Clinical and Translational Medicine最新文献

{"title":"Screening of candidate analgesics using a patient-derived human iPSC model of nociception identifies putative compounds for therapeutic treatment","authors":"Jack R. Thornton, Alberto Capurro, Sally Harwood, Thomas C Henderson, Adrienne Unsworth, Franziska Görtler, Sushma Nagaraja-Grellscheid, Vsevolod Telezhkin, Majlinda Lako, Evelyne Sernagor, Lyle Armstrong","doi":"10.1002/ctm2.70339","DOIUrl":"https://doi.org/10.1002/ctm2.70339","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>In this study, we applied an induced pluripotent stem cell (iPSC)-based model of inherited erythromelalgia (IEM) to screen a library of 281 small molecules, aiming to identify candidate pain-modulating compounds.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>Human iPSC-derived sensory neuron-like cells, which exhibit action potentials in response to noxious stimulation, were evaluated using whole-cell patch-clamp and microelectrode array (MEA) techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>Sensory neuron-like cells derived from individuals with IEM showed spontaneous electrical activity characteristic of genetic pain disorders. The drug screen identified four compounds (AZ106, AZ129, AZ037 and AZ237) that significantly decreased spontaneous firing with minimal toxicity. The calculated IC<sub>50</sub> values indicate the potential efficacy of these compounds. Electrophysiological analysis confirmed the compounds’ ability to reduce action potential generation in IEM patient-specific iPSC-derived sensory neuron-like cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and implications</h3>\u0000 \u0000 <p>Our screening approach demonstrates the reproducibility and effectiveness of human neuronal disease modelling offering a promising avenue for discovering new analgesics. These findings address a critical gap in current therapeutic strategies for both general and neuropathic pain, warranting further investigation. This study highlights the innovative use of patient-derived iPSC sensory neuronal models in pain research and emphasises the potential for personalised medicine in developing targeted analgesics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Utilisation of human iPSCs for efficient differentiation into sensory neuron-like cells offers a novel strategy for studying pain mechanisms.</li>\u0000 \u0000 <li>IEM sensory neuron-like cells exhibit key biomarkers and generate action potentials in response to noxious stimulation.</li>\u0000 \u0000 <li>IEM sensory neuron-like cells display spontaneous electrical activity, providing a relevant nociceptive model.</li>\u0000 \u0000 <li>Screening of 281 compounds identified four candidates that significantly reduced spontaneous firing with low cytotoxicity.</li>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD248 deficiency promotes angiotensin II-induced aortic lesion by attenuating receptor stability in smooth muscle cells","authors":"Tai-Tzu Hsieh, Ya-Chu Ku, Chu-Jen Chen, Cheng-Hsiang Kuo, Bi-Ing Chang, Chien-Hung Yu, Yi-Heng Li, Pei-Jane Tsai, Shu-Wha Lin, Hua-Lin Wu, Chwan-Yau Luo, Yau-Sheng Tsai","doi":"10.1002/ctm2.70352","DOIUrl":"https://doi.org/10.1002/ctm2.70352","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Abdominal aortic aneurysm (AAA) is characterized by progressive dilation of the abdominal aorta that has a high prevalence of death due to aortic rupture. The hallmark of AAA is severe degeneration of the aortic media with the loss of vascular smooth muscle cells (VSMCs), the main source of extracellular matrix (ECM) proteins. CD248 was originally implicated in angiogenesis and tumourigenesis, but its role in the development of AAA remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice lacking CD248 (<i>Cd248</i><sup>−/−</sup>) were generated and evaluated for angiotensin II (Ang II) and high-cholesterol diet feeding induced AAA. Loss-of-function approaches in A7r5 and C3H10T1/2 cells were used to study the involvement of CD248 in the Ang II signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CD248 expression was upregulated in the media and adventitia of patients and mice with aortic aneurysm. CD248 deficiency in mice exacerbates Ang II-induced aortic lesion along with severe disruption of elastic fibres and the VSMC layer. Interestingly, while compensatory ECM deposition was found in the aortic lesion of <i>Cd248</i><sup>−/−</sup> mice, collagen I content and p38 activation were significantly attenuated. Silencing of CD248 in VSMCs downregulated mitogen-activated protein kinase activation and ECM production. Loss of CD248 in VSMCs destabilized the membrane receptors for Ang II and platelet-derived growth factor (PDGF), and the C-terminal cytoplasmic domain of CD248 is apparently involved in this interaction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The findings reveal that CD248 regulates the stability of the membrane receptors for Ang II and PDGF in VSMCs to transduce signals for collagen production in combating the loss of aortic wall strength during vascular remodelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>CD248 reduces the occurrence of angiotensin II (Ang II)-induced aortic lesion by facilitating collagen production to provide load-bearing properties to the aortic wall.