Clinical and translational discovery最新文献

{"title":"An important step to translate single-cell measurement into clinical practice: Stereoscopic cells","authors":"Xiangdong Wang,&nbsp;Wanxin Duan,&nbsp;Xuanqi Liu,&nbsp;Jia Fan","doi":"10.1002/ctd2.70049","DOIUrl":"https://doi.org/10.1002/ctd2.70049","url":null,"abstract":"<p>Clinical single-cell biomedicine is an emerging disciplines within molecular medicine that brings more advanced alternatives for disease diagnoses and therapies. With the rapid development of biotechnologies such as Stereo-seq and Stereo-cell, it is now possible to explore the spatiotemporal and dynamical changes of intracellular element and organelle locations, distributions, and functional and morphological phenomes in stereological single cells at multiple layers and orientations. Stereological single cells (StereoCell) will provide the precise multidimensional information on molecular interactions, organelle communications, and signaling pathways, as well as on the interventions involving small molecule-, protein-, and cell-based therapies with targets. This is achieved by integrating morphological images, molecular multi-omics, and clinical phenomics. StereoCell is one of biotechnological breakthroughs and milestones during of clinical translation of single-cell measurements to pathology, biochemistry, hematology, and bioliquid tests. It is also a new approach to discover and develop new diagnostic biomarkers and therapeutic targets, and a new way to dynamically monitor the disease progression and therapeutic effects. Thus, we believe that SereoCell, detected by Stereo-seq and Stereo-cell, will provide new insights into human diseases and reforming clinical practices.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new member at the table: Granzyme K as a lymphocyte-born complement initiator","authors":"Manoj Kumar Pandey","doi":"10.1002/ctd2.70069","DOIUrl":"https://doi.org/10.1002/ctd2.70069","url":null,"abstract":"<p>The complement system, classically defined by its three canonical activation pathways, that is, classical, lectin, and alternative has long been considered a liver-derived, plasma-resident immune surveillance system. These pathways converge at the cleavage of complement (C3) and C5, generating potent effectors, such as C3a, C3b, C5a, and C5b that orchestrate immune clearance via inflammation, opsonisation, and membrane attack complex (MAC) formation<span>^{1, 2}</span> (Figure 1a–c). However, emerging evidence over the past decade has radically reshaped this view. We now recognise a spectrum of non-canonical complement activation routes including intracellular complosome activity, proteolytic cleavage by thrombin, kallikrein, cathepsins, and redox-driven activation that integrate complement into broader immune, metabolic and stress response networks.<span>^2-9</span></p><p>A recent study by Donado et al.<span>¹⁰</span> introduced a novel addition to this expanding repertoire granzyme K (GZMK), a serine protease released by cytotoxic lymphocytes, as a direct initiator of complement activation. In contrast to thrombin, kallikrein, and cathepsin, which bypass early steps to directly cleave C3 and C5 intracellularly,<span>^{3, 7, 9}</span> GZMK uniquely cleaves C4 and C2 on the cell surface, generating the classical C3 convertase (C4b2a) and C5 convertase (C4b2a3b) independent of antibody–antigen complexes or MBL/Ficolin. This places GZMK mechanistically alongside C1r and C1s and MASPs but fundamentally distinct in origin and context cell-autonomous, lymphocyte-derived, and recognition-independent (Figure 2a–f). This discovery reframes complement as not just a fluid-phase sentinel but also a cellularly initiated effector system.</p><p>Granzymes, a conserved family of serine proteases (GZMA, GZMB, GZMK, GZMM, GZMH in humans), are best known for their role in perforin-mediated cytotoxicity by CD8⁺ T cells and natural killer (NK) cells.<span>¹¹</span> Yet beyond cytolysis, granzymes increasingly appear as modulators of inflammation and tissue remodelling. GZMB, for instance, cleaves extracellular matrix proteins and promotes autoantigen formation in autoimmune diseases.<span>^12-17</span> GZMA, GZMB, and GZMM are implicated in viral control and inflammation, often via extracellular routes.</p><p>Amongst them, GZMK stands out as a non-cytolytic effector with immunoregulatory and pro-inflammatory properties. It is expressed in γδ T cells, invariant natural killer T (NKT) cells, and CD56bright⁺ NK cells and is upregulated in aging and chronic immune activation replication.<span>^18-20</span> Structurally homologous to trypsin and GZMA, GZMK contains a unique heparin-binding domain that enables its interaction with cell-surface heparan sulphate proteoglycans (HSPGs).