Clinical and Translational Medicine最新文献

{"title":"The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing","authors":"Na Zhao,&nbsp;Guojian Wang,&nbsp;Shuang Long,&nbsp;Xiaofan Lv,&nbsp;Xinze Ran,&nbsp;Junping Wang,&nbsp;Yongping Su,&nbsp;Tao Wang","doi":"10.1002/ctm2.70291","DOIUrl":"https://doi.org/10.1002/ctm2.70291","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Effective control of inflammation is crucial for the healing of cutaneous wounds, but the molecular mechanisms governing inflammation resolution during wound closure are still not yet clear. Here, we describe a homeostatic mechanism that facilitates the inflammation resolution by timely regulating the targeted proteases activities through antiprotease Spink7 (serine peptidase inhibitor, kazal type 7).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression pattern of Spink7 was investigated by quantitative RT-PCR, immunohistochemistry (IHC) and in situ hybridization. In both Spink7 knockdown and knockout models, quantitative comparisons were made between the healing rate of wounds and histopathological morphometric analysis. Microarrays, multiple chemokine assays, IHC, immunofluorescence, protease activity measurement were performed to explore the underlying mechanisms of Spink7 knockout in impaired wound healing. Radiation-wound combined injury (R-W-CI) model was employed to evaluate the therapeutic effects of Spink7 manipulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our study demonstrates that Spink7 is significantly upregulated in the differentiated epidermal granular keratinocytes of proliferative phase during murine wound closure. Both local knockdown of Spink7 levels in wounds using siRNA gel and systemic knockout of Spink7 using KO mice resulted in delayed wound closure with sustained neutrophil infiltration. Loss of Spink7 leads to augmented inflammatory responses, increased production of multiple chemokines/cytokines, and impaired M2 polarization of macrophages in wound healing. Furthermore, loss of Spink7 results in elevated proteolytic activities of uPA, MMP2/9 and KLK5/7 in proliferative phase. However, inhibiting KLK5/7 downstream PAR2 activation exacerbates the phenotype of KO mice. In R-W-CI model, further significant induction of Spink7 is observed in wounds with insufficient inflammatory response. Local suppression of Spink7 promotes wound healing in the R-W-CI model by augmenting inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Maintaining an endogenous balance between Spink7 and its target proteases is a crucial checkpoint for regulating inflammation resolution during healing. Therefore, manipulating levels of Spink7 might be an effective treatment for impaired wounds caused by inflammatory dysregulation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717114","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":"Sendotypes predict worsening renal function in chronic kidney disease patients","authors":"Thomas McLarnon,&nbsp;Steven Watterson,&nbsp;Sean McCallion,&nbsp;Eamonn Cooper,&nbsp;Andrew R. English,&nbsp;Ying Kuan,&nbsp;David S. Gibson,&nbsp;Elaine K. Murray,&nbsp;Frank McCarroll,&nbsp;Shu-Dong Zhang,&nbsp;Anthony J. Bjourson,&nbsp;Taranjit Singh Rai","doi":"10.1002/ctm2.70279","DOIUrl":"https://doi.org/10.1002/ctm2.70279","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Senescence associated secretory phenotype (SASP) contributes to age-related pathology, however the role of SASP in Chronic Kidney Disease (CKD) is unclear. Here, we employ a variety of omic techniques to show that senescence signatures can separate CKD patients into distinct senescence endotypes (Sendotype).