</li>\u0000 \u0000 <li>CD248 regulates the stability of the membrane receptors for Ang II and PDGF in VSMCs.</li>\u0000 \u0000 <li>The C-terminal cytoplasmic tail of CD248 is a crucial domain that potentially regulates the stability of Ang II and PDGF receptors.</li>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70352","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial metabolism mediates the deteriorative effects of sedentary behaviour on insulin resistance","authors":"Jingmeng Ju, Jialin He, Bingqi Ye, Siqi Li, Jiaqi Zhao, Wanlan Chen, Qi Zhang, Wanying Zhao, Jialu Yang, Ludi Liu, Yi Li, Min Xia, Yan Liu","doi":"10.1002/ctm2.70348","DOIUrl":"https://doi.org/10.1002/ctm2.70348","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Prolonged sedentary time is a strong risk factor for insulin resistance. Recent evidence indicates that gut microbiota may influence the regulation of insulin sensitivity and demonstrates a distinct profile between sedentary and physically active individuals. However, whether and how microbial metabolism mediates the progression of insulin resistance induced by prolonged sedentary time remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>560 male participants without hypoglycaemic therapy were included, and insulin resistance was evaluated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). The gut microbiota was identified through metagenomics, host genetic data were obtained using a genotyping array, and plasma metabolites were quantified by liquid chromatography mass spectrometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A panel of 15 sedentary-related species and 38 sedentary-associated metabolic capacities accounted for 31.68% and 21.48% of the sedentary time-related variation in HOMA-IR, respectively. Specifically, decreased <i>Roseburia</i> sp. <i>CAG:471</i>, <i>Intestinibacter bartlettii</i>, and <i>Firmicutes bacterium CAG:83</i>, but increased <i>Bacteroides xylanisolvens</i> related to longer sedentary time, were causally linked to the development of insulin resistance. Furthermore, integrative analysis with metabolomics identified reduced L-citrulline and L-serine, resulting from a suppression of arginine biosynthesis as key microbial effectors linking longer sedentary time to enhanced insulin resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, our findings provide insights into the mediating role of gut microbiota on the progression of insulin resistance induced by excessive sedentary time, and highlight the possibility of counteracting the detrimental effect of prolonged sedentary time on insulin resistance by microbiota-modifying interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Prolonged sedentary time leads to a depletion of <i>Roseburia</i> sp. <i>CAG:471</i> and <i>Firmicutes bacterium CAG:83</i>, and suppresses arginine biosynthesis.</li>\u0000 \u0000 <li>Decreased L-citrulline and L-serine function as key microbial effectors mediating the adverse effect of sedentary time on insulin sensitivity.</li>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VSIG4 Promotes Tumour-Associated Macrophage M2 Polarization and Immune Escape in Colorectal Cancer via Fatty Acid Oxidation Pathway","authors":"Jiafeng Liu, WenXin Zhang, Lu Chen, Xinhai Wang, Xiang Mao, Zimei Wu, Huanying Shi, Huijie Qi, Li Chen, Yuxin Huang, Jiyifan Li, Mingkang Zhong, Xiaojin Shi, Qunyi Li, Tianxiao Wang","doi":"10.1002/ctm2.70340","DOIUrl":"https://doi.org/10.1002/ctm2.70340","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>V-set and immunoglobulin domain containing 4 (VSIG4) is a B7-family-related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour-associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>THP-1 monocyte-derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co-culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin-bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR-γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Colorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la-METTL14-m6A axis.