cells, the fundamental units of the human body and their functions has deepened significantly. The structural and functional characteristics of cells are increasingly recognised as multidimensional and complex, shaped by their tissue and organ locations, intercellular connections, interactions in the extracellular fluids and the dynamics of subcellular organelles and molecules. Cellular heterogeneity among cells primarily arises from variations in the extracellular microenvironment, intracellular genetic diversity, and the spatial and dynamic arrangement of subcellular components, including nuclei, organelles, molecules and cytoplasm. Recent research has evidenced that a large proportion of proteins are spatially allocated in intracellular compartments, including both membrane-bound and membrane-less organelles. This localisation forms protein-driven spatial networks that link these organelles, and orient interconnections among the compartments.¹ These spatiotemporal distributions of proteins dynamically altered in response to extracellular stimuli and pathogens, regulating protein movements, remodelling and functions independently of mere changes in protein abundance. Trans-compartmental translocations of intracellular components orientate dynamic and multiple regulations of signalling and functions. Studies on the spatiotemporal dynamics of intracellular proteomic and phosphor-proteomic signalling networks have demonstrated that receptor adaptor proteins can be re-distributed among subcellular compartments. This can perform transition from a free cytosolic form to membrane-bound fractions and be targeted to receptors through vesicles, a process activated by the phosphorylation of tyrosine residues in the receptor such as the interaction between epidermal growth factor and epidermal growth factor receptor.² Various subcellular compartmentations are recognised and defined by specific biomarkers at a two-dimensional (2D) level, which partly shows the spatialisation and temporalisation of compartments and molecular relocations in stereological cells (See Figure 1)

To distinguish this from conventional 1D or 2D spatialisation, we define the concept of the ‘stereologically spatiotemporal cell’ (SST-cell) to describe the precise 3D localisation and interactions of intra- and extracellular components at the single-cell levels. We propose that understanding the SST-cell represents a new frontline in clinical single-cell biomedicine, providing new insights for the clinical translation and application of molecular medicine.³ Changes in intracellular components result in a high complexity of intercellular heterogeneity and multidimensional dynamics, posing challenges for real-time monitoring and reproducibility. One of the major challenges is to accurately delineate and interpret the complex multidimensional st

Marine biomedicine is an important field in oceanology and bio-ecosystem and has evolved significantly alongside advances in biotechnology and growing understanding of marine life. In this perspective, we propose a refined concept of clinical marine biomedicine, with a clear mission to establish an emerging discipline that bridges marine biomedicine and clinical practice. The exploration of marine-origin sources should be emphasised, with a strong focus on the identification, validation and development of human disease-specific diagnostics and target-oriented pharmaceutics. The perspective headlines some of critical components, including marine-oriented human evolution and development, humanised marine-based models, biomarker innovation and validation, marine microbiomes and metabolites, and target nutrition and therapy. We envision that clinical marine biomedicine will become a crucial pillar clinical molecular medicine, contributing to the improvement of human health and the prognosis of patient.

Phosphatidylethanolamine (PE) is a pivotal glycerophospholipid that constitutes a significant portion of cellular membranes, playing a crucial role in maintaining membrane fluidity, supporting protein integration, and mediating signal transduction. In the lungs, PE is also a key component of pulmonary surfactant, which is essential for preserving alveolar stability and facilitating efficient gas exchange. Recent research has highlighted the association between dysregulated PE metabolism and various lung diseases, such as asthma, pulmonary fibrosis and chronic obstructive pulmonary disease. Nevertheless, the molecular mechanisms underlying these associations remain poorly understood, and the potential of PE as a therapeutic target or biomarker for lung diseases has yet to be fully explored. This review aims to provide a comprehensive overview of the biological functions and biosynthetic pathways of PE, with a particular focus on its roles in pulmonary physiology and pathology. We summarise current findings on PE alterations in different lung diseases and discuss the potential implications of targeting PE metabolism for therapeutic interventions.