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using specific numbers of senescent proteins, we clustered CKD patients into two distinct sendotypes based on proteomic expression. These clusters were evaluated with three independent criteria assessing inter and intra cluster distances. Differential expression analysis was then performed to investigate differing proteomic expression between sendotypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>These clusters accurately stratified CKD patients, with patients in each sendotype having different clinical profiles. Higher expression of these proteins correlated with worsened disease symptomologies. Biological signalling pathways such as TNF, Janus kinase-signal transducers and activators of transcription (JAK-STAT) and NFKB were differentially enriched between patient sendotypes, suggesting potential mechanisms driving the endotype of CKD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our work reveals that, combining clinical features with SASP signatures from CKD patients may help predict whether a patient will have worsening or stable renal trajectory. This has implications for the CKD clinical care pathway and will help clinicians stratify CKD patients accurately.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Senescent proteins are upregulated in severe patients compared to mild patients</li>\u0000 \u0000 <li>Senescent proteins can stratify patients based on disease severity</li>\u0000 \u0000 <li>High expression of senescent proteins correlates with worsening renal trajectories</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":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717115","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":"KMT2C/D mutations in newly diagnosed acute myeloid leukaemia: Clinical features, genetic co-occurrences and prognostic significance","authors":"Wenting Wang,&nbsp;Miao Yang,&nbsp;Xue Zhang,&nbsp;Jiayuan Chen,&nbsp;Shaowei Qiu,&nbsp;Bingcheng Liu,&nbsp;Yingchang Mi,&nbsp;Jianxiang Wang,&nbsp;Hui Wei","doi":"10.1002/ctm2.70284","DOIUrl":"https://doi.org/10.1002/ctm2.70284","url":null,"abstract":"&lt;p&gt;To the Editor:&lt;/p&gt;&lt;p&gt;Acute myeloid leukaemia (AML) is a diverse and complex category of malignant disease with poor outcomes. Despite advancements in prognostication and treatment strategies, the molecular landscape of AML remains complex and is not fully understood. Epigenetic factors are acknowledged as crucial in tumour development and progression.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The &lt;i&gt;KMT2&lt;/i&gt; (histone-lysine N-methyltransferase 2) family encompasses six key proteins: &lt;i&gt;KMT2A/B&lt;/i&gt;, &lt;i&gt;KMT2C/D&lt;/i&gt;, &lt;i&gt;KMT2F&lt;/i&gt; and &lt;i&gt;KMT2G&lt;/i&gt;, which is most notably associated with AML.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;KMT2A&lt;/i&gt; is associated with &lt;i&gt;KMT2A&lt;/i&gt;-rearranged leukaemia.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;KMT2B&lt;/i&gt; is identified as a hotspot for rearrangements.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;KMT2C/D&lt;/i&gt; mutations occurred frequently in various malignancies.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, the clinical characteristics of &lt;i&gt;KMT2C/D&lt;/i&gt; mutations in AML remain poorly defined. We found that &lt;i&gt;KMT2C&lt;/i&gt; and &lt;i&gt;KMT2D&lt;/i&gt; mutations are relatively rare and mutually exclusive in newly diagnosed AML, with &lt;i&gt;KMT2C&lt;/i&gt; mutations enriched in &lt;i&gt;CEBPA&lt;/i&gt;-mutated and &lt;i&gt;KMT2D&lt;/i&gt; in &lt;i&gt;NPM1&lt;/i&gt;-mutated AML subtypes, respectively. In general, &lt;i&gt;KMT2C&lt;sup&gt;MUT&lt;/sup&gt;&lt;/i&gt; and &lt;i&gt;KMT2C&lt;sup&gt;WT&lt;/sup&gt;&lt;/i&gt;, as well as &lt;i&gt;KMT2D&lt;sup&gt;MUT&lt;/sup&gt;&lt;/i&gt; and &lt;i&gt;KMT2D&lt;sup&gt;WT&lt;/sup&gt;&lt;/i&gt; AML, exhibit distinct mutational spectrums, similar clinical characteristics and survival outcomes.&lt;/p&gt;&lt;p&gt;We reviewed 1935 AML patients who underwent next-generation sequencing (NGS) analyses between 2015 and 2024. Of these, 1050 were eligible for &lt;i&gt;KMT2C&lt;/i&gt; analysis and 1777 for &lt;i&gt;KMT2D&lt;/i&gt; analysis. The &lt;i&gt;KMT2C&lt;/i&gt; mutation rate was 1.90% (20/1050), consistent with previous studies.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; The &lt;i&gt;KMT2D&lt;/i&gt; mutation rate was 1.41% (25/1777), lower than that reported in a small-sample study.