</p>\u0000 </l","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage C1q contributes to pulmonary fibrosis by disturbing the metabolism of alveolar epithelial cells","authors":"Fenja Prüfer, Beatrix Steer, Eva Kaufmann, Peter Wolf, Barbara Adler, Martina Korfei, Andreas Günther, Melanie Königshoff, Heiko Adler","doi":"10.1002/ctm2.70341","DOIUrl":"https://doi.org/10.1002/ctm2.70341","url":null,"abstract":"<p>Dear Editor,</p><p>Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease, driven primarily by damage and dysfunction of type-II alveolar epithelial cells (AECII). Since there is still no cure for IPF, new therapeutic approaches are desirable. In this study, we identified the complement component C1q as a source of disturbance of AECII metabolism.</p><p>When analyzing publicly available data,<span><sup>1</sup></span> we found that C1q mRNA expression is upregulated in IPF patients (Figure S1). Therefore, we analyzed bronchoalveolar lavage fluids (BALF) of IPF patients for the presence of C1qA. Compared to controls, significantly increased levels of C1qA were present in BALF of IPF patients (Figure 1A). To investigate the role of C1q in fibrosis development, we used a virus-induced mouse model of IPF.<span><sup>2</sup></span> First, we determined C1qA gene expression in lungs of both control (wild-type) and fibrosis-prone (interferon [IFN]-γR-/-) mice, analyzing uninfected mice and mice 14 days (acute inflammation phase), around 45 days (early fibrosis phase), and around 100 days (fibrosis phase) after infection with murine gammaherpesvirus 68 (MHV-68). C1qA was highly expressed in the acute inflammation phase in both mouse strains. It subsequently declined over time in wild-type mice whereas the decline was much less pronounced in IFN-γR-/- mice (Figure 1B). No differences were observed when comparing whole lung tissue protein levels (Figure 1C). However, mice with lung fibrosis (IFN-γR-/-) showed significantly elevated C1qA protein in BALF (Figure 1D). This was due to local production and secretion as in mice with increased C1qA in BALF (Figure S2A), C1qA in serum remained constant (Figure S2B). Higher C1qA gene expression in fibrotic mice was also observed in other fibrosis mouse models when analyzing publicly available data (Figure S3).</p><p>To determine the cellular source of C1q in the lung, we analyzed C1q gene expression in publicly available single-cell RNA sequencing data (Figure S4). In human lungs, macrophages are the main producers of C1qA, C1qB and C1qC. We immuno-stained sequential slices of murine lungs with the macrophage marker F4/80 and anti-C1qA (Figure S5A), and sequential slices of human lungs with anti-C1qA, the macrophage marker CD68 and the AECII marker proSPC (Figure S5B). In both cases, macrophages stained positive for C1qA. To further analyze C1q production by macrophages, we polarized MH-S cells (a murine alveolar macrophage cell line) into either M1 or M2 macrophages. Treatment with LPS + IFN-γ led to an increase in Nos2 expression, an M1 marker, while treatment with IL-4 resulted in increased Arg1 expression, an M2 marker (Figure S6A). Polarization into M2 macrophages did not increase cell-associated C1qA (Figure S6B) but significantly increased C1qA in the supernatant (Figure S6C).</p><p>We hypothesized that secreted C1qA might affect other cells in a paracrine fashion and focused on AECI","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroimmune interactions: The bridge between inflammatory bowel disease and the gut microbiota","authors":"Jinxia Zhai,&nbsp;Yingjie Li,&nbsp;Jiameng Liu,&nbsp;Cong Dai","doi":"10.1002/ctm2.70329","DOIUrl":"https://doi.org/10.1002/ctm2.70329","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The multidimensional regulatory mechanism of the gut–brain–immune axis in the context of inflammatory bowel disease (IBD) has garnered significant attention, particularly regarding how intestinal microbiota finely regulates immune responses through immune cells and sensory neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>Metabolites produced by intestinal microbiota influence the phenotype switching of immune cells via complex signalling pathways, thereby modulating their anti-inflammatory and pro-inflammatory functions during intestinal inflammation. Furthermore, sensory neurons exhibit heightened sensitivity to microbial-derived signals, which is essential for preserving intestinal balance and controlling pathological inflammation by integrating peripheral environmental signals with local immune responses. The dynamic equilibrium between immune cells and the neuroimmunoregulation mediated by sensory neurons collectively sustains immune homeostasis within the intestine. However, this coordination mechanism is markedly disrupted under the pathological conditions associated with IBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>An in-depth exploration of the interactions among immune cells, gut microbiota and sensory neurons may yield significant insights into the pathological mechanisms underlying IBD and guide the creation of new treatment approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The gut microbiota regulates the gut-brain-immune axis, modulating neuroimmune interactions in IBD.