Clinical and translational discovery最新文献

{"title":"Effects of ketogenic and low-carbohydrate diet on glucose and weight control in type 2 diabetes mellitus patients along with metabolome change","authors":"Yao Wang, Haozhe He, Zhenjing Lyu, Yeyang Wang, Li Chen, Junbin Liang, Cong Lin, Huanhuan Wang, Shiping Zhang, Gugen Xu, Junzhang Tian, Kejing Zeng","doi":"10.1002/ctd2.70177","DOIUrl":"https://doi.org/10.1002/ctd2.70177","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Few trials have explored associations between diets, diet-induced metabolomic changes and metabolic outcomes in type 2 diabetes mellitus (T2DM), especially weight-stratified management. This study aimed to identify diet-specific metabolomic signatures by defining ketogenic diet (KD) and low-carbohydrate diet (LCD) applicability in T2DM patients with varying body mass index (BMI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 611 patients with T2DM were prescreened, and 505 eligible participants were included after exclusions. All participants received metformin and were allocated to either the LCD or KD group according to the study protocol and clinical dietary management process. BMI-stratified medical phenotype analysis was performed, with clinical/serum profiles measured at baseline and 3 months. High-throughput untargeted chromatography-mass spectrometry analysed serum metabolome. Associations between metabolites and diet intake were examined and diet-induced metabolomic changes versus diabetes prognosis were analysed via correlation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 611 prescreened participants, 505 eligible participants were included in the final analysis after completing the 12-week intervention: Obese patients in the KD group had the most significant glycated haemoglobin (HbA1c) (8.18 ± 2.2 vs. 5.87 ± 0.98%) and weight (88.51 ± 15.8 vs. 80.5 ± 15.3 kg) reductions. Overweight patients benefited from both diets for weight and glucose control. Metabolomic analysis identified 2410 markers post-intervention: KD group (279 vs. 259, up and downregulated); LCD group (300 vs. 288). Correlation regression: for the LCD group, weight negatively with histidinyl hydroxyproline; HbA1c positively with 4-hydroxyphenylacetylglutamic acid. As for the KD group, HbA1c positively correlated with glutamyl isoleucine and negatively correlated with diethanolamine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Both LCD and KD are effective for overweight and obese patients with T2DM. In the obese subgroup, LCD showed a numerically greater HbA1c reduction than KD, while both diets were suitable for overweight patients. For patients with normal BMI, LCD demonstrated no weight loss benefit. Metabolomic signatures sensitively reflect the effects of different diets and are closely associated with clinical metabolic improvements in T2DM, which is crucial for optimising dietary strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registrati","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467498","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":"Systemic immune-inflammation indices and MSI-H/dMMR status in colorectal cancer: Published evidence synthesis with exploratory local clinical and pathological corroboration","authors":"Yue Huang, Xuefei Chen, Zizhen Xu","doi":"10.1002/ctd2.70174","DOIUrl":"https://doi.org/10.1002/ctd2.70174","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) colorectal cancer (CRC) is a biologically distinct subtype with important clinical implications. While tissue-based assays remain the standard, accessible preoperative surrogate markers are of interest. Systemic inflammatory indices, including the systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR), have been explored, but their relationship with MSI-H/dMMR status remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the association between systemic inflammatory indices and MSI-H/dMMR status using published evidence, local clinical data and pathological corroboration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included three components: (1) evidence synthesis of published cohorts comparing inflammatory indices between MSI-H/dMMR and MSS/pMMR CRC; (2) a retrospective cohort of 28 patients (20 MSS and eight MSI-H) assessing peripheral blood profiles and exploratory associations; and (3) immunohistochemical quantification of CD8 and myeloperoxidase (MPO) using a Python/OpenCV workflow.