<span>^21-25</span> It cleaves substrates such as SET nuclear proto-oncogene (a nucleosome assembly protein (SET)","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative analyses of single-cell and bulk RNA sequencing reveal tumour microenvironment features associated with neoadjuvant immunochemotherapy response in oesophageal squamous cell carcinoma","authors":"Xianxian Wu,&nbsp;Xiaoxing Ye,&nbsp;Wei Ji,&nbsp;Xiangyang Yu,&nbsp;Ahuan Xie,&nbsp;Zichang Xiang,&nbsp;Zhilin Sui,&nbsp;Jiquan Tang,&nbsp;Zhentao Yu","doi":"10.1002/ctd2.70080","DOIUrl":"https://doi.org/10.1002/ctd2.70080","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neoadjuvant chemotherapy combined with immunotherapy (NACI) has shown promise in oesophageal squamous cell carcinoma (ESCC). However, a significant proportion of patients exhibit resistance to NACI, and the underlying mechanisms remain unresolved.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We integrated single-cell RNA sequencing data, including seven patients with ESCC treated with NACI and 69 patients with ESCC treated with surgery alone. Bulk RNA sequencing data were obtained from a public database. Immunohistochemistry and multiplexed immunofluorescence staining were performed to verify the role of important immune cells and molecules in clinical treatment outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we profiled the transcriptomes of 512 736 cells from 76 patients with ESCC, revealing that the nonresponder baseline tumour microenvironment exhibited a relative absence of major histocompatibility complex II molecules expressed on CD20⁺B cells and a low expression of CXCL13 on CD4_Tfh and CD8_Tex cells. We also identified CD68⁺CD163⁺ macrophages that highly expressed the immunosuppressive LGALS9 gene and preferentially accumulated in the nonresponders after NACI treatment. In addition, nonresponders had a higher baseline fraction of POSTN⁺fibroblasts, which is associated with higher infiltration of CD68⁺CD163⁺ macrophages and lower infiltration of germinal centre B cells. Finally, we described the different characteristics of malignant epithelial cells from different pathological responses to tumours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study has unveiled a potential regulatory network among immune cells, stromal cells and malignant epithelial cells under different pathological response conditions and provides a valuable resource for discovering novel targeted therapies for ESCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B-cell lymphoma classification using vision-language models and in-context learning","authors":"Mobina Shrestha,&nbsp;Bishwas Mandal,&nbsp;Vishal Mandal,&nbsp;Amir Babu Shrestha","doi":"10.1002/ctd2.70081","DOIUrl":"https://doi.org/10.1002/ctd2.70081","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Accurate classification of B-cell lymphoma is essential for leading treatment decisions and prognostic assessments. Subtypes such as chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) often show overlapping morphologic features, particularly in small biopsies or poorly preserved samples. Even with supporting ancillary tests, distinguishing between these subtypes can be difficult, especially outside large university centers where hematopathology subspecialists may not be available. Digital pathology has brought with it the possibility of augmenting diagnostic accuracy with artificial intelligence (AI), particularly through deep learning algorithms. Several studies have shown promising results when convolutional neural networks are trained on thousands of annotated images to identify lymphoid neoplasms and other malignancies.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; But these approaches often require large-scale, curated datasets, annotated by domain experts.&lt;/p&gt;&lt;p&gt;This is where in-context learning (ICL) offers a meaningful alternative. ICL allows models to generate predictions based on just a few labelled examples shown at inference time, without the need for annotated datasets or model retraining. This mirrors how clinicians’ reason through new cases by recalling similar prior examples and using them to guide interpretation. Large vision-language models (VLMs) have demonstrated this ability in domains like dermatopathology, radiology, and gastrointestinal histology. However, despite the progress, to this date there have been no studies applying ICL to lymphoma subtyping. Given that B-cell lymphomas have well-described morphologic patterns and are amongst the most common lymphoid neoplasms encountered in practice, they are an ideal test case for this approach.