Clinical and Translational Medicine最新文献

{"title":"Targeting capacity, safety and efficacy of engineered extracellular vesicles delivered by transdermal microneedles to treat plasmacytoma in mice","authors":"Yulin Cao, Xuan Hu, Di Wu, Yuxuan Jiang, Yali Yu, Shan Wang, Wenlan Chen, Yaoying Long, Liuyue Xu, Jiao Qu, Bianlei Yang, Blal Chakhabi, Hongxiang Wang, Yong Deng, Lei Chen, Zhichao Chen, Qiubai Li","doi":"10.1002/ctm2.70327","DOIUrl":"https://doi.org/10.1002/ctm2.70327","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Engineered extracellular vesicles (EVs) are emerging as a highly potential platform for targeted drug delivery in cancer therapy. Although intravenous injection is commonly used in EV treatment, there is growing interest in using microneedles (MNs) for transdermal EV delivery; however, comprehensive studies comparing the tissue distribution, safety and antitumour efficacy of these two approaches for delivering engineered EVs remain scarce.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used EVs derived from umbilical cord mesenchymal stem cells, modified with phospholipid‒polyethylene glycol‒N-hydroxysuccinimide and conjugated with CD38 peptides (CD38-EVs), to target myeloma cells that highly express CD38 antigen, and tested their safety and antitumour efficacy in mice with subcutaneous plasmacytoma, administrated via dissolvable transdermal MNs or intravenous injection. Flow cytometry, immunofluorescence and fluorescence molecular projection imaging analysis were employed to evaluate the distribution of CD38-EVs at the cellular level and within living systems. Additionally, histopathological analysis and biochemical analyses were conducted to assess the antitumour effects and safety of CD38-EVs loaded with doxorubicin (CD38-EVs-Dox).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to standard EVs, CD38-EVs exhibited enhanced uptake by CD38<sup>high</sup> tumour cells and reduced uptake by CD38-negative non-tumour cells in vitro. In plasmacytoma NOD/SCID mouse models, CD38-EVs encapsulated within MNs (CD38-EVs<sup>MNs</sup>) effectively targeted the tumour cells much more than the standard EVs encapsulated within MNs (EVs<sup>MNs</sup>) and CD38-EVs intravenously administrated (CD38-EVs<sup>i.v</sup>), with reduced distribution to the lungs and spleen. Additionally, CD38-EVs-Dox induced significantly greater cytotoxicity against the tumour cells than EVs-Dox in vitro, and CD38-EVs-Dox<sup>MNs</sup> significantly reduced tumour burden compared to both EVs-Dox<sup>MNs</sup> and CD38-EVs-Dox<sup>i.v</sup>, while maintaining favourable safety profiles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CD38-EVs-Dox<sup>MNs</sup> have superior efficacy and safety in treating plasmacytoma mice, compared to CD38-EVs-Dox<sup>i.v</sup>, providing novel insights into the potential of MNs as a platform for delivering targeted engineered EVs in tumour therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70327","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901036","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":"Tackling aggression: Translating preclinical insights into clinical relevance","authors":"Mingyue Lv, Scott J. Russo, Long Li","doi":"10.1002/ctm2.70334","DOIUrl":"https://doi.org/10.1002/ctm2.70334","url":null,"abstract":"<p>Aggression is a clinically significant and often disruptive behavioural symptom that spans a wide range of brain disorders. Despite distinct pathologies, both psychiatric and neurodegenerative diseases frequently manifest aggression, complicating disease management, threatening safety and worsening long-term outcomes.<span><sup>1</sup></span></p><p>In psychiatric disorders, particularly schizophrenia, aggression is frequently observed during acute psychotic episodes marked by paranoia, hostility, and agitation. In inpatient settings, the prevalence of aggression among individuals with schizophrenia ranges from 10% to over 50%.<span><sup>2</sup></span> Broader epidemiological studies, such as the Epidemiologic Catchment Area project, have demonstrated that individuals with schizophrenia, bipolar disorder, mania or major depression are approximately five times more likely to engage in violent acts—a figure that increases 16-fold when substance abuse is also present.