Bei Xu, Lili Ji, Hao Pang, Luya Cheng, Yanxia Zhan, Pu Chen, Hao Chen, Jie Cheng, Yunfeng Cheng
Background
Primary immune thrombocytopenia (ITP) is the most common bleeding disorder in hematological diseases, characterized by platelet count decrease in peripheral blood and higher risk of bleeding. Thrombopoietin receptor agonist (TPO-RA) is widely used as preferred second-line agent for patients with ITP. However, to date there are no predictors for its efficacy evaluation, combination therapy necessities, or tapering off opportunities.
Methods
The study enrolled 27 ITP patients, 27 normal controls and 15 chemotherapy-induced thrombocytopenia patients to examine the prognostic role of mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR) in TPO-RA treatment.
Results
The results revealed that MPV increased in ITP patients prior to the TPO-RA treatment and decreased in patients with good response after the treatment. NLR was higher in ITP patients both before and after TPO-RA treatment.
Conclusion
In patients with TPO-RA maintenance, MPV combined with NLR could predict the platelet count improvement of ITP patients.
{"title":"Platelet volume could predict the efficacy of thrombopoietin receptor agonists in the treatment of patients with primary immune thrombocytopenia","authors":"Bei Xu, Lili Ji, Hao Pang, Luya Cheng, Yanxia Zhan, Pu Chen, Hao Chen, Jie Cheng, Yunfeng Cheng","doi":"10.1002/ctd2.70096","DOIUrl":"https://doi.org/10.1002/ctd2.70096","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Primary immune thrombocytopenia (ITP) is the most common bleeding disorder in hematological diseases, characterized by platelet count decrease in peripheral blood and higher risk of bleeding. Thrombopoietin receptor agonist (TPO-RA) is widely used as preferred second-line agent for patients with ITP. However, to date there are no predictors for its efficacy evaluation, combination therapy necessities, or tapering off opportunities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study enrolled 27 ITP patients, 27 normal controls and 15 chemotherapy-induced thrombocytopenia patients to examine the prognostic role of mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR) in TPO-RA treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results revealed that MPV increased in ITP patients prior to the TPO-RA treatment and decreased in patients with good response after the treatment. NLR was higher in ITP patients both before and after TPO-RA treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In patients with TPO-RA maintenance, MPV combined with NLR could predict the platelet count improvement of ITP patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145750739","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}
This commentary discusses the important study by Wang et al. on how tumor matrix stiffness drives radiotherapy resistance in hepatocellular carcinoma (HCC). The key breakthrough of this research lies in the discovery that the metabolic enzyme PFKFB3 undergoes nuclear translocation under mechanical stimulation and directly binds to the DNA repair protein Ku70. These findings not only highlight the contribution of matrix rigidity in the tumor microenvironment to HCC growth and DNA damage repair but also reveal a previously unrecognized non-metabolic function of PFKFB3, thereby extending its functional scope from classical glycolytic regulation to direct maintenance of genomic stability. In our view, this discovery holds significant paradigm-shifting importance, enriching the understanding of mechanical signaling in tumor biology and providing a mechanistic explanation for the adaptive survival of tumors.
{"title":"PFKFB3 drives hepatocellular carcinoma growth and radiotherapy resistance under matrix mechanical forces","authors":"Haixia Gu, Ming Yang, Rishang Lu, Cheng Zhang","doi":"10.1002/ctd2.70108","DOIUrl":"https://doi.org/10.1002/ctd2.70108","url":null,"abstract":"<p>This commentary discusses the important study by Wang et al. on how tumor matrix stiffness drives radiotherapy resistance in hepatocellular carcinoma (HCC). The key breakthrough of this research lies in the discovery that the metabolic enzyme PFKFB3 undergoes nuclear translocation under mechanical stimulation and directly binds to the DNA repair protein Ku70. These findings not only highlight the contribution of matrix rigidity in the tumor microenvironment to HCC growth and DNA damage repair but also reveal a previously unrecognized non-metabolic function of PFKFB3, thereby extending its functional scope from classical glycolytic regulation to direct maintenance of genomic stability. In our view, this discovery holds significant paradigm-shifting importance, enriching the understanding of mechanical signaling in tumor biology and providing a mechanistic explanation for the adaptive survival of tumors.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695040","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}
Li Ma, Ming-yang Wu, Cui-cui Tian, Hao-ze Shi, Dan Song
Background
Glucose metabolic reprogramming is a hallmark of cancer, best exemplified by the Warburg effect. It plays a central role in driving tumour growth, metastasis and resistance to therapy.