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Six studies (<i>n</i> = 1598) were included in the NLR synthesis. The pooled random-effects standardised mean difference was 0.93 (95% confidence interval [CI] 0.016–1.852), suggesting higher NLR in MSI-H/dMMR cases, although heterogeneity was high (<i>I</i><sup>2</sup> = 97.8%). Excluding one influential study reduced the effect to 0.34 (95% CI −0.00 to 0.68). One study of SII suggested a modest increase in MSI-H/dMMR cases. In the local cohort, lymphocyte count was higher in MSI-H cases (<i>p</i> = .009), whereas SII and NLR were lower but not significant. Receiver operating characteristic analysis showed modest discrimination (SII area under the curve [AUC] = 0.675; NLR AUC = 0.656). Pathological quantification showed increased CD8 and reduced MPO/CD8 ratio in MSI-H tumours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MSI-H/dMMR CRC exhibits a distinct but context-dependent immune-inflammatory phenotype. Systemic indices show heterogeneous patterns, while tissue findings indicate a lymphocyte-enriched microenvironment. These markers may provide supportive immune context, but further validation is required.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial registration</h3>\u0000 ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467497","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 multi-omics analysis prioritizes DPEP1 as a genetically supported candidate associated with skin cancer risk","authors":"Fan Shen,&nbsp;Yongkai Yu,&nbsp;Zongfeng Liao,&nbsp;Liye Mao,&nbsp;Qianyun Wang,&nbsp;Wanju Wang,&nbsp;Yuanhui Liu,&nbsp;Ling Li","doi":"10.1002/ctd2.70165","DOIUrl":"https://doi.org/10.1002/ctd2.70165","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Skin cancer (SC) is among the most prevalent malignancies, yet causal circulating proteins and tractable therapeutic targets remain poorly defined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a proteome-wide Mendelian randomization (MR) analysis of 4972 proteins across large GWAS datasets (discovery: 23 694 cases and 372 016 controls; replication cohorts: &gt; 42 000 cases and &gt; 810 000 controls). Sensitivity analyses, bidirectional MR, Steiger filtering and SMR testing supported robustness. Based on an integrated prioritization framework, DPEP1 was selected for downstream analyses. We then explored DPEP1-associated transcriptional programs using bulk and single-cell transcriptomic datasets and performed virtual screening, docking and molecular dynamics (MD) simulations to prioritize candidate DPEP1-binding ligands for future validation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MR identified six genetically supported proteins associated with SC risk, and DPEP1 was prioritized for downstream characterization based on an explicit target-prioritization framework. In the murine Dpep1-knockout dataset, <i>Dpep1</i> deficiency was associated with altered stromal and immune programs, including reduced fibroblast abundance, lower YAP-TEAD/TGF-β pathway activity and increased CD8⁺ T-cell cytotoxicity scores. In human melanoma single-cell analyses, DPEP1 expression was enriched in fibroblasts and inferred ligand–receptor analyses suggested potential communication between DPEP1⁺ ·fibroblasts and immune subsets, including CXCL12–CXCR4 and MIF–CD74/CXCR4 interactions. Structure-based screening identified Balsaminone B as a top-ranked predicted high-affinity ligand, supported by stable docking and MD trajectories, with additional candidates including Ergotamine, Evobioside, MOL012579 and Venetoclax.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Together, these findings prioritize DPEP1 as a genetically supported candidate associated with skin cancer risk and provide supportive transcriptomic and computational evidence for future mechanistic and therapeutic investigation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467494","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":"Protein stereo-folding and proteostasis: A new path for clinical and translational medicine","authors":"Yuhan Wang,&nbsp;Yuyang Qiu,&nbsp;Xiangdong Wang","doi":"10.1002/ctd2.70163","DOIUrl":"https://doi.org/10.1002/ctd2.70163","url":null,"abstract":"&lt;p&gt;Proteins are fundamental biochemical elements in the body and play important roles in maintaining the biological functions of cells and organs. Protein homeostasis (proteostasis) within intra- and extracellular microenvironments promotes molecular communication among organs, cells, and organelles. The nature, content, network, and spatiotemporal dynamics of extracellular proteostasis, including chaperones, proteolytic machineries, and the regulators, change during the development of cellular and organ dysfunction, tumourigenesis, inflammation, and aging.