<span><sup>3</sup></span></p><p>Aggression is not limited to psychiatric disorders. It is also a prevalent and challenging symptom in neurodegenerative conditions such as Alzheimer's disease (AD). Nearly 28% of patients with AD and around 7% of those with mild cognitive impairment exhibit aggressive behaviours, including verbal hostility, physical aggression and resistance to care.<span><sup>4</sup></span> Aggression is a leading cause of institutionalization, with one study reporting that 34.2% of dementia-related hospitalizations were triggered by aggressive episodes.<span><sup>5</sup></span> Notably, male patients tend to display higher levels of physical and verbal aggression, alongside other disruptive behaviours such as disinhibition and wandering.<span><sup>6</sup></span></p><p>Taken together, these findings underscore aggression as a transdiagnostic symptom that cuts across disease boundaries. Its prevalence across disparate conditions suggests the involvement of shared neural substrates, warranting further investigation into the underlying circuit and molecular mechanisms. Such insights could pave the way for novel interventions that target aggression regardless of disease category.</p><p>Our recent study, published in <i>Nature</i>,<span><sup>7</sup></span> uncovers a previously unrecognized neural circuit centered on estrogen receptor 1-expressing (Esr1⁺) neurons within the posterolateral cortical amygdala (COApl) that selectively regulates male aggression. Using an integrative approach—encompassing whole-brain cFos mapping, in vivo calcium imaging, viral tracing and genetic perturbation—we found that Esr1<sup>COApl</sup> neurons act as a key node encoding the motivational drive for aggression.</p><p>Activity mapping revealed that the COApl is consistently activated in aggressive male mice, acting as a functional hub that orchestrates coordinated neural activity across multiple aggression-related regions. In-vivo fiber photometry further demonstrated that Esr1<sup>COApl</su","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901035","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":"Deciphering of intra-tumoural heterogeneity and the interplay between metastasis-associated meta-program and myofibroblasts in gastric cancer","authors":"Xiongyan Wu, Zhijian Jin, Baolong Li, Yifan Lu, Junyi Hou, Lizhong Yao, Zhenjia Yu, Qingqing Sang, Beiqin Yu, Jianfang Li, Chen Li, Chao Yan, Zhenggang Zhu, Kaiwen Tang, Bingya Liu, Liping Su","doi":"10.1002/ctm2.70319","DOIUrl":"https://doi.org/10.1002/ctm2.70319","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gastric cancer (GC) exhibits high heterogeneity that relies on the oncogenic properties of cancer cells and multicellular interactions in the tumour microenvironment. However, the heterogeneity of GC and their molecular characteristics are still largely unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed single-cell and spatial transcriptomics to comprehensively map the intra-tumoural heterogeneity within GC. Additionally, in vitro experiments, clinical sample analyses, and patient-derived organoid models (PDOs) were conducted to validate the key interaction patterns between tumor cells and stromal cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Seven robust meta-programs (MP1–MP7) in GC were defined with distinct biological significance and spatial distributions. MP3 and MP4 were intimately associated with distinct CD8 T cells skewed toward a cytotoxic or exhaustion state, while MP7, characterised by the highest degree of malignancy, harboured an immune lockdown microenvironment around it and spatially associated with myofibroblasts (myCAFs). Notably, we clarified the interplay between the MP7 and myCAFs, where MP7 induces the chemotactic migration of fibroblasts and promoting their transformation into myCAFs via GDF15/TGFBR2, and in turn, myCAFs-derived RSPO3 up-regulates EGR1 to promote the transformation to MP7 in GC cells and human PDOs. Ultimately, the accumulation of myCAFs around MP7 led to fewer infiltration of CD8 T cells, resulting an immune-deprived microenvironment and the diminished efficacy of immunotherapy. Additionally, based on the gene expression signatures of MP7 GC cells, we predicted specific drugs and verified more potent inhibitory effects of Taselisib and Lapatinib for MP7 GC cells than conventional drugs at the same concentration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, these results deepened the understanding of GC heterogeneity and paved the way for novel therapeutic strategies by targeting MP7 GC cells and their interaction loop with myCAFs in GC treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Seven robust meta-programs (MP1-MP7) were identified in gastric cancer.