</li>\u0000 \u0000 <li>Microbiota-derived metabolites influence immune cells, thereby affecting neurons.</li>\u0000 \u0000 <li>Neurons secrete mediators, enabling bidirectional neuroimmune communication essential for intestinal homeostasis.</li>\u0000 \u0000 <li>Disruptions contribute to IBD, offering therapeutic targets.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative impact of proton versus photon irradiation on triple-negative breast cancer: Role of VEGFC in tumour aggressiveness","authors":"Saharnaz Sarlak,&nbsp;Delphine Marotte,&nbsp;Arthur Karaulic,&nbsp;Jessy Sirera,&nbsp;Alessandra Pierantoni,&nbsp;Meng-Chen Tsai,&nbsp;Roxane Sylvestre,&nbsp;Clement Molina,&nbsp;Arthur Gouraud,&nbsp;Aurélien Bancaud,&nbsp;Paraskevi Kousteridou,&nbsp;Marie Vidal,&nbsp;Joël Hérault,&nbsp;Jérôme Doyen,&nbsp;Maeva Dufies,&nbsp;Florent Morfoisse,&nbsp;Barbara Garmy-Susini,&nbsp;Frédéric Luciano,&nbsp;Gilles Pagès","doi":"10.1002/ctm2.70330","DOIUrl":"https://doi.org/10.1002/ctm2.70330","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;In this study, we demonstrated that proton (P) and photon (X) radiotherapies (RT) lead to different molecular changes in triple-negative breast cancer (TNBC) cells. P-irradiated tumours tended to make larger tumours, while X-irradiated ones exhibited increased aggressiveness. Both types of radiation increased gene expression related to angiogenesis (blood vessel formation) and lymphangiogenesis (lymph vessel formation), which are associated with more aggressive cancer behaviour. We also found that targeting the lymphangiogenesis-related gene, vascular endothelial growth factor C (VEGFC), alongside either type of RT, could improve the prognosis for TNBC patients.&lt;/p&gt;&lt;p&gt;Breast cancer (BC) is the most common type of cancer among women.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Its aggressive forms, like TNBC, tend to be highly vascularized and often have an increased network of lymphatic vessels, which allows the cancer to metastasize more rapidly.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Standard treatment involves with a combination of surgery, chemotherapy and RT to target both local and systemic diseases. Despite these treatments, recurrence remains a significant challenge in aggressive forms of BC.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Proton therapy, a newer form of RT, offers more precise targeting than conventional X-RT, potentially reducing side effects by narrowing the radiation field.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Ongoing clinical trials are investigating whether P-RT might offer advantages over conventional X-RT, as recent research suggests promising advantages.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Here, we investigated how irradiation impacts TNBC cell behaviour and their microenvironment, building on our prior study of P- and X-RT effects on head and neck cancer.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Specifically, we investigated whether irradiation might inadvertently promote tumour growth by altering cells to release growth factors or cytokines that support tumour survival and progression.&lt;/p&gt;&lt;p&gt;To examine these effects, we developed TNBC cell populations (MDAMB231 and BT549) that are resilient to repeated X- or P-RT. The traits of aggressiveness, such as proliferation and migration were evaluated in these multi-irradiated cells. While proliferation rates in irradiated cells were like controls (Figure 1A,B), migration abilities were enhanced (Figure 1C,D), suggesting that these cells could have a greater potential for metastasis. This increase in migration mirrors findings in X-resistant medulloblastoma cells.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Since metastasis in TNBC frequently occurs via lymphatic vessels,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; we investigated the impact of X- and P-RT on the expression of VEGFC, a key regulator of lymphangiogenesis, in our TNBC cell lines which exhibit higher basal levels of VEGFC compared to cell lines of other BC subtypes (Figure S1). Both irradiation types significantly upregulated VEGFC mRNA expression (Figure 1E) and increased secretion of VEGFC prot","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulated CEMIP promotes intervertebral disc degeneration via AP-1-mediated change in chromatin accessibility","authors":"Shibin Shu,&nbsp;Xin Zhang,&nbsp;Zhenhua Feng,&nbsp;Zhen Liu,&nbsp;Kaiyang Wang,&nbsp;Fengrui Li,&nbsp;Yating Wu,&nbsp;Bo Shi,&nbsp;Yong Qiu,&nbsp;Zezhang Zhu,&nbsp;Hongda Bao","doi":"10.1002/ctm2.70322","DOIUrl":"https://doi.org/10.1002/ctm2.70322","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Intervertebral disc degeneration (IDD), a chronic and multifactorial skeletal disorder, is the primary cause of low back pain. It results in reduced disc height and nucleus pulposus hydration due to proteoglycan loss and nucleus pulposus cells (NPCs) dysfunction within a hypoxic microenvironment. Metabolic dysregulation initiates catabolic processes, leading to extracellular matrix (ECM) degradation and compromising disc biomechanical integrity. Emerging evidence highlights epigenetic modifications as pivotal in IDD, influencing NPC gene expression transcriptionally and post-transcriptionally.