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; No patient had concurrent &lt;i&gt;KMT2C&lt;/i&gt; and &lt;i&gt;KMT2D&lt;/i&gt; mutations. Characteristics of AML patients with and without &lt;i&gt;KMT2C/D&lt;/i&gt; mutation are presented in Table 1. Clinical characteristics did not differ significantly between wild-type and &lt;i&gt;KMT2C/D&lt;/i&gt;-mutated AML patients, except that &lt;i&gt;KMT2D&lt;sup&gt;WT&lt;/sup&gt;&lt;/i&gt; patients had higher haemoglobin levels than &lt;i&gt;KMT2D&lt;sup&gt;MUT&lt;/sup&gt;&lt;/i&gt; patients (&lt;i&gt;p &lt;/i&gt;&lt; .001). Among &lt;i&gt;KMT2C&lt;/i&gt; mutated patients, nine (45%) were male and their median age was 43.9 years. For AML classification, 10 of 20 patients were classified as AML with &lt;i&gt;CEBPA&lt;/i&gt; mutation. Patients with &lt;i&gt;KMT2D&lt;/i&gt; mutations included 11 (44%) males, with a median age of 42.0, and 11 (44%) were recognised as AML with &lt;i&gt;NPM1&lt;/i&gt; mutation. Patients with &lt;i&gt;KMT2C&lt;/i&gt; and &lt;i&gt;KMT2D&lt;/i&gt; mutations were enriched by AML with &lt;i&gt;CEBPA&lt;/i&gt; and &lt;i&gt;NPM1&lt;/i&gt; mutations, respectively. Additionally, most patients had normal karyotypes, including 50% of &lt;i&gt;KMT2C&lt;sup&gt;MUT&lt;/sup&gt;&lt;/i&gt; patients and 72% of &lt;i&gt;KMT2D&lt;sup&gt;MUT&lt;/sup&gt;&lt;/i&gt; patients.&lt;/p&gt;&lt;p&gt;We identified 22 mutation sites in the &lt;i","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707277","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/ctm2.70295","DOIUrl":"https://doi.org/10.1002/ctm2.70295","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689956","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":"An in-depth benchmark framework for evaluating single cell RNA-seq dropout imputation methods and the development of an improved algorithm afMF","authors":"Jinghan Huang,&nbsp;Anson C. M. Chow,&nbsp;Nelson L. S. Tang,&nbsp;Sheung Chi Phillip Yam","doi":"10.1002/ctm2.70283","DOIUrl":"10.1002/ctm2.70283","url":null,"abstract":"&lt;p&gt;Dear editor,&lt;/p&gt;&lt;p&gt;The presence of the inflated zeros in single cell RNA-seq still represents a challenge. Imputation of zeros can be performed but it is not commonly used in real applications because of their uncertain benefits and the lack of in-depth benchmark for various downstream analyses. Here, we performed two tasks: an in-depth benchmark framework was developed to compare imputation algorithms; second, an improved algorithm, afMF, was developed. Our results indicated that matrix-theory-based algorithms such as afMF had great and stable performance across various applications and generally outperformed raw log-normalization and others. In contrast, complicated methods were prone to overfitting and data distortion.&lt;/p&gt;&lt;p&gt;Imputation has raised some discussions&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt;: downstream analyses could benefit from it,&lt;sup&gt;3–&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; while false-positives may be introduced and zeros may contain important information too.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; No definitive conclusion has been reached so far. Imputation algorithms have been developed for years. Meanwhile, several comparative studies for dropout imputation have been conducted&lt;span&gt;&lt;sup&gt;1, 7-9&lt;/sup&gt;&lt;/span&gt; but had several obvious issues: (1) lack of in-depth analysis, for example, automatic cell type annotation, pseudobulk DE analysis, GSEA, cell–cell communication, AUCell and SCENIC, integration with spatial transcriptomics, etc.; (2) limited number of datasets, dataset types and tested algorithms, that is, only less than 5 or 6 datasets were used and the evaluated algorithms were developed a few years ago; (3) using biased, unreasonable performance metrics or confined to basic summary statistics only; (4) confined to using many simulated datasets (which have been shown to be much simpler and cannot reflect the complexity of real data). These limitations are also complicated by lack of real datasets with given ground truth. At the moment, most of the imputation algorithms are not used in any real-world applications or only confined to be used in a limited number of downstream applications (e.g., cell type clustering). A more thorough benchmark of the compatibility between imputation and key downstream applications is required.