</li>\u0000 \u0000 <li>MP7 was strongly correlated with cancer metastasis and poor survival of gastric cancer patients.</li>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70319","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879949","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":"cGAS/STING signalling in macrophages aggravates obliterative bronchiolitis via an IFN-α-dependent mechanism after orthotopic tracheal transplantation in mice","authors":"Junhao Wan, Hao Liu, Chuangyan Wu, Ting Zhou, Fengjing Yang, Xiaoyue Xiao, Song Tong, Sihua Wang","doi":"10.1002/ctm2.70323","DOIUrl":"https://doi.org/10.1002/ctm2.70323","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Our previous findings have underscored the role of innate immunity in obliterative bronchiolitis (OB). However, despite the central importance of the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway in innate immune responses, its specific contribution to OB progression remains largely unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A murine orthotopic tracheal transplantation model was established to replicate OB pathogenesis. RNA sequencing and single-cell RNA sequencing data were analysed to investigate mechanisms underlying OB. Key molecules of the cGAS/STING pathway were assessed using immunofluorescence staining. Macrophage-specific <i>Sting1</i> knockout mice were generated to investigate the role of the cGAS/STING pathway in OB. Haematoxylin and eosin staining and Masson's trichrome staining were utilised to evaluate allograft stenosis and fibrosis. Immune cell infiltration and cytokine expression were analysed using immunofluorescence staining and qRT-PCR. Flow cytometry was used to characterise splenic T-cell subsets and assess co-stimulatory molecule expression in macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The cGAS/STING pathway was upregulated in macrophages infiltrating allografts. Macrophage-specific <i>Sting1</i> knockout significantly attenuated alloreactive T-cell responses and alleviated OB. Furthermore, <i>Sting1</i> deletion reduced the expression of inflammatory marker NOS2, antigen-presenting molecule MHC class II and co-stimulatory molecules (CD80 and CD86) in macrophages. Mechanistically, <i>Sting1</i> knockout inhibited the production of interferon-α2 (IFN-α2), while the protective effect of macrophage-specific <i>Sting</i> knockout was reversed by IFN-α2 administration. Importantly, STING inhibition enhanced the allograft tolerance-promoting effects of cytotoxic T-lymphocyte-associated antigen 4-Ig (CTLA4-Ig), leading to the preservation of the airway epithelium.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study demonstrated that cGAS/STING signalling pathway exacerbated allograft rejection in an IFN-α2-dependent manner. These findings provide insights into potential novel strategies for prolonging allograft survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>cGAS/STING signalling pathway was activated in macrophages infiltrating ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879950","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":"Intermittent fasting and health: Does timing matter?","authors":"Manuel Dote-Montero, Antonio Clavero-Jimeno, Idoia Labayen, Jonatan R. Ruiz","doi":"10.1002/ctm2.70325","DOIUrl":"https://doi.org/10.1002/ctm2.70325","url":null,"abstract":"<p>The global rise in obesity has stimulated interest in innovative nutritional strategies for managing body weight and cardiometabolic related alterations. Time-restricted eating (TRE), a novel form of intermittent fasting that does not require calorie counting and can help to reduce body weight and improve cardiometabolic health by simply ‘watching the clock’, has garnered increasing attention.