Main Findings
This review systematically delineates the molecular underpinnings of this metabolic shift, encompassing the roles of key glycolytic enzymes, transporters, oncogenic signalling pathways and multilayered epigenetic regulation. We further propose a novel framework that conceptualizes glucose metabolism as an integrated system for signal transduction and niche engineering, which remodels the tumour microenvironment to promote immunosuppression.
Translational Significance
Finally, we highlight the translational applications of these insights, including metabolic imaging for diagnosis and prognosis and therapeutic strategies targeting glycolytic pathways, applied both as monotherapies and in rational combinations with conventional and emerging treatments.
Conclusion
Targeting glucose metabolic reprogramming offers a promising perspective and novel strategies for cancer diagnosis and therapy.
{"title":"Mechanisms, impacts and therapeutic strategies of glucose metabolic reprogramming in tumours","authors":"Li Ma, Ming-yang Wu, Cui-cui Tian, Hao-ze Shi, Dan Song","doi":"10.1002/ctd2.70100","DOIUrl":"https://doi.org/10.1002/ctd2.70100","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Glucose metabolic reprogramming is a hallmark of cancer, best exemplified by the Warburg effect. It plays a central role in driving tumour growth, metastasis and resistance to therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Findings</h3>\u0000 \u0000 <p>This review systematically delineates the molecular underpinnings of this metabolic shift, encompassing the roles of key glycolytic enzymes, transporters, oncogenic signalling pathways and multilayered epigenetic regulation. We further propose a novel framework that conceptualizes glucose metabolism as an integrated system for signal transduction and niche engineering, which remodels the tumour microenvironment to promote immunosuppression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Translational Significance</h3>\u0000 \u0000 <p>Finally, we highlight the translational applications of these insights, including metabolic imaging for diagnosis and prognosis and therapeutic strategies targeting glycolytic pathways, applied both as monotherapies and in rational combinations with conventional and emerging treatments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Targeting glucose metabolic reprogramming offers a promising perspective and novel strategies for cancer diagnosis and therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695109","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}
Wanxin Duan, Mingjie Wang, Yifei Liu, Celine Desoyer, Christian Baumgartner, Xiangdong Wang
Precision medicine has evolved through distinct phases, from the origins of the Human Genome Project to mutation-based targeted therapies. This editorial posits that ‘stereological cell biomedicine’ could be a new approach promoting the development of the next generation of precision medicine. This emerging discipline transitions the focus from genomic data to the multi-dimensional and spatiotemporal complexity of single cells. Driven by advances in Stereo single-cell multi-omics (Stereo Cell-seq), spatial transcriptomics (Stereo-seq) and single-cell surfaceomics (sc-surfaceome), this approach aims to capture the stereologically dynamic interactions between organelles within a cell and between cells in the tissue. We argue that understanding the spatiotemporal location of molecules, particularly protein interactions at organelle interfaces and on the cell surface, is as critical as their abundance for defining cellular function in health and disease. Integrating these high-resolution measurements with artificial intelligence and computational modelling will bridge the gap between advanced omics and pathology. Initiatives such as the newly established European Stereo Cell Center signal a global shift towards this new paradigm, which promises to unlock novel diagnostic biomarkers and therapeutic targets for truly multi-factorial and dynamic precision medicine.