&lt;/p&gt;&lt;p&gt;Here, we evaluated the compatibility between prior imputation algorithms and various downstream tasks. This issue is obvious when applying downstream algorithms that have in-situ imputation steps or are designed for sparse data, as prior imputation may be unnecessary or worsen the results. Some researchers used zero-inflated models instead of imputation but such methods may not perfectly fit for scRNA-seq.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Motivated by the benchmark review,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; we developed an improved benchmark framework to address these issues by including previously well-established metrics and various novel features (Figure 1). These novel advantages includes: (1) using more than 25 real (mixture/puri","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676593","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":"Preclinical B cell depletion and safety profile of a brain-shuttled crystallizable fragment-silenced CD20 antibody","authors":"Vanessa L. Schumacher,&nbsp;Solen Pichereau,&nbsp;Juliana Bessa,&nbsp;Juergen Bachl,&nbsp;Sylvia Herter,&nbsp;Felix C. Weber,&nbsp;Johannes Auer,&nbsp;Anja Kipar,&nbsp;Michael Winter,&nbsp;Martina Stirn,&nbsp;Michael B. Otteneder,&nbsp;Kevin Brady,&nbsp;Anne Eichinger-Chapelon,&nbsp;Adrian Roth,&nbsp;Nadine Stokar-Regenscheit,&nbsp;Nicole Clemann,&nbsp;Shanon Seger,&nbsp;Claudia Senn,&nbsp;Juliane Hönig,&nbsp;Cordula Jany,&nbsp;Elisa Di Lenarda,&nbsp;Alain C. Tissot,&nbsp;Christian Klein,&nbsp;H.-Christian von Büdingen,&nbsp;Robert Mader,&nbsp;Mohammed Ullah,&nbsp;Niels Janssen,&nbsp;Eduard Urich","doi":"10.1002/ctm2.70178","DOIUrl":"10.1002/ctm2.70178","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The blood–brain barrier (BBB) presents a major challenge for the development of monoclonal antibody (mAb)-based therapies for brain disorders. To improve the likelihood of success of such therapies, Roche Brainshuttle technology utilizes a single anti-transferrin receptor 1 (TfR1)-antigen-binding antibody fragment linked to a therapeutic antibody, allowing engagement with TfR1 to transport the therapeutic antibody into the brain via receptor-mediated transcytosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared Fc-silenced and Fc-competent variants of the Brainshuttle and the parental (non-shuttled) type II CD20 mAb, obinutuzumab in in vitro and in vivo (mouse and cynomolgus macaque) models. Endpoints assessed included B cell binding, B cell killing, tolerability, and ability to cross the BBB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The Fc-silenced Brainshuttle construct showed a superior safety profile compared with the Fc-competent construct while maintaining the ability to cross the BBB and to deplete B cells in head-to-head comparisons in human and mouse in vitro and in mouse and cynomolgus macaque in vivo models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Together, our data provide a path forward for the future development of safe and efficacious brain-targeted B-cell-depleting therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The BBB hinders mAb-based brain disorder therapies</li>\u0000 \u0000 <li>A brain-targeted B-cell-depleting mAb for MS that efficiently crosses the BBB via hTfR1 was developed using Brainshuttle^™ technology (1a and 1b)</li>\u0000 \u0000 <li>The Brainshuttle^™-CD20 mAb was well tolerated (2a and 2b) and displayed B-cell-killing properties (1c), paving the way for future development and clinical translation of TfR1-targetingtherapies for increased brain penetration</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673401","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":"HIF-1α-induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP-ribosylation","authors":"Yangjun Wu,&nbsp;Yu Zeng,&nbsp;Yong Wu,&nbsp;Xinyu Ha,&nbsp;Zheng Feng,&nbsp;Chaohua Liu,&nbsp;Ziqi Liu,&nbsp;Jiajia Wang,&nbsp;Xingzhu Ju,&nbsp;Shenglin Huang,&nbsp;Linhui Liang,&nbsp;Bin Zheng,&nbsp;Lulu Yang,&nbsp;Jun Wang,&nbsp;Xiaohua Wu,&nbsp;Shengli Li,&nbsp;Hao Wen","doi":"10.1002/ctm2.70244","DOIUrl":"10.1002/ctm2.70244","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chemoresistance remains a major hurdle in ovarian cancer (OC) treatment, as many patients eventually develop resistance to platinum-based chemotherapy and/or PARP inhibitors (PARPi).