<span><sup>1, 2</sup></span> TRE involves consuming unrestricted types and amounts of food within a limited and consistent 4- to 10-h daily eating window, followed by fasting for the remaining hours of the day.<span><sup>3</sup></span> This approach has been associated with modest reductions in body weight and slight improvements in cardiometabolic health,<span><sup>4</sup></span> likely due to an unintentional decrease in energy intake (∼200–550 kcal/day). However, important questions remain, particularly regarding TRE's effects on body fat distribution, specifically subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). In obesity, limited SAT expandability may lead to increased VAT accumulation, a fat depot surrounding the internal organs strongly associated with increased cardiometabolic risk and mortality.<span><sup>5</sup></span></p><p>Not only what we eat, but also when we eat, plays a critical role in cardiometabolic health, as the circadian system orchestrates key metabolic processes over the 24-h cycle.<span><sup>6</sup></span> It has been hypothesised that concentrating energy intake earlier in the day may offer greater cardiometabolic benefits rather than extending it into the evening or night.<span><sup>7</sup></span> In this context, it is of both scientific and clinical relevance to determine whether the timing of TRE influences cardiometabolic health, or whether the observed benefits of TRE are attributable solely to the restriction of the eating window, irrespective of the time at which it is implemented.</p><p>In our recent study,<span><sup>8</sup></span> we investigated the effects of three distinct TRE schedules – an 8-h eating window in the early part of the day (early TRE), an 8-h eating window later in the day (late TRE), and a participant-selected eating window (self-selected TRE) – combined with usual care (UC), which included twice-monthly group nutritional education sessions based on the Mediterranean diet. These were compared to UC alone over 12 weeks, with a focus on changes in VAT and cardiometabolic health among men and women with overweight or obesity.<span><sup>8</sup></span></p><p>In this multicentre randomised controlled trial conducted in Granada (southern Spain) and Pamplona (northern Spain), a total of 197 participants (50% of whom were women), aged between 30 and 60 years, with a body mass index ≥25.0 and < 40.0 kg/m<sup>2</sup> and abdominal obesity were randomly assigned to one of four groups: UC (49 participants), early TRE (49 participants), late TRE (52 participants), or self-selected TRE (47 pa","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879968","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":"Enhancing the safety and efficacy of cell therapy with programmed sense-and-respond function","authors":"Andrew J. Walters, Xiaoyu Yang, Scott D. Olson, Caleb J. Bashor","doi":"10.1002/ctm2.70328","DOIUrl":"https://doi.org/10.1002/ctm2.70328","url":null,"abstract":"<p>Over the past decade, cell-based therapies have emerged as a transformative pharmaceutical modality, offering unprecedented potential for treating previously incurable diseases.<span><sup>1</sup></span> Whilst most cell-based therapies rely on intrinsic cell properties to achieve their therapeutic effects, genetic modification has gained traction as a strategy to enhance treatment safety and efficacy.<span><sup>2, 3</sup></span> Amongst the most impactful therapeutic advancements are genetic engineering of adoptive T cell therapeutics, particularly for liquid tumour malignancies.<span><sup>4</sup></span> Key breakthroughs include the development of chimeric antigen receptors (CARs) that reprogram T cell cytotoxicity towards tumour cells,<span><sup>5</sup></span> protein-based safety switches that trigger apoptosis upon administration of a small-molecule drug<span><sup>6</sup></span> and, most recently, synthetic multi-gene circuits that enable T cells to detect tumour antigens or soluble factors and conditionally deliver anti-tumour or immunomodulatory payloads in response.