{"title":"Stereo cell: A new approach to the next generation of clinical precision medicine","authors":"Wanxin Duan, Mingjie Wang, Yifei Liu, Celine Desoyer, Christian Baumgartner, Xiangdong Wang","doi":"10.1002/ctd2.70105","DOIUrl":"https://doi.org/10.1002/ctd2.70105","url":null,"abstract":"<p>Precision medicine has evolved through distinct phases, from the origins of the Human Genome Project to mutation-based targeted therapies. This editorial posits that ‘stereological cell biomedicine’ could be a new approach promoting the development of the next generation of precision medicine. This emerging discipline transitions the focus from genomic data to the multi-dimensional and spatiotemporal complexity of single cells. Driven by advances in Stereo single-cell multi-omics (Stereo Cell-seq), spatial transcriptomics (Stereo-seq) and single-cell surfaceomics (sc-surfaceome), this approach aims to capture the stereologically dynamic interactions between organelles within a cell and between cells in the tissue. We argue that understanding the spatiotemporal location of molecules, particularly protein interactions at organelle interfaces and on the cell surface, is as critical as their abundance for defining cellular function in health and disease. Integrating these high-resolution measurements with artificial intelligence and computational modelling will bridge the gap between advanced omics and pathology. Initiatives such as the newly established European Stereo Cell Center signal a global shift towards this new paradigm, which promises to unlock novel diagnostic biomarkers and therapeutic targets for truly multi-factorial and dynamic precision medicine.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626693","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}
Kewei Ma, Guanqi Shi, Xiao Li, Wanwei Zheng, Zhongguang Luo
Gastric cancer continues to be a major threat to global health, accounting for a significant number of cancer deaths annually, with precancerous lesions representing critical intervention windows to halt malignant progression. Current risk stratification for malignant transformation in gastric precancerous lesions relies heavily on invasive endoscopic and histopathological assessments, which lack precision in quantifying individual transformation risk. Recent research points to the significance of epigenetic dysregulation in driving the evolution of gastric precancerous lesions: DNA methylation, 5-hydroxymethylcytosine, non-coding RNAs, RNA editing and modifications. Integrating multi-omics epigenetic signatures offers a transformative approach to refining risk stratification, guiding personalised surveillance intervals and therapeutic interventions. Future efforts should prioritise large-scale clinical validation of epigenetic biomarkers, standardisation of detection technologies, and development of cost-effective, non-invasive platforms to bridge mechanistic insights into precision prevention strategies for gastric carcinogenesis.
{"title":"Epigenetic dynamics in gastric cancer precancerous lesions: From molecular mechanisms to precision risk stratification","authors":"Kewei Ma, Guanqi Shi, Xiao Li, Wanwei Zheng, Zhongguang Luo","doi":"10.1002/ctd2.70102","DOIUrl":"https://doi.org/10.1002/ctd2.70102","url":null,"abstract":"<p>Gastric cancer continues to be a major threat to global health, accounting for a significant number of cancer deaths annually, with precancerous lesions representing critical intervention windows to halt malignant progression. Current risk stratification for malignant transformation in gastric precancerous lesions relies heavily on invasive endoscopic and histopathological assessments, which lack precision in quantifying individual transformation risk. Recent research points to the significance of epigenetic dysregulation in driving the evolution of gastric precancerous lesions: DNA methylation, 5-hydroxymethylcytosine, non-coding RNAs, RNA editing and modifications. Integrating multi-omics epigenetic signatures offers a transformative approach to refining risk stratification, guiding personalised surveillance intervals and therapeutic interventions. Future efforts should prioritise large-scale clinical validation of epigenetic biomarkers, standardisation of detection technologies, and development of cost-effective, non-invasive platforms to bridge mechanistic insights into precision prevention strategies for gastric carcinogenesis.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626194","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}
Kristian M. Hargadon, Balázs Györffy, James B. Wall
Background
The forkhead box family transcription factor FOXC2 has emerged as an important oncogene in cancers of epithelial origin, where it has been associated with several hallmarks of cancer progression. In this study, we provide clinical evidence of a role for FOXC2 in the progression of melanoma. Using bioinformatics-based approaches, we aimed to gain insight into the oncogenic functions of this transcription factor in this cancer of non-epithelial origin.