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Among these alterations, the spatial shifting and remodelling of extra- and intra-cellular proteostasis are highly dependent upon the evolution of para-cellular microenvironmental functions and responses to systemic and local challenges. For example, altered proteostasis may reflect the microenvironment-dependent microglial cell states and heterogeneity of myeloid cells in the human brain and identify the blood–brain barrier, meningeal components and cell–cell interactions in brain diseases. These changes can be measured by integrating the codetection by indexing with the high-parameter capabilities of single-cell technologies with spatial resolution in brain tissue.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Spatial proteostasis maintains stereological spatialisation and interactions among stereo-cells and organelles and represents an important component of stereo-cell biomedicine,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; a new approach advancing the identification and development of disease-specific biomarkers and therapeutic targets,&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; and an innovative pathway towards next generation clinical translation and precision medicine.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; The current Commentary highlights the importance of protein stereo-folding and proteostasis as components of the intra-and extra-cellular microenvironment that maintain optimal bio-ecosystems for cell and organelle interactions. Through artificial intelligent (AI) system analyses and virtual screening, an efficient and accurate protein structure prediction modelling developed is accelerating the translational progress from protein biology to drug discovery and to novel therapies.&lt;/p&gt;&lt;p&gt;The dynamic changes in protein stereo-folding and structure determine the biochemical nature and function of proteostasis. Mutations in amino acids or abnormal alterations in stereo-folding along the protein chain can cause structural instability and dysfunction, representing critical factors that influence the quality of proteostasis. These elements highlight a dynamic protein folding continuum shaped by the microenvironment (Figure 1A). The significance of protein stereo-folding in clinical and translational medicine remains underestimated and further exploration is required, as the complex three-dimensional structure of individual proteins has historically been difficult to be characterised because of challenges in identifying stere","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467487","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":"Thromboinflammatory biomarkers in obstetric pathophysiology: Predictive insights into placental insufficiency and feto-maternal adverse outcomes","authors":"Emmanuel Ifeanyi Obeagu","doi":"10.1002/ctd2.70175","DOIUrl":"https://doi.org/10.1002/ctd2.70175","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Placental insufficiency is a key pathological process underlying major obstetric complications, including pre-eclampsia, fetal growth restriction (FGR), placental abruption, recurrent pregnancy loss, preterm birth and stillbirth. Emerging evidence identifies thromboinflammation—the interplay between coagulation, inflammation, endothelial dysfunction, platelet activation and complement pathways—as a central contributor to these adverse outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To critically evaluate the current evidence on thromboinflammatory biomarkers associated with placental insufficiency and adverse feto-maternal outcomes, emphasising their biological relevance, predictive value and clinical applicability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A narrative review of literature from PubMed, Scopus, Web of Science, Embase and Google Scholar was conducted. Priority was given to systematic reviews, meta-analyses, prospective studies and international guidelines. Evidence on coagulation, inflammatory, angiogenic, endothelial, complement and emerging molecular biomarkers was synthesised.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among available biomarkers, the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio demonstrates the strongest clinical utility for predicting and managing placental dysfunction and pre-eclampsia. Conventional markers, including D-dimer, fibrinogen, platelet indices, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, provide additional prognostic information, but show variable predictive performance. Emerging biomarkers such as neutrophil extracellular traps, extracellular vesicles, complement activation products, cell-free DNA and circulating microRNAs offer mechanistic insights but remain investigational due to limited standardisation and validation. Multimarker approaches appear superior to individual biomarkers for risk prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Thromboinflammatory