<span><sup>7</sup></span> The continued evolution of this dynamic cell technology for broader clinical applications hinges on ongoing engineering innovations that enhance circuit precision and expand target detection capabilities. Towards this goal, we recently reported a circuit engineering toolkit that uses phosphorylation to drive circuit function, opening the door to engineering therapeutic sense-and-respond functionality that operates with the speed and precision of native cellular signalling pathways.<span><sup>8</sup></span></p><p><b><i>Advantages of programming therapeutic cells to sense and respond</i></b>. The implementation of synthetic sense-and-respond circuitry in therapeutic cells represents a paradigm shift in precision medicine, and has the potential to address long-standing challenges in drug delivery.<span><sup>1</sup></span> Traditional therapeutic modalities, such as small molecules and biologics, can suffer from short in vivo half-lives and unfortunate side effects. Many cell therapies are challenged by invasive administration requirements for hard-to-reach tissues and significant off-target toxicities, including cytokine release syndrome and on-target, off-tissue toxicity.<span><sup>5</sup></span> Synthetic circuits offer a potential solution to these challenges by furnishing cells with the ability to sense disease- or tissue-specific markers and respond by delivering therapeutic payloads with precisely defined spatial, temporal and dose profiles. Beyond enhancing therapeutic precision and minimising side effects, this approach effectively decouples therapeutic mode-of-action from the intrinsic properties of the host cell, facilitating programmable, context-specific responses to be engineered independently from the myriad complexities of native cellular function (Figure 1).</p><p><b><i>Current state of engineering sense and respond for cell therapies</","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70328","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879969","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":"Myeloid deficiency of Z-DNA binding protein 1 restricts septic cardiomyopathy via promoting macrophage polarisation towards the M2-subtype","authors":"Yifan Shi,&nbsp;Lu He,&nbsp;Jie Ni,&nbsp;Yuyuan Zhou,&nbsp;Xiaohua Yu,&nbsp;Yao Du,&nbsp;Yang Li,&nbsp;Xi Tan,&nbsp;Yufang Li,&nbsp;Xiaoying Xu,&nbsp;Si Sun,&nbsp;Lina Kang,&nbsp;Biao Xu,&nbsp;Jibo Han,&nbsp;Lintao Wang","doi":"10.1002/ctm2.70315","DOIUrl":"https://doi.org/10.1002/ctm2.70315","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Septic cardiomyopathy is a frequent complication in patients with sepsis and is associated with a high mortality rate. Given its clinical significance, understanding the precise underlying mechanism is of great value.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>Our results unveiled that Z-DNA binding protein 1 (ZBP1) is upregulated in myocardial tissues of lipopolysaccharide (LPS)-treated mice. Single-cell mRNA sequencing (scRNA-seq) and single-nucleus mRNA sequencing (snRNA-seq) indicated that <i>Zbp1</i> mRNA in endothelial cells, fibroblasts and macrophages appeared to be elevated by LPS, which is partially consistent with the results of immunofluorescence. Through echocardiography, we identified that global deletion of ZBP1 improves cardiac dysfunction and the survival rate of LPS-treated mice. Mechanistically, snRNA-seq showed that ZBP1 is mainly expressed in macrophages and deletion of ZBP1 promotes the macrophage polarisation towards M2-subtype, which reduces inflammatory cell infiltration. Notably, myeloid-specific deficiency of ZBP1 also promotes M2 macrophage polarisation and improves cardiac dysfunction, validating the role of macrophage-derived ZBP1 in septic myocardial dysfunction. Finally, we revealed that LPS increases the transcription and expression of ZBP1 through signal transducer and activator of transcription 1 (STAT1). Fludarabine, the inhibitor of STAT1, could also promote M2 macrophage polarisation and improve cardiac dysfunction of LPS-treated mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provides evidence of a novel STAT1-ZBP1 axis in macrophage promoting septic cardiomyopathy, and underscores the potential of macrophage-derived ZBP1 as a therapeutic target for septic cardiomyopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Macrophage-derivedZBP1 exacerbates LPS-induced myocardial dysfunction and inflammatory cellinfiltration.