&lt;/p&gt;&lt;p&gt;Therefore, in this study, we evaluated four state-of-the-art VLMs, that is, GPT-4o, Paligemma, CLIP and ALIGN in classifying CLL, FL, and MCL using digital histopathology images. We assess model performance in zero-shot and few-shot settings, simulating real-world diagnostic constraints where only a handful of reference cases may be available. Our aim is not to replace pathologists but to explore whether this type of AI can be used as a low-barrier, annotation-efficient tool to support lymphoma diagnosis, especially in environments where expert pathology review is limited.&lt;/p&gt;&lt;p&gt;In this study, a total of 150 Haematoxylin and Eosin (H&amp;E) stained histopathology images with 50 each of CLL, FL and MCL were used. All images were obtained from the publicly available malignant lymphoma classification dataset on Kaggle.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Testing for GPT-4o was performed via the OpenAI Python API. Paligemma was implemented using the pretrained checkpoint (google/paligemma-3b-mix-224) from the Hugging Face model hub, configured for image-text inference. CLIP was implemented using the ViT-B/32 backbone (openai/clip-vit-base-patch32). ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probe-capture targeted next-generation sequencing: A novel approach for pathogen and antimicrobial resistance detection in sepsis","authors":"Chitra Ravi,&nbsp;Adam D. Irwin,&nbsp;Patrick N. A. Harris","doi":"10.1002/ctd2.70079","DOIUrl":"https://doi.org/10.1002/ctd2.70079","url":null,"abstract":"<p>Sepsis is a syndrome of life-threatening organ dysfunction caused by a dysregulated immune response to infection.<span>^{1, 2}</span> It is a global health priority as recognised by the World Health Organisation<span>³</span> 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.<span>⁴</span> Bloodstream infections (BSIs), defined by the presence of viable bacteria (or fungi) in the bloodstream, are an important cause of sepsis.<span>^{5, 6}</span> Early identification of a causative pathogen and its antimicrobial resistance (AMR) profile is essential for appropriate and timely treatment.<span>^{7, 8}</span> However, using the current gold standard of microbial identification through blood cultures (BCs), a causative pathogen is only detected in around 30% of cases.<span>⁹</span> Although culture-based methods are inexpensive and simple, their turnaround time (TAT) can stretch to several days<span>¹⁰</span> (Figure 1), delaying diagnoses and leading to inappropriate antimicrobial treatment.<span>¹¹</span> Furthermore, BCs may fail due to slow-growing, fastidious or non-culturable microbes, low microbial load or prior antibiotic treatment.<span>^12-14</span> 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<span>^15-18</span> (Figure 1). mNGS provides a high-throughput pathogen detection method and is increasingly employed in various infectious syndromes, including BSI,<span>^{19, 20}</span> central nervous system,<span>²¹</span> bone and joint,<span>²²</span> respiratory infections.<span>²³</span> Although mNGS is pathogen agnostic and could be quicker than BC (Figure 1), sensitivity can be compromised due to high human DNA background (&gt;99%) in blood samples and low microbial loads during BSI (1–10 colony-forming units [CFU]/mL).<span>^24-27</span> Thus, a more sensitive approach for diagnosing BSI using NGS is urgently required.</p><p>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.<span>³²</span> 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.<span>^33-35</span> This method enables greater genome coverage by using overlapping probes, ensuring more comprehensive target capture and reduced background or host DNA<span>^{32, 36}</span> ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sticky situation, strategic strike: Targeting neutrophil extracellular trap-work in cancer","authors":"Bo Cao,&nbsp;Ting La","doi":"10.1002/ctd2.70068","DOIUrl":"https://doi.org/10.1002/ctd2.70068","url":null,"abstract":"<p>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 <i>Clinical and Translational Medicine</i>, reveal that NETs are dynamically regulated by the tumour microenvironment (TME) and exhibit context-dependent pro- or anti-tumour effects.<span>¹</span> 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.<span>²</span> 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.</p><p>The burgeoning field of NETs in oncology holds immense potential, but significant challenges and exciting opportunities lie ahead. Future studies should prioritise (Figure 1).