Clinical and Translational Medicine最新文献

{"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}

{"title":"Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti-programmed death 1 therapy in liver cancer","authors":"Chen Liang,&nbsp;Mu Ye,&nbsp;Lei Yu,&nbsp;Peng-Fei Zhang,&nbsp;Xiao-Jun Guo,&nbsp;Xian-Long Meng,&nbsp;Hai-Ying Zeng,&nbsp;Shu-Yang Hu,&nbsp;Dao-Han Zhang,&nbsp;Qi-Man Sun,&nbsp;Ying-Hao Shen,&nbsp;Jia-Bin Cai,&nbsp;Shuang-Qi Li,&nbsp;Zhen Chen,&nbsp;Ying-Hong Shi,&nbsp;Ai-Wu Ke,&nbsp;Yujiang G. Shi,&nbsp;Jian Zhou,&nbsp;Jia Fan,&nbsp;Fei-Zhen Wu,&nbsp;Xiao-Yong Huang,&nbsp;Guo-Ming Shi,&nbsp;Zheng Tang,&nbsp;Jia-Cheng Lu","doi":"10.1002/ctm2.70335","DOIUrl":"https://doi.org/10.1002/ctm2.70335","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;Immune checkpoint blockade, particularly targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), shows promise in treating hepatocellular carcinoma (HCC). However, acquired resistance, especially in patients with ‘hot tumours’, limits sustained benefits. Lysine-specific demethylase 1 (LSD1) plays a role in converting ‘cold tumours’ to ‘hot tumours’, but its involvement in PD-1 inhibitor resistance in HCC is unclear.&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;LSD1 and PD-L1 expression, along with CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration, were assessed using immunohistochemistry in HCC tissues, correlating these markers with patient prognosis. The impact of LSD1 deletion on tumour cell proliferation and CD8&lt;sup&gt;+&lt;/sup&gt; T cell interactions was examined in vitro. Mouse models were used to study the combined effects of LSD1 inhibition and anti-PD-1 therapy on tumour growth and the tumour microenvironment (TME). The clinical relevance of LSD1, CD74 and effector CD8&lt;sup&gt;+&lt;/sup&gt; T cells was validated in advanced HCC patients treated with PD-1 blockade.&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;LSD1 overexpression in HCC patients correlated with reduced PD-L1 expression, less CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration and poorer prognosis. LSD1 deletion increased PD-L1 expression, boosted effector CD8&lt;sup&gt;+&lt;/sup&gt; T cells in vitro and inhibited tumour growth in vivo. While anti-PD-1 monotherapy initially suppressed tumour growth, it led to relapse upon antibody withdrawal. In contrast, combining LSD1 inhibition with anti-PD-1 therapy effectively halted tumour growth and prevented relapse, likely through TME remodelling, enhanced CD8&lt;sup&gt;+&lt;/sup&gt; T cell activity and improved CD74-mediated antigen presentation. Clinically, low LSD1 expression was associated with better response to anti-PD-1 therapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;LSD1 deletion reshapes the TME, enhances CD8&lt;sup&gt;+&lt;/sup&gt; T cell function and prevents acquired resistance to anti-PD-1 therapy in HCC. The combination of LSD1 inhibitors and PD-1 blockade offers a promising strategy for overcoming resistance in advanced HCC.&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;Uncovering the synthetic lethality resulting from LSD1 deletion and PD1 inhibitor co-administration, evaluating their combined effects on tumour growth and TME remodelling.&lt;/li&gt;\u0000 ","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/ctm2.70335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938859","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":"IRF4 contributes to chemoresistance in IGH::BCL2-positive diffuse large B-cell lymphomas by mediating BCL2-induced SOX9 expression","authors":"Yirong Zhang,&nbsp;Zizhen Xu,&nbsp;Ruixin Sun,&nbsp;Yixuan Gao,&nbsp;Innocent Agida,&nbsp;Kasimujiang Aximujiang,&nbsp;Lin Yuan,&nbsp;Jiao Ma","doi":"10.1002/ctm2.70336","DOIUrl":"https://doi.org/10.1002/ctm2.70336","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;Diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin's lymphoma, has a high relapse/refractory rate. We previously identified sex-determining region Y (SRY)-box transcription factor (SOX9) as a transcription factor that serves as a prognostic biomarker, particularly in BCL2-overexpressing DLBCL, and plays a vital role in lymphomagenesis. However, the molecular mechanisms that modulate the aberrant expression of SOX9 in this DLBCL subset remain unknown.&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;Cell viability, apoptosis and cell cycle assays were performed to determine whether SOX9 contributes to DLBCL chemoresistance and rescues silencing IRF4-induced phenotypes. Protein‒protein interactions and protein ubiquitination were elucidated using immunoprecipitation, immunohistochemistry, immunofluorescence and immunoblotting. Chromatin immunoprecipitation sequencing (ChIP-seq), ChIP and dual-luciferase reporter assays were used to investigate IRF4 binding to the SOX9 promoter. The therapeutic potential of IRF4 inhibition was evaluated in vitro and in a mouse model of DLBCL xenografts.&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;SOX9 enhanced the resistance of the BCL2-overexpressing DLBCL subset to chemotherapy or a BCL2 inhibitor. Moreover, BCL2 inhibition downregulated SOX9 in an immunoglobulin heavy chain/BCL2-positive DLBCL subset. We further identified IRF4 as a key regulator of BCL2-induced SOX9 expression, and ChIP-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promotes IRF4 entry into the nucleus by enhancing protein stability and downregulating proteasomal ubiquitination, thereby enforcing SOX9-mediated phenotypes. Finally, in a DLBCL cell line and xenografted mouse model, in vivo inhibition of IRF4 with an hIRF4 antisense oligonucleotide repressed lymphomagenesis and DLBCL chemoresistance.&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;Our data support the conclusion that IRF4 plays an essential role in BCL2-induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapsed and refractory DLBCL.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Keypoints/