</li>\u0000 \u0000 <li>Deletionof ZBP1 promotes macrophage polarisation from M1 to M2.</li>\u0000 \u0000 <li>STAT1-ZBP1axis promotes septic cardiomyopathy.</li>\u0000 \u0000 <li>ZBP1has emerged as a potential therapeutic target for inflammationand septic cardiomyopathy.</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":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880034","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":"Machine-learning analysis identifies “elite” viral controllers with increased survival and homeostatic responses in critical COVID-19","authors":"Nadia García-Mateo,&nbsp;Alejandro Álvaro-Meca,&nbsp;Tamara Postigo,&nbsp;Alicia Ortega,&nbsp;Amanda de la de la Fuente,&nbsp;Raquel Almansa,&nbsp;Noelia Jorge,&nbsp;Laura González-González,&nbsp;Lara Sánchez Recio,&nbsp;Isidoro Martínez,&nbsp;María Martín-Vicente,&nbsp;María José Muñoz-Gómez,&nbsp;Vicente Más,&nbsp;Mónica Vázquez,&nbsp;Olga Cano,&nbsp;Daniel Vélez-Serrano,&nbsp;Luis Tamayo,&nbsp;José Ángel Berezo,&nbsp;Rubén Herrán-Monge,&nbsp;Jesús Blanco,&nbsp;Pedro Enríquez,&nbsp;Pablo Ryan-Murua,&nbsp;Amalia de la Martínez de la Gándara,&nbsp;Covadonga Rodríguez,&nbsp;Gloria Andrade,&nbsp;Elena Bustamante-Munguira,&nbsp;Gloria Renedo Sánchez-Girón,&nbsp;Ramón Cicuendez Ávila,&nbsp;Juan Bustamante-Munguira,&nbsp;Wysali Trapiello,&nbsp;Elena Gallego Curto,&nbsp;Alejandro Úbeda-Iglesias,&nbsp;María Salgado-Villén,&nbsp;Enrique Berruguilla-Pérez,&nbsp;María del Carmen del de la Torre,&nbsp;Estel Güell,&nbsp;Fernando Casadiego,&nbsp;Ángel Estella,&nbsp;María Recuerda Núñez,&nbsp;Juan Manuel Sánchez Calvo,&nbsp;Sandra Campos-Fernández,&nbsp;Yhivian Peñasco-Martín,&nbsp;María Teresa García Unzueta,&nbsp;Ignacio Martínez Varela,&nbsp;María Teresa Bouza Vieiro,&nbsp;Felipe Pérez-García,&nbsp;Ana Moreno-Romero,&nbsp;Lorenzo Socias,&nbsp;Juan López Messa,&nbsp;Leire Pérez Bastida,&nbsp;Pablo Vidal-Cortés,&nbsp;Lorena del del Río-Carbajo,&nbsp;Jorge del Nieto del Olmo,&nbsp;Estefanía Prol-Silva,&nbsp;Víctor Sagredo Meneses,&nbsp;Noelia Albalá Martínez,&nbsp;Milagros González-Rivera,&nbsp;José Manuel Gómez,&nbsp;Nieves Carbonell,&nbsp;María Luisa Blasco,&nbsp;David de de Gonzalo-Calvo,&nbsp;Jessica González,&nbsp;Jesús Caballero,&nbsp;Carme Barberá,&nbsp;María Cruz Martín Delgado,&nbsp;Luis Jorge Valdivia,&nbsp;Caridad Martín-López,&nbsp;María Teresa Nieto,&nbsp;Ruth Noemí Jorge García,&nbsp;Emilio Maseda,&nbsp;Ana Loza-Vázquez,&nbsp;José María Eiros,&nbsp;Anna Motos,&nbsp;Laia Fernández-Barat,&nbsp;Joan Casenco-Ribas,&nbsp;Adrián Ceccato,&nbsp;Ferrán Barbé,&nbsp;David J. Kelvin,&nbsp;Jesús F. Bermejo-Martin,&nbsp;Ana P. Tedim,&nbsp;Salvador Resino,&nbsp;Antoni Torres","doi":"10.1002/ctm2.70241","DOIUrl":"https://doi.org/10.1002/ctm2.70241","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;The outcome of COVID-19 disease is strongly related to the interaction between the virus and the host immune response, which may become dysregulated in critically ill patients. This dysregulated response is characterized by elevated levels of inflammatory mediators, an overactivation of the innate immune system,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; lymphopenia,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; delayed antibody and interferon responses,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and a massive dissemination of viral components into the blood,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; all of which contribute to severity and increased mortality.&lt;span&gt;&lt;sup&gt;5-7&lt;/sup&gt;&lt;/span&gt; These immune and non-immune parameters can be integrated into so-called combitypes&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; to identify subgroups of patients with different immune profiles and outcomes, helping to guide clinical strategies. In a previous study we used viral RNA levels in plasma to categorize a multicentre cohort of critically ill COVID-19 patients into three subgroups with different mortality rate.