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed transcriptome-wide analysis by RNA sequencing (RNA-seq) data of platinum-resistant and -sensitive OC tissues. We demonstrated the role of LINC02776 in platinum resistance in OC cells, mice models and patient-derived organoid (PDO) models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identify the long noncoding RNA LINC02776 as a critical factor of platinum resistance. Elevated expression of LINC02776 is observed in platinum-resistant OC and serves as an independent prognostic factor for OC patients. Functionally, silencing LINC02776 reduces proliferation and DNA damage repair in OC cells, thereby enhancing sensitivity to platinum and PARPi in both xenograft mouse models and patient-derived organoid (PDO) models with acquired chemoresistance. Mechanistically, LINC02776 binds to the catalytic domain of poly (ADP-ribose) polymerase 1 (PARP1), promoting PARP1-dependent polyADP-ribosylation (PARylation) and facilitating homologous recombination (HR) restoration. Additionally, high HIF-1α expression in platinum-resistant tissues further stimulates LINC02776 transcription.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings suggest that targeting LINC02776 represents a promising therapeutic strategy for OC patients who have developed resistance to platinum or PARPi.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>LINC02776 promotes OC cell proliferation by regulating DNA damage and apoptosis signaling pathways.</li>\u0000 \u0000 <li>LINC02776 binds PARP1 to promote DNA damage-triggered PARylation in OC cells.</li>\u0000 \u0000 <li>LINC02776 mediates cisplatin and olaparib resistance in OC cells by enhancing PARP1-mediated PARylation activity and regulating the PARP1-mediated HR pathway.</li>\u0000 \u0000 <li>The high expression of LINC02776 is induced by HIF-1α in platinum-resistant OC cells and tissues.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673398","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":"Interleukin 27 deficiency drives dilated cardiomyopathy by ferroptosis","authors":"Yan Zhao,&nbsp;Jing Dai,&nbsp;Angwei Gong,&nbsp;Sheng Jin,&nbsp;Chengjian Guan,&nbsp;Keke Wang,&nbsp;Qianli Ma,&nbsp;Haijuan Hu,&nbsp;Yuming Wu,&nbsp;Bing Xiao","doi":"10.1002/ctm2.70269","DOIUrl":"10.1002/ctm2.70269","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;The molecular mechanisms underlying dilated cardiomyopathy (DCM) pathogenesis remain incompletely understood. In this study, we provide comprehensive evidence demonstrating that interleukin 27 (IL27) exerts protective effects in DCM by inhibiting ferroptosis, potentially opening new therapeutic options for DCM.&lt;/p&gt;&lt;p&gt;DCM features ventricular dilation with impaired cardiac function, demonstrating substantial morbidity and mortality. Despite therapeutic advancements, the 10-year survival rate remains approximately 60%, emphasizing the urgent need for innovative therapeutic strategies.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; IL27, originating from immune cells, plays a key role in regulating the progression of various cardiovascular diseases.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Recent clinical studies have indicated the cardiac tissues from DCM patients had higher IL27 mRNA levels, suggesting a potential link between IL27 and DCM.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, the precise mechanism through which IL27 influences DCM progression has remained elusive.