Methods
We investigated multiple RNA-sequencing datasets from biopsies of independent melanoma patient cohorts to identify genes whose expression correlated with that of the FOXC2 gene. These data were analysed using topology-based Impact Pathway and high-specificity pruning Gene Ontology approaches.
Results
We identified novel biologic pathways and processes significantly impacted by FOXC2-correlated genes, including those related to Rap1 signalling and collagen fibril organisation. For these novel pathways/processes, as well as others previously linked with the activity of FOXC2, our study also revealed specific FOXC2-correlated genes associated with these biological phenomena.
Conclusions
Together, our data offer novel insights into the oncogenic functions of FOXC2 in melanoma and other cancers.
{"title":"Impact pathway and gene ontology analyses of FOXC2-correlated genes in melanoma reveal a role for the FOXC2 transcription factor in several oncogenic pathways and processes","authors":"Kristian M. Hargadon, Balázs Györffy, James B. Wall","doi":"10.1002/ctd2.70104","DOIUrl":"https://doi.org/10.1002/ctd2.70104","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The forkhead box family transcription factor FOXC2 has emerged as an important oncogene in cancers of epithelial origin, where it has been associated with several hallmarks of cancer progression. In this study, we provide clinical evidence of a role for FOXC2 in the progression of melanoma. Using bioinformatics-based approaches, we aimed to gain insight into the oncogenic functions of this transcription factor in this cancer of non-epithelial origin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated multiple RNA-sequencing datasets from biopsies of independent melanoma patient cohorts to identify genes whose expression correlated with that of the <i>FOXC2</i> gene. These data were analysed using topology-based Impact Pathway and high-specificity pruning Gene Ontology approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified novel biologic pathways and processes significantly impacted by <i>FOXC2</i>-correlated genes, including those related to Rap1 signalling and collagen fibril organisation. For these novel pathways/processes, as well as others previously linked with the activity of FOXC2, our study also revealed specific <i>FOXC2</i>-correlated genes associated with these biological phenomena.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Together, our data offer novel insights into the oncogenic functions of FOXC2 in melanoma and other cancers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572077","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}
Peng-Fei Wang, Shi-Han Mu, Fang Jin, Bing-Dong Sui
<div> <section> <h3> Background</h3> <p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease posing a growing global health burden. Current therapies face safety concerns and fail to induce mucosal healing. Mesenchymal stem cell (MSC) therapy has emerged as a promising alternative due to its immunomodulatory and regenerative properties. However, its integration into precision medicine paradigms remains challenging.</p> </section> <section> <h3> Methods</h3> <p>This review examines the key challenges hindering the clinical translation of MSC therapy for UC and proposes innovative strategies to optimize this cell-based modality. The analysis is based on a systematic evaluation of the current literature, encompassing the biological properties of MSCs, preclinical studies, clinical trial data, biomanufacturing processes, and emerging technological platforms.</p> </section> <section> <h3> Results</h3> <p>Our analysis identifies key barriers to precision MSC therapy across biomanufacturing, clinical translation, and mechanistic understanding. To address these challenges, we propose a strategic framework that progresses from challenge identification to developing biological strategies for enhancing MSC potency and homing, streamlining therapeutic workflows, and integrating intelligent systems.</p> </section> <section> <h3> Conclusion</h3> <p>As a viable therapy for UC, MSC therapy faces significant challenges within the precision medicine paradigm. The convergence of novel approaches with artificial intelligence (AI) is paving the way for precision frameworks, and their rigorous validation through clinical trials will be crucial to delivering reliable, patient-specific therapies.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li> <p>Overviews key challenges and innovative strategies in MSC therapy for UC within a precision medicine framework.</p> </li> <li> <p>Examines barriers in MSC biomanufacturing, clinical translation, and host microenvironment adaptation.</p> </li> <li> <p>Highlights emerging approaches, encompassing pharmacological preconditioning, 3D culture, cellular engineering, and advanced delivery platforms to enhance MSC potency and homing.</p>