</p><p>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","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-PF4 antibody inhibit proliferation of lung cancer cells without TP53 mutation by inducing apoptosis and cell cycle arrest","authors":"Mengjia Qian,&nbsp;Zhihui Min,&nbsp;Yanxia Zhan,&nbsp;Lili Ji,&nbsp;Bijun Zhu,&nbsp;Miaomiao Zhang,&nbsp;Qi Shen,&nbsp;Pengcheng Xu,&nbsp;Hao Chen,&nbsp;Yunfeng Cheng","doi":"10.1002/ctd2.70075","DOIUrl":"https://doi.org/10.1002/ctd2.70075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elevated platelet count is correlated with poor survival of lung cancer. Platelet factor 4 (PF4), a platelet-specific protein, plays an important role in platelet function. Emerging evidence suggests that regulation of PF4 can modulate platelet function to impact the progression of lung cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Anti-PF4 antibody was used to neutralise PF4 to regulate platelet function in the co-culture of platelets and lung cancer cells lines of H1299 and A549. The proliferation, apoptosis and cell cycle were examined by cell counting kit-8 (CCK-8) test and flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Anti-PF4 antibody inhibited the proliferation of H1299 and A549 cells when stimulated with platelets, yet induced cell cycle arrest and cell apoptosis only in A549, not H1299. The proliferation, cell cycle distribution and apoptosis were not affected by anti-PF4 antibody in A549^TP53‒ cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Anti-PF4 antibody exerted anti-proliferative effects by inducing apoptosis and cell cycle arrest in lung cancer cells without TP53 mutation via p53 signalling pathway when stimulated with platelets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patients with symptoms of haemolytic anaemia and thrombocytopenia revealed by genetic testing as sitosterolemia","authors":"Mengjia Qian,&nbsp;Pu Chen,&nbsp;Yanxia Zhan,&nbsp;Bijun Zhu,&nbsp;Lingyan Wang,&nbsp;Miaomiao Zhang,&nbsp;Yujie Zhou,&nbsp;Hao Chen,&nbsp;Lili Ji,&nbsp;Yunfeng Cheng","doi":"10.1002/ctd2.70071","DOIUrl":"https://doi.org/10.1002/ctd2.70071","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sitosterolemia is a rare, inherited, autosomal recessive disorder of lipid metabolism. Patients with sitosterolemia may exhibit diverse, distinct clinical characteristics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>We report cases of sitosterolemia with haematological abnormalities as primary initial symptoms. Both patients were seen with symptoms of haemolytic anaemia and thrombocytopenia. Their plasma levels of low-density lipoprotein-cholesterol were normal. Genetic tests were arranged as stomatocytes were found in their peripheral blood smears. Three heterozygous mutations in adenosine triphosphate-binding cassette subfamily G member 5 (ABCG5) were identified in case 1. A mutation in integrin beta 3 was discovered in case 2, while no mutations were found in ABCG5 or ABCG8. Sitosterolemia was considered for both cases, and Ezetimibe was used for treatment, with quick curative responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>For patients with unexplained haemolytic anaemia, thrombocytopenia, especially with stomatocytes present in peripheral blood, the diagnosis of sitosterolemia should be considered, and genetic testing is recommended.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential of NAT10-mediated ac4C acetylation in clinical translation","authors":"Xuqiao Mei,&nbsp;Wanxin Duan,&nbsp;Jiawei Hu,&nbsp;Shisiyu Zheng,&nbsp;Yuhuang Xu,&nbsp;Yongguang Zhang,&nbsp;Jianming Weng,&nbsp;Xiao Yang","doi":"10.1002/ctd2.70061","DOIUrl":"https://doi.org/10.1002/ctd2.70061","url":null,"abstract":"&lt;p&gt;RNA modifications have recently garnered significant attention as key players in epigenetic regulation,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; 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.&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, the precise molecular mechanisms by which NAT10 increases mRNA stability through ac4C modification remain to be fully elucidated, requiring further in-depth research.&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; 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.&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; 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","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significance of stereologically spatiotemporal cells in molecular medicine","authors":"Xuanqi Liu,&nbsp;Wanxin Duan,&nbsp;Yuyang Qiu,&nbsp;Ruyi Li,&nbsp;Yuanlin Song,&nbsp;Xiangdong Wang","doi":"10.1002/ctd2.70077","DOIUrl":"https://doi.org/10.1002/ctd2.70077","url":null,"abstract":"<p>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.<span>¹</span> 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.<span>²</span> 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)</p><p>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.<span>³</span> 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","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}