biomarkers provide valuable insights into placental dysfunction and adverse pregnancy outcomes. While angiogenic biomarkers currently have the greatest clinical utility, integrated multimarker models may enhance future precision obstetric care. Further large-scale validation studies are required for clinical translation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148466925","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":"From scarring to healing: Emerging regenerative therapies for pulmonary fibrosis using MSCs and exosomes","authors":"Hajar Nasiri,&nbsp;Farbod Khosravi,&nbsp;Fatemeh Eskandari,&nbsp;Tahereh Manoochehrabadi,&nbsp;Ali Samadikuchaksaraei,&nbsp;Ehsan Lotfi,&nbsp;Jila Majidi,&nbsp;Fatemeh Rafati,&nbsp;Zeynab Ghorbani","doi":"10.1002/ctd2.70172","DOIUrl":"https://doi.org/10.1002/ctd2.70172","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pulmonary fibrosis is a progressive and often fatal disease featuring the disruption of lung architecture by excessive extracellular matrix deposition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>Mesenchymal stem cells (MSCs) have strong immunomodulatory, anti-inflammatory and regenerative capacities that enable them to restore lung function through the targeting of key fibrotic mechanisms. Their migration into sites of injury and interaction with immune and structural cells through cytokines and growth factors underlines their therapeutic value. Recently, exosomes derived from MSCs have emerged as a promising cell-free treatment option capable of crossing biological barriers and delivering anti-fibrotic molecules like miRNAs, siRNAs, and proteins directly to fibrotic tissues. These vesicles enhance therapeutic precision and safety compared with cell therapy. Despite challenges in standardization, large-scale production, and heterogeneity among MSCs sources, ongoing advances in biotechnology and clinical trial design are rapidly bridging the gap between preclinical promise and clinical application.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This present review discusses the pathogenesis and modelling of pulmonary fibrosis and underlines MSCs and exosome-based regenerative strategies as an effective and transforming approach in the future therapy of pulmonary fibrosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381159","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":"Microfluidic nanochips for rapid exosome isolation and multiplex biomarker profiling from a single blood drop: Toward sample-to-answer liquid biopsy","authors":"Daniel Ejim Uti,&nbsp;Esther Ugo Alum,&nbsp;Josephine E. Egbung,&nbsp;Waheeb Sami Aggad,&nbsp;Hailah M. Almohaimeed,&nbsp;Zuhair M. Mohammedsaleh,&nbsp;Manpreet Kaur,&nbsp;Kranti Kiran Reddy Ealla","doi":"10.1002/ctd2.70170","DOIUrl":"https://doi.org/10.1002/ctd2.70170","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Exosomes and other small extracellular vesicles carry molecular cargo that can reflect disease status, therapeutic response, and relapse dynamics. Currently, most exosome-analysis workflows are centralized, require milliliter-sized blood samples, involve extended isolation procedures, and depend on separate downstream assays. Single-drop microfluidic nanochips, which can process finger-prick blood volumes of approximately 1050 µL within a closed cartridge, offer a promising route toward integrated sample-to-answer liquid biopsy platforms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>These systems may integrate plasma handling, exosome enrichment, cargo access, multiplex biomarker detection, and algorithmic classification. This review highlights key on-chip enrichment techniques, including immunoaffinity, size selection, electrokinetic, acoustofluidic, and hybrid methods. It also discusses nano-biointerface designs that improve vesicle capture efficiency while reducing fouling and shear-induced vesicle damage. In addition, multiplex sensing architectures for optical, electrochemical, and plasmonic transduction are explored, with particular attention to challenges associated with whole-blood measurements, including anticoagulation, sample variability, platelet activation, viscosity, and hemolysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Single-drop exosome nanochips have the potential to transform liquid biopsy by enabling rapid, low-volume, integrated analysis of extracellular vesicles. However, successful clinical translation will require clear validation requirements, standardized reporting expectations, and defined use-case roadmaps for screening, disease monitoring, and therapeutic-response assessment. Establishing realistic performance standards and robust engineering parameters will be essential for making single-lab exosome nanochip platforms reproducible and clinically applicable.