{"title":"Mesenchymal stem cell therapy for ulcerative colitis: Opportunities and challenges in precision medicine","authors":"Peng-Fei Wang, Shi-Han Mu, Fang Jin, Bing-Dong Sui","doi":"10.1002/ctd2.70101","DOIUrl":"https://doi.org/10.1002/ctd2.70101","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease posing a growing global health burden. Current therapies face safety concerns and fail to induce mucosal healing. Mesenchymal stem cell (MSC) therapy has emerged as a promising alternative due to its immunomodulatory and regenerative properties. However, its integration into precision medicine paradigms remains challenging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review examines the key challenges hindering the clinical translation of MSC therapy for UC and proposes innovative strategies to optimize this cell-based modality. The analysis is based on a systematic evaluation of the current literature, encompassing the biological properties of MSCs, preclinical studies, clinical trial data, biomanufacturing processes, and emerging technological platforms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our analysis identifies key barriers to precision MSC therapy across biomanufacturing, clinical translation, and mechanistic understanding. To address these challenges, we propose a strategic framework that progresses from challenge identification to developing biological strategies for enhancing MSC potency and homing, streamlining therapeutic workflows, and integrating intelligent systems.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>As a viable therapy for UC, MSC therapy faces significant challenges within the precision medicine paradigm. The convergence of novel approaches with artificial intelligence (AI) is paving the way for precision frameworks, and their rigorous validation through clinical trials will be crucial to delivering reliable, patient-specific therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Overviews key challenges and innovative strategies in MSC therapy for UC within a precision medicine framework.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Examines barriers in MSC biomanufacturing, clinical translation, and host microenvironment adaptation.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Highlights emerging approaches, encompassing pharmacological preconditioning, 3D culture, cellular engineering, and advanced delivery platforms to enhance MSC potency and homing.</p>\u0000 ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530030","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}
<p>The maternal-foetal interface represents a remarkably unique and highly dynamic immune microenvironment, in which the multiple cellular interactions explain a fundamental biological paradox: how to establish and maintain immune tolerance toward the semi-allogeneic foetus—which expresses paternal antigens—while preserving the capacity for effective immune defence against pathogens, thereby ensuring a successful pregnancy.<span><sup>1</sup></span> This equilibrium is not merely a state of immune suppression, but rather the outcome of proactive, orderly, and finely tuned immunoregulatory processes. Dysregulation of this balance is closely associated with various pregnancy complications, such as recurrent pregnancy loss (RPL), preeclampsia, foetal growth restriction, preterm birth and other conditions.<span><sup>1</sup></span></p><p>The establishment and maintenance of this distinctive immune-tolerant milieu rely on intricate and coordinated interactions among diverse uterine immune cells—such as decidual natural killer cells (dNKs), decidual macrophages (dMφs), regulatory T cells (Tregs) and dendritic cells (DCs)—and non-immune cells, including trophoblasts and decidual stromal cells. Together, these players form a functionally complementary network that supports pregnancy.<span><sup>1</sup></span></p><p>Among uterine immune cells, dNKs constitute the most abundant population during early pregnancy. Unlike their peripheral blood counterparts, which are predominantly CD56<sup>dim</sup>CD16<sup>+</sup> and highly cytotoxic, dNKs display a unique phenotype: they are mainly CD56<sup>bright</sup>CD16<sup>–</sup>, exhibit lower cytotoxicity, and possess robust secretory activity, with abundant cytoplasmic granules containing granzymes and perforins.<span><sup>2</sup></span> Numerous studies have revealed the crucial roles of dNKs in interacting with trophoblasts and various immune cells to embody both supervisory and supportive functions at the maternal-foetal interface. Recent single-cell transcriptomic studies have further delineated five functionally distinct dNK subsets (dNKp, dNK1–dNK4) in human early pregnancy decidua.