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In order to understand the epigenetic underpinnings of IDD, our study provided a comprehensive profile of chromatin accessibility changes in degenerated NPCs using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq).\u0000&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;With motif enrichment analysis, we identified the activator protein-1 (AP-1) transcription factor critical in driving the chromatin accessibility changes during IDD. Integrative ATAC-seq and transcriptional profiling revealed cell migration-inducing protein (CEMIP) as a key biomarker and contributor to IDD, exhibiting marked upregulation in IDD. Furthermore, we demonstrated that the AP-1 family, especially, c-Fos, orchestrates the upregulation of CEMIP. Elevated CEMIP plasma levels correlated with clinical IDD severity, and CEMIP knockout mice demonstrated improved IDD.\u0000&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Mechanistically, CEMIP disrupted ECM homeostasis through its regulation of high molecular weight hyaluronic acid (HMW-HA) degradation, and its contribution to fibrotic changes. Our findings highlight CEMIP's vital role in IDD and identify the AP-1 family as a critical regulator of IDD, providing new potential therapeutic targets for novel IDD interventions.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Integrative ATAC-seq and transcriptional profiling revealed CEMIPas a key biomarker and contributor to IDD, exhibiting marked upregulation in IDD.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Further, we demonstrated that the AP-1 family, especially, c-Fos, orchestrates the upregulation of CEMIP.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Elevated CEMIP plasma levels correlated ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70332","DOIUrl":"https://doi.org/10.1002/ctm2.70332","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70332","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-derived vesicles: A promising and potential target for tumour therapy","authors":"Xueqiang Peng,&nbsp;Yu Gao,&nbsp;Jiaxing Liu,&nbsp;Xinxin Shi,&nbsp;Wei Li,&nbsp;Yingbo Ma,&nbsp;Xuexin Li,&nbsp;Hangyu Li","doi":"10.1002/ctm2.70320","DOIUrl":"https://doi.org/10.1002/ctm2.70320","url":null,"abstract":"<p>Mitochondria-derived vesicles (MDVs) participate in early cellular defence mechanisms initiated in response to mitochondrial damage. They maintain mitochondrial quality control (MQC) by clearing damaged mitochondrial components, thereby ensuring the normal functioning of cellular processes. This process is crucial for cell survival and health, as mitochondria are the energy factories of cells, and their damage can cause cellular dysfunction and even death. Recent studies have shown that MDVs not only maintain mitochondrial health but also have a significant impact on tumour progression. MDVs selectively encapsulate and transport damaged mitochondrial proteins under oxidative stress and reduce the adverse effects of mitochondrial damage on cells, which may promote the survival and proliferation of tumour cells. Furthermore, it has been indicated that after cells experience mild stress, the number of MDVs significantly increases within 2–6 h, whereas mitophagy, a process of clearing damaged mitochondria, occurs 12–24 h later. This suggests that MDVs play a critical role in the early stress response of cells. Moreover, MDVs also have a significant role in intercellular communication, specifically in the tumour microenvironment. They can carry and transmit various bioactive molecules, such as proteins, nucleic acids, and lipids, which regulate tumour cell's growth, invasion, and metastasis. This intercellular communication may facilitate tumour spread and metastasis, making MDVs a potential therapeutic target. Advances in MDV research have identified novel biomarkers, clarified regulatory mechanisms, and provided evidence for clinical use. These breakthroughs pave the way for novel MDV-targeted therapies, offering improved treatment alternatives for cancer patients. Further research can identify MDVs' role in tumour development and elucidate future cancer treatment horizons.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70320","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}