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; In this study, we combined virological data (SARS-CoV-2 N1 RNA plasma load and N-antigenemia) and 32 host response biomarkers to improve classification of critically ill COVID-19 patients, with the objective to identify biological clues explaining survival.&lt;/p&gt;&lt;p&gt;We conducted a prospective cohort study in 785 critically ill COVID-19 patients with a plasma EDTA sample collected at intensive care unit (ICU) admission. The detailed methods and the biological parameters measured are summarized in the Supporting Information. The biological characteristics of 90-day survivors compared to non-survivors (Table S1) indicated that non-survivors were more likely to exhibit the presence of SARS-CoV-2 N antigen, along with higher viral RNA load in plasma, higher tissue damage (RNase P RNA), lower lymphocyte counts, and higher neutrophils levels. Additionally, non-survivors exhibited increased concentrations of multiple biomarkers involved in endothelial dysfunction (angiopoietin 2, endothelin-1, ICAM-1 and VCAM-1), inflammation (TNF-α, IL-15 and IL-6), coagulation (D-dimmer), chemotaxis (CXCL10, CCL2, and IL-8), immunosuppression (IL-10, PD-L1, and IL1-RA), T-cell biology (CD27), apoptosis (Fas) and innate immune-related proteins (EGF and SP-D).&lt;/p&gt;&lt;p&gt;Based on these biological characteristics, XGBoost algorithm was employed to develop a model for predicting 90-day mortality (AUROC of 0.80) (Supplementary Figure 1) and SHAP values were obtained to evaluate the influence of each biological feature on the outcome variable (Figure 1). Levels of SARS-CoV-2 N1 RNA was the parameter ranking the first to predict 90-day mortality, following by endothelin-1, IL-15, IL-8, neutrophils, IL-6, TREM-1, CCL2, CD27, SP-D, myeloperoxidase, IL-10, D-dimer, PTX-3, CXCL10, RNase P and VCAM-1, suggesting that viral control, endothelial dysregulation, pro-inflammatory mechanisms and chemotaxis are key biological functions in deter","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875497","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":"SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability","authors":"Manuela Mancini,&nbsp;Sara De Santis,&nbsp;Cecilia Monaldi,&nbsp;Fausto Castagnetti,&nbsp;Miriam Iezza,&nbsp;Alessandra Iurlo,&nbsp;Daniele Cattaneo,&nbsp;Sara Galimberti,&nbsp;Marco Cerrano,&nbsp;Isabella Capodanno,&nbsp;Massimiliano Bonifacio,&nbsp;Maura Rossi,&nbsp;Claudio Agostinelli,&nbsp;Manja Meggendorfer,&nbsp;Torsten Haferlach,&nbsp;Michele Cavo,&nbsp;Gabriele Gugliotta,&nbsp;Simona Soverini","doi":"10.1002/ctm2.70163","DOIUrl":"https://doi.org/10.1002/ctm2.70163","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>The <i>SETD2</i> tumour suppressor encodes a histone methyltransferase that specifically trimethylates histone H3 on lysine 36 (H3K36me3), a key histone mark implicated in the maintenance of genomic integrity among other functions. We found that SETD2 protein deficiency, mirrored by H3K36me3 deficiency, is a nearly universal event in advanced-phase chronic myeloid leukemia (CML) patients. Similarly, K562 and KCL22 cell lines exhibited markedly reduced or undetectable SETD2/H3K36me3 levels, respectively. This resulted from altered SETD2 protein turnover rather than mutations or transcriptional downregulation, and proteasome inhibition led to the accumulation of hyper-ubiquitinated SETD2 and to H3K36me3 rescue suggesting that a functional SETD2 protein is produced but abnormally degraded. We demonstrated that phosphorylation by Aurora-A kinase and ubiquitination by MDM2 plays a key role in the proteasome-mediated degradation of SETD2. Moreover, we found that SETD2 and H3K36me3 loss impinges on the activation and proficiency of homologous recombination and mismatch repair. Finally, we showed that proteasome and Aurora-A kinase inhibitors, acting via SETD2/H3K36me3 rescue, are effective in inducing apoptosis and reducing clonogenic growth in cell lines and primary cells from advanced-phase patients. Taken together, our results point to SETD2/H3K36me3 deficiency as a mechanism, already identified by our group in systemic mastocytosis, that is reversible, druggable, and BCR::ABL1-independent, able to cooperate with BCR::ABL1 in driving genetic instability in CML.