<span><sup>3, 4</sup></span> Among these, the CD56⁺CD39⁺ dNK1 subset shows high expression of genes associated with immune tolerance and trophoblast invasion, such as <i>KIR2DL1</i>, <i>LILRB1</i> and <i>CSF1</i> (which encodes macrophage colony-stimulating factor [M-CSF]). In RPL patients, however, the proportion of the dNK1 subset is markedly reduced, with concomitant expansion of the pro-inflammatory CD56⁺CD16⁺ dNK4 subset, alongside a shift in macrophages and T cells toward inflammatory phenotypes.<span><sup>3</sup></span> Follow-up studies using humanized NOG (NOD/Shi-<i>scid</i>/IL-2Rγ<sup>null</sup>) mouse models confirmed the functional importance of human dNK1 cells in promoting trophoblast differentiation along both invasive and syncytial pathways primarily through cytokine production, including M-CSF, and thereby supporti
{"title":"Guardians and guides: The dual roles of immune cells in maintaining homeostasis at the maternal-foetal interface","authors":"Xiao Fang, Yang Hu, Yan-Ling Wang, Xuan Shao","doi":"10.1002/ctd2.70103","DOIUrl":"https://doi.org/10.1002/ctd2.70103","url":null,"abstract":"<p>The maternal-foetal interface represents a remarkably unique and highly dynamic immune microenvironment, in which the multiple cellular interactions explain a fundamental biological paradox: how to establish and maintain immune tolerance toward the semi-allogeneic foetus—which expresses paternal antigens—while preserving the capacity for effective immune defence against pathogens, thereby ensuring a successful pregnancy.<span><sup>1</sup></span> This equilibrium is not merely a state of immune suppression, but rather the outcome of proactive, orderly, and finely tuned immunoregulatory processes. Dysregulation of this balance is closely associated with various pregnancy complications, such as recurrent pregnancy loss (RPL), preeclampsia, foetal growth restriction, preterm birth and other conditions.<span><sup>1</sup></span></p><p>The establishment and maintenance of this distinctive immune-tolerant milieu rely on intricate and coordinated interactions among diverse uterine immune cells—such as decidual natural killer cells (dNKs), decidual macrophages (dMφs), regulatory T cells (Tregs) and dendritic cells (DCs)—and non-immune cells, including trophoblasts and decidual stromal cells. Together, these players form a functionally complementary network that supports pregnancy.<span><sup>1</sup></span></p><p>Among uterine immune cells, dNKs constitute the most abundant population during early pregnancy. Unlike their peripheral blood counterparts, which are predominantly CD56<sup>dim</sup>CD16<sup>+</sup> and highly cytotoxic, dNKs display a unique phenotype: they are mainly CD56<sup>bright</sup>CD16<sup>–</sup>, exhibit lower cytotoxicity, and possess robust secretory activity, with abundant cytoplasmic granules containing granzymes and perforins.<span><sup>2</sup></span> Numerous studies have revealed the crucial roles of dNKs in interacting with trophoblasts and various immune cells to embody both supervisory and supportive functions at the maternal-foetal interface. Recent single-cell transcriptomic studies have further delineated five functionally distinct dNK subsets (dNKp, dNK1–dNK4) in human early pregnancy decidua.<span><sup>3, 4</sup></span> Among these, the CD56⁺CD39⁺ dNK1 subset shows high expression of genes associated with immune tolerance and trophoblast invasion, such as <i>KIR2DL1</i>, <i>LILRB1</i> and <i>CSF1</i> (which encodes macrophage colony-stimulating factor [M-CSF]). In RPL patients, however, the proportion of the dNK1 subset is markedly reduced, with concomitant expansion of the pro-inflammatory CD56⁺CD16⁺ dNK4 subset, alongside a shift in macrophages and T cells toward inflammatory phenotypes.<span><sup>3</sup></span> Follow-up studies using humanized NOG (NOD/Shi-<i>scid</i>/IL-2Rγ<sup>null</sup>) mouse models confirmed the functional importance of human dNK1 cells in promoting trophoblast differentiation along both invasive and syncytial pathways primarily through cytokine production, including M-CSF, and thereby supporti","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530056","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}
Jishanth Mattumpuram, Muhammad Talha Maniya, Ayesha Noman, Craig Albert Luke Fernandes, Muhammad Faez Tahir, Rafay Khan, Mohammad Hamza, Vikash Jaiswal, Kamran Ali, Brijesh Sathian, Javed Iqbal, Asraf Hussain
Objective
We aimed to determine if omega-3 fatty acid (FA) supplementation significantly reduces cardiovascular (CV) events in patients with established CV disease or at high CV risk.