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381139","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":"TCF/LEF family transcription factors: Molecular landscape and prognostic scoring in pan-cancer","authors":"Zhengjun Yang,&nbsp;D. Q. Cai,&nbsp;Zhen Zhao,&nbsp;Zhixiang Jian,&nbsp;Mude Shi,&nbsp;Yajin Chen,&nbsp;Jueming Chen,&nbsp;Chunhua Qu,&nbsp;Diankui Cai","doi":"10.1002/ctd2.70168","DOIUrl":"https://doi.org/10.1002/ctd2.70168","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>TCF/LEF transcription factors (TFs) are indispensable for canonical Wnt signal transduction, acting through the recruitment of β-catenin and its co-activators to Wnt response elements at target gene promoters. Dysregulation of TCF/LEF family TFs is implicated in various cancers, yet their comprehensive molecular landscape and prognostic implications across cancers remain incompletely characterised.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed data from The Cancer Genome Atlas and GTEx databases to assess the expression patterns and correlations of four TCF/LEF family TFs (TCF1/TCF7, LEF1, TCF7L1 and TCF7L2) across 33 cancer types, validating findings in tumour cell lines using the CCLE database. We conducted a systematic characterisation of the molecular landscape, encompassing copy number alterations, somatic mutations and DNA methylation patterns. In parallel, we built molecular regulatory networks leveraging motif‒TF relationships and mRNA‒miRNA interactions. Using gene set variation analysis, we calculated TCF/LEF scores and stratified pan-cancer samples into high-score (<i>H</i>-score) and low-score (<i>L</i>-score) subgroups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Functional enrichment analysis confirmed the previously reported significant positive correlation between TCF/LEF gene expression and Wnt/β-catenin signalling, as well as pathways involved in cell differentiation and development. Immune infiltration analysis showed strong associations between TCF/LEF scores and specific immune subsets: positive correlations with CAFs, NKT, MAIT, CD4 T cells (naïve and regulatory subtypes), dendritic cells (various subsets), B cells (naïve) and Tfh cells; and negative correlations with Th1, Th17, pDC, pro-B cells, M2 macrophages, neutrophils and NK cells. We also examined seven metabolic features and uncovered significant associations between TCF/LEF scores and metabolic reprogramming. Drug sensitivity analysis using the CellMiner database and connectivity map identified potential compounds targeting the TCF/LEF score. Prognostic analysis demonstrated the efficacy of the TCF/LEF score in predicting patient survival (overall survival or progression-free interval). We also constructed a THYM-specific nomogram for prognostic prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, we developed a TCF/LEF family TF-based pan-cancer transcriptomic signature with promising potential for predicting prognosis and therapeutic response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300128","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":"Identification of immune-infiltrated and stroma-enriched subtypes in HER2+ breast cancer","authors":"Ying Yang,&nbsp;Wei Zeng,&nbsp;Xin Wei,&nbsp;Juan Li,&nbsp;Xuelian Chen,&nbsp;Zuyi Zhou,&nbsp;Bo Yang,&nbsp;Jie Li,&nbsp;Li Li","doi":"10.1002/ctd2.70169","DOIUrl":"https://doi.org/10.1002/ctd2.70169","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits substantial biological heterogeneity, yet the diversity of its tumour immune microenvironment has not been fully characterised. This study aimed to systematically define immune–stromal variation within HER2+ breast cancer and explore its prognostic relevance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Transcriptomic and clinical data from The Cancer Genome Atlas Breast Invasive Carcinoma cohort (TCGA-BRCA) and four Gene Expression Omnibus (GEO) cohorts were integrated. Immune and stromal infiltration was quantified using single-sample gene set enrichment analysis, MCP-counter and Estimation of STromal and Immune cells in MAlignant Tumour tissues using Expression data (ESTIMATE). Consensus clustering was performed to identify microenvironmental subtypes. Survival analysis and weighted gene co-expression network analysis were further conducted to evaluate subtype-specific prognostic features and hub genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Five microenvironmental subtypes were identified. Among them, an immune-infiltrated subtype (C3) and a stroma-dominant subtype (C2) emerged as the major phenotypes. Cluster C3 showed high infiltration of adaptive and innate immune cells and