&lt;/p&gt;&lt;p&gt;To establish a potential causal relationship between IL27 and DCM, we conducted Mendelian randomization analysis using genome-wide association study data. The study design principles and framework are shown in Figure S1A,B, respectively. Through systematic analysis, we identified a previously unreported single nucleotide polymorphism (SNP), rs181209. The Wald ratio method suggested a significant inverse correlation between plasma IL27 levels and DCM risk (odds ratio 0.91, 95% confidence interval 0.84–0.98, &lt;i&gt;p&lt;/i&gt; = .01) (Supplementary Figure 1C). This finding expanded upon previous research linking IL27 polymorphisms to DCM susceptibility, particularly the previously identified SNP rs153109.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Notably, our identification of rs181209 provided new insights into the genetic architecture underlying IL27's cardioprotective effects and strengthened the evidence for a causal relationship between IL27 and DCM pathogenesis.&lt;/p&gt;&lt;p&gt;To validate our genetic findings and explore underlying mechanisms, we constructed multiple experimental models. First, we developed a doxorubicin (Dox)-induced DCM model based on previous studies.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Echocardiographic analysis revealed significant cardiac abnormities in Dox-treated mice, characterized by reduced left ventricular ejection fraction and fractional shortening (LVEF and LVFS), thinning of both anterior and posterior left ventricular walls during systole (LVAWs and LVPWs), and enlarged left ventricular end-systolic internal diameter (LVIDs) (Figure S2A–F). Histological analysis using Masson staining exposed a conspicuous rise in the myocardial fibrotic area (Figure S2G,H). Importantly, Dox treatment significantly decreased IL27 levels in both plasmas (Figure S2J) and cardiac tissue (Figure S2I,L), accompanied by increased IL27 receptor (IL27Ra) expression in cardiac tissue (Figure S2I,K), possibly reflecting a compensatory r","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70269","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673403","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":"Interferon regulatory factor 5 suppresses epithelial-to-mesenchymal transition and metastasis by inducing GATA2 expression in colorectal cancer","authors":"Teng Pan,&nbsp;Zaoqu Liu,&nbsp;Xue Feng,&nbsp;Deyu zhang,&nbsp;Lifeng Li,&nbsp;Yu Song,&nbsp;Qi Luo,&nbsp;Xiaojin Luo,&nbsp;Xiaohang Chen,&nbsp;Yao Yao,&nbsp;Guanglin Zhou,&nbsp;Jose M Vicencio,&nbsp;Weilong Zhang,&nbsp;Mingzhu Yin,&nbsp;Dan Wang,&nbsp;Jinhai Deng,&nbsp;Xuerui Tan,&nbsp;Fengxiang Wei","doi":"10.1002/ctm2.70077","DOIUrl":"10.1002/ctm2.70077","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Approximately one-third of colorectal cancer (CRC) patients develop metastasis, resulting in a mere 15% five-year relative overall survival rate, underscoring metastasis as a pressing clinical concern. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Epithelial-to-mesenchymal transition (EMT) is a biological process that confers high plasticity to cells and is heavily implicated in cancer metastasis and progression. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Interferon regulatory factor 5 (IRF5) can induce target gene expression by binding to their promoters upon translocation to the nucleus upon activation. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Despite its well-known role as a key mediator of immune regulation, IRF5 has been reported to regulate the migratory capacity of cancer cells through transcription-dependent/independent mechanisms. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; We, here, investigated the role of IRF5 in CRC metastasis regulation.&lt;/p&gt;&lt;p&gt;We first performed gene set enrichment analysis on normalized IRF5 expression data from the Cancer Genome Atlas (TCGA) database. IRF5 expression was strongly associated with EMT signalling (Figure 1A). Three pairs of primary colorectal tumour tissues and liver metastatic counterparts were collected for RNA-Seq analysis. Results showed significantly downregulated expression of IRF5 in metastatic tissues compared to primary ones, with other key regulators of metastasis showing up, including SFRP2, OLFML2B, PLVAP, IBSP, COL11A1, MMP, etc. (Figure 1B). Immunohistochemistry (IHC) analysis of tumour samples revealed significant downregulation of IRF5 in tissues with distant metastasis (Figure 1C,D). Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot showed that IRF5 expression had a decrease in CRC tissues with metastasis compared to counterparts without metastasis, confirming decreased IRF5 expression at both transcriptional and translational levels (Figure 1E,F). Using the chi-square test, we found an inverse correlation between IRF5 and tumour metastasis, including N stage and M stage (Table S1).&lt;/p&gt;&lt;p&gt;To test the involvement of immune regulation, multiple public datasets were analyzed to examine the relationship between IRF5 expression and diverse immune cell types. Unexpectedly, the results showed that IRF5 was found to be significantly positively correlated with M2 macrophages (Figure S1). However, M2 macrophages have been identified to facilitate tumour metastasis. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Thus, the role of IRF5 involved in metastasis was not dependent on immune regulation. Further, we knocked out &lt;i&gt;IRF5&lt;/i&gt; (&lt;i&gt;IKO&lt;/i&gt;) in HCT116 and HCT15 cells by CRISPR-Cas9 (Figure 2A) and analyzed transcriptional profiles of control (&lt;i&gt;NTC&lt;/i&gt;) and &lt;i&gt;IKO&lt;/i&gt; cells using RNA sequencing, revealing that cell migration and EMT-related pathways were observed (Figure 2B, Figure S2 and Table S2). Functional a","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669302","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":"Single-cell RNA sequencing of peripheral blood mononuclear cells from bronchopulmonary dysplasia","authors":"Yufeng Liu,&nbsp;Chun Yan,&nbsp;Yushan Li,&nbsp;Ruoxing Zhou,&nbsp;Xiaoyu Lin,&nbsp;Qiong Meng,&nbsp;Sitao Li,&nbsp;Limei Zhong,&nbsp;Yanfang Tan,&nbsp;Wangkai Liu","doi":"10.1002/ctm2.70276","DOIUrl":"https://doi.org/10.1002/ctm2.70276","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bronchopulmonary dysplasia (BPD) is a severe respiratory disease that primarily affects premature infants, characterized by persistent inflammation and abnormal immune activation. This study aimed to elucidate the immunological mechanisms underlying BPD by integrating single-cell RNA sequencing with T/B cell receptor profiling of peripheral blood mononuclear cells (PBMCs) from preterm infants with BPD, complemented by validation in a murine BPD model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We profiled PBMCs from preterm infants diagnosed with BPD and healthy controls, identifying 22 distinct cell clusters corresponding to major immune cell types.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Significant alterations were observed in myeloid and lymphoid subsets, with neutrophils undergoing metabolic reprogramming toward oxidative phosphorylation. T and B cell subsets exhibited phenotypic and functional changes, with B cells serving as crucial interaction hubs in cell communication networks. Progenitor cell analysis in BPD mouse models revealed specific alterations in hematopoietic stem cells. Analysis of cell–cell communication networks highlighted intricate intercellular interactions in BPD, emphasizing a pivotal role for the BTLA-TNFRSF14 signaling axis in disease pathogenesis. Additionally, pharmacological blockade of BTLA in mouse models alleviated disease severity, suggesting its potential therapeutic effects through modulation of the BTLA-TNFRSF14 pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings enhance the understanding of the BPD immune microenvironment and lay the foundation for developing targeted immunomodulatory therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Single-cell sequencing revealed immune cell profiles in bronchopulmonary dysplasia (BPD).</li>\u0000 \u0000 <li>Neutrophils underwent metabolic changes, and B cells were key in immune communication.</li>\u0000 \u0000 <li>Targeting B and T lymphocyte attenuator (BTLA)-TNFRSF14 signalling reduced BPD severity in mouse models, suggesting a potential therapy.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70276","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638760","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}