Methods
We conducted a comprehensive literature search on PubMed, Embase and Cochrane CENTRAL. The results of our analyses were presented as risk ratios (RRs) with 95% confidence intervals (CIs) and pooled using a random effects model. Meta-regression bubble plots were generated to visualise the results of the analysis, while the detailed results were tabulated. A p-value less than-.05 was considered significant in all cases.
Results
A total of 42 studies (176 253 participants) were included in our analysis. The pooled analysis demonstrates that omega-3 FA are associated with a significant reduction in CV mortality (p =-.02), CV disease (p =-.03), coronary heart disease (CHD) (p =-.007), myocardial infarction (MI) (p =-.008), fatal MI (p =-.0004) and revascularisation (p =-.003), and a significant increase in atrial fibrillation (p =-.01), and gastrointestinal (GI) adverse events (p =-.02). Subgroup analysis demonstrated a significant improvement with EPA monotherapy compared to EPA+DHA combination therapy in the risk of CV mortality (p = 0.01), CVD events (p <-.00001), MACE (p < .00001), CHD (p < .00001), MI (p <-.00001), fatal MI (p =-.004) and revascularisation (p <-.0001). EPA monotherapy was associated with a significant increase in the risk of atrial fibrillation (p =-.01). Regression analysis demonstrates a dose–response relationship between omega-3 FA (EPA or EPA+DHA) and CVD events (p =-.001), CHD (p =-.035), revascularisation (p =-.035) and ischemic stroke (p =-.003).
Conclusion
Our study demonstrated a significant reduction in the risk of cardiovascular outcomes with omega-3 FA administration.
{"title":"Effect of omega-3 fatty acids on cardiovascular disease risk: A systematic review and meta-analysis with meta-regression","authors":"Jishanth Mattumpuram, Muhammad Talha Maniya, Ayesha Noman, Craig Albert Luke Fernandes, Muhammad Faez Tahir, Rafay Khan, Mohammad Hamza, Vikash Jaiswal, Kamran Ali, Brijesh Sathian, Javed Iqbal, Asraf Hussain","doi":"10.1002/ctd2.70094","DOIUrl":"https://doi.org/10.1002/ctd2.70094","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We aimed to determine if omega-3 fatty acid (FA) supplementation significantly reduces cardiovascular (CV) events in patients with established CV disease or at high CV risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a comprehensive literature search on PubMed, Embase and Cochrane CENTRAL. The results of our analyses were presented as risk ratios (RRs) with 95% confidence intervals (CIs) and pooled using a random effects model. Meta-regression bubble plots were generated to visualise the results of the analysis, while the detailed results were tabulated. A <i>p</i>-value less than-.05 was considered significant in all cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 42 studies (176 253 participants) were included in our analysis. The pooled analysis demonstrates that omega-3 FA are associated with a significant reduction in CV mortality (<i>p</i> =-.02), CV disease (<i>p</i> =-.03), coronary heart disease (CHD) (<i>p</i> =-.007), myocardial infarction (MI) (<i>p</i> =-.008), fatal MI (<i>p</i> =-.0004) and revascularisation (<i>p</i> =-.003), and a significant increase in atrial fibrillation (<i>p</i> =-.01), and gastrointestinal (GI) adverse events (<i>p</i> =-.02). Subgroup analysis demonstrated a significant improvement with EPA monotherapy compared to EPA+DHA combination therapy in the risk of CV mortality (<i>p</i> = 0.01), CVD events (<i>p</i> <-.00001), MACE (<i>p</i> < .00001), CHD (<i>p</i> < .00001), MI (<i>p</i> <-.00001), fatal MI (<i>p</i> =-.004) and revascularisation (<i>p</i> <-.0001). EPA monotherapy was associated with a significant increase in the risk of atrial fibrillation (<i>p</i> =-.01). Regression analysis demonstrates a dose–response relationship between omega-3 FA (EPA or EPA+DHA) and CVD events (<i>p</i> =-.001), CHD (<i>p</i> =-.035), revascularisation (<i>p</i> =-.035) and ischemic stroke (<i>p</i> =-.003).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study demonstrated a significant reduction in the risk of cardiovascular outcomes with omega-3 FA administration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145529959","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}
Mohammed Elmujtba Adam Essa, Shahd Elbadri, Abdelkareem A. Ahmed, Hamid Noori
Background
The advent of cancer immunotherapy, particularly immune checkpoint inhibitors, has revolutionised the treatment landscape for many malignancies. However, a significant proportion of patients exhibit primary, adaptive, or acquired resistance to these therapies, limiting their broad clinical benefit. Tumour microenvironment (TME), a complex and dynamic ecosystem of cancer cells, immune cells, stromal cells and extracellular matrix, has emerged as a critical determinant of immunotherapy response and a major driver of resistance.