enrichment of chemotaxis- and cytokine-related pathways, suggesting robust immune activation. In contrast, cluster C2 was characterised by increased fibroblast and endothelial cell infiltration, together with strong activation of extracellular matrix (ECM) organisation and collagen remodelling pathways. Survival analyses across TCGA-BRCA and GEO cohorts showed that the immune-infiltrated subtype had better disease-free survival, progression-free survival and overall survival than the stroma-enriched subtype. Weighted gene co-expression network analysis identified an immune activation-related MEblue module associated with C3 and an ECM-remodelling MEturquoise module associated with C2, each containing subtype-specific hub genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings reveal clinically meaningful immune–stromal heterogeneity within HER2+ breast cancer and support microenvironment-based stratification for improved prognostic assessment and therapeutic decision making.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282428","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":"Integrating a methylation-based liquid biopsy into early liver cancer diagnostic pathways: Clinical insights from a trial","authors":"Jie Zhao,&nbsp;Shuangzhen Gu,&nbsp;Zhen Wu,&nbsp;Xiaoliang Han","doi":"10.1002/ctd2.70167","DOIUrl":"https://doi.org/10.1002/ctd2.70167","url":null,"abstract":"&lt;p&gt;Primary liver cancer is a major global health challenge and ranks as one of the top causes of cancer-related deaths, with recent estimates indicating that it is the third leading cause of cancer mortality worldwide.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Hepatocellular carcinoma (HCC) accounts for the vast majority of primary liver cancers. Its aetiologies are mainly divided into two categories: (1) metabolic liver diseases driven by risk factors such as alcohol abuse and obesity; (2) chronic viral hepatitis, particularly chronic hepatitis B virus (HBV) infection, which progresses over time to liver fibrosis, cirrhosis, and ultimately HCC.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Patients with these high-risk conditions are recommended to undergo regular surveillance, typically referred to as high-risk population screening, using serum alpha-fetoprotein (AFP) testing combined with abdominal ultrasonography every 6 months, with dynamic contrast-enhanced computed tomography or magnetic resonance imaging reserved for individuals with positive ultrasound findings or elevated AFP.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, ultrasound plus AFP has suboptimal sensitivity (approximately 60%–70%), highlighting the urgent need for more accurate tools for the early diagnosis of liver cancer.&lt;/p&gt;&lt;p&gt;Building on these considerations, a translational and clinical study we involved developed a blood-based cell-free DNA methylation assay, the liver cancer-hypermethylated markers-combined (LC-HMC) model, incorporating three liver cancer-specific markers, RNF135, CHFR, and PAX5.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Using a systematic multi-cohort discovery pipeline and validation in a prospective multicentre trial, the model achieved excellent diagnostic performance for liver cancer (94.43% sensitivity and 95.16% specificity), with particularly strong sensitivity for stage I disease (93.10%). Notably, it maintained high sensitivity and specificity across challenging clinical trial settings, including high-proportioned stage-I patients in the case group, HBV/ hepatitis C virus (HCV) infections and cirrhosis in the control group, and samples with other cancer interference.&lt;/p&gt;&lt;p&gt;Of particular note is the trial's dual-cohort strategy: a retrospective “Diagnosed” group and a prospective “Diagnosing” group. The former was used to confirm the effectiveness of the methylation-based diagnostic model, whereas the latter was designed to simulate real-world clinical scenarios in which the diagnosis was initially unknown. The “Diagnosing” group enrolled both asymptomatic high-risk surveillance individuals and patients presenting with suspected symptoms, with an overall ratio of approximately 1.5:1, which increased to about 2.7:1 among patients with stage-I liver cancer.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Asymptomatic high-risk individuals—primarily those with chronic HBV/HCV infection or cirrhosis—constitute the majority of incident liver cancer cases,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and are therefore expected to represent the main source o","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"6 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282165","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}