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Virtually all CML patients in blast crisis display SETD2 loss of function.</li>\u0000 \u0000 <li>SETD2 loss seems to be accomplished at the posttranslational level rather than being the result of genetic/genomic hits or transcriptional repression.</li>\u0000 \u0000 <li>Phosphorylation by Aurora kinase A and ubiquitination by MDM2 contribute to SETD2 proteasome-mediated degradation in blast crisis CML patients.</li>\u0000 \u0000 <li>Loss of SETD2 results in increased DNA damage.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871540","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":"Exploring glomeruli and renal tubules transcriptomic data: Crucial role of the AASS gene in membranous nephropathy","authors":"Congcong Jiao,&nbsp;Yuxin Zhao,&nbsp;Yang Shao,&nbsp;Haoshen Feng,&nbsp;Cong Ma,&nbsp;Xiangnan Hao,&nbsp;Xiaomei Liu,&nbsp;Junjun Luan,&nbsp;Xu Yang,&nbsp;Hua Zhou","doi":"10.1002/ctm2.70317","DOIUrl":"https://doi.org/10.1002/ctm2.70317","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Membranous nephropathy (MN) is one of the most prevalent causes of nephrotic syndrome. Approximately 80% of patients with MN are diagnosed as primary, which is associated with M-type phospholipase A2 receptor (PLA2R). The remaining cases are considered secondary MN, whose underlying causes including infections, tumors, autoimmune diseases, or the usage of certain medications.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The pathophysiological mechanisms of MN are intricate and continue to be investigated. We utilised machine learning and experimental validation to analyse glomeruli and renal tubules transcriptomic data to identify key genes associated with MN, focusing on their expressions and underlying mechanisms in MN.&lt;/p&gt;&lt;p&gt;A preliminary screening of target genes was conducted using transcriptome data from glomeruli and renal tubules (Figure 1A), retrieved from the GEO database (Table S1). The datasets for glomeruli (GSE108109, GSE180393, GSE200828) and renal tubules (GSE108112, GSE180394, GSE200818) were merged and adjusted using the sva package. Differential analysis (|log&lt;sub&gt;2&lt;/sub&gt;FC| &gt; 1, &lt;i&gt;P &lt;/i&gt;&lt; 0.05) identified 416 differentially expressed genes (DEGs) in glomeruli and 81 DEGs in renal tubules, with 37 intersecting DEGs obtained from both datasets (Figure 1B,C). Enrichment analyses [Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Metascape] revealed that intersecting DEGs are involved in gas transport, cytochrome P450, and drug metabolism (Figure 1D–F), with cytochrome P450 playing a critical role in the metabolism of various medications.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Understanding the expression changes of these genes may provide insights into the drug-processing capabilities of kidneys.&lt;/p&gt;&lt;p&gt;We employed random forest (RF) and support vector machine (SVM) to improve the prediction accuracy, thereby identifying key genes in MN (Figure 2A, Figure S1). By employing root mean square error analysis, the 10 most significant genes were determined (Figure 2B, C), leading to the identification of AASS, CYP3A5, IP6K3, and PDK4 in glomeruli data (Figure 2D), while AASS and MT1A were highlighted in renal tubular analysis (Figure 2E). Differential analysis indicates low expression of all these genes in MN patients (Figure 2F,G). Receiver operating characteristic (ROC) curve analysis (Figure 2H–M) revealed that AASS had the highest Area under the curve (AUC) values in both glomeruli and renal tubules. AASS encodes a bifunctional enzyme involved in the early steps of lysine degradation,&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; and AASS low expression in diabetic nephropathy was found to correlate positively with estimated glomerular filtration rate (eGFR) and negatively with serum creatinine, emphasising its significance in renal disease.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Then, we explored the expression of AASS in renal tissue and its correlation with clinical indicators (Figure 3A). Renal tissues were obtained from 40 serum PLA2R-p","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865776","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}