Main body
This review provides a comprehensive overview of the intricate mechanisms by which the TME fosters an immunosuppressive milieu, thereby impeding effective anti-tumour immunity. We delineate the key cellular and molecular components of the TME that contribute to immunotherapy resistance, including tumour-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and cancer-associated fibroblasts. We then discuss the diverse and innovative strategies being developed to reprogram the TME and overcome these resistance mechanisms. These emerging approaches include targeting immunosuppressive cell populations, modulating tumour metabolism, epigenetic reprogramming, normalising the tumour vasculature and employing engineered cell therapies such as chimeric antigen receptor T cells and oncolytic viruses. The potential of combination therapies to synergistically dismantle the immunosuppressive TME is also explored.
Conclusion
Reprogramming the TME represents a paradigm shift in cancer treatment, moving beyond direct tumour cell targeting to modulate the entire tumour ecosystem. While significant challenges remain, including TME heterogeneity and the need for predictive biomarkers, the strategies discussed herein hold immense promise for overcoming immunotherapy resistance and improving patient outcomes. A deeper understanding of the complex interplay between the tumour and its microenvironment will be crucial for the development of next-generation, personalised immunotherapeutic strategies.
{"title":"Reprogramming the tumour microenvironment: Emerging strategies to overcome immunotherapy resistance","authors":"Mohammed Elmujtba Adam Essa, Shahd Elbadri, Abdelkareem A. Ahmed, Hamid Noori","doi":"10.1002/ctd2.70098","DOIUrl":"https://doi.org/10.1002/ctd2.70098","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The advent of cancer immunotherapy, particularly immune checkpoint inhibitors, has revolutionised the treatment landscape for many malignancies. However, a significant proportion of patients exhibit primary, adaptive, or acquired resistance to these therapies, limiting their broad clinical benefit. Tumour microenvironment (TME), a complex and dynamic ecosystem of cancer cells, immune cells, stromal cells and extracellular matrix, has emerged as a critical determinant of immunotherapy response and a major driver of resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body</h3>\u0000 \u0000 <p>This review provides a comprehensive overview of the intricate mechanisms by which the TME fosters an immunosuppressive milieu, thereby impeding effective anti-tumour immunity. We delineate the key cellular and molecular components of the TME that contribute to immunotherapy resistance, including tumour-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and cancer-associated fibroblasts. We then discuss the diverse and innovative strategies being developed to reprogram the TME and overcome these resistance mechanisms. These emerging approaches include targeting immunosuppressive cell populations, modulating tumour metabolism, epigenetic reprogramming, normalising the tumour vasculature and employing engineered cell therapies such as chimeric antigen receptor T cells and oncolytic viruses. The potential of combination therapies to synergistically dismantle the immunosuppressive TME is also explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Reprogramming the TME represents a paradigm shift in cancer treatment, moving beyond direct tumour cell targeting to modulate the entire tumour ecosystem. While significant challenges remain, including TME heterogeneity and the need for predictive biomarkers, the strategies discussed herein hold immense promise for overcoming immunotherapy resistance and improving patient outcomes. A deeper understanding of the complex interplay between the tumour and its microenvironment will be crucial for the development of next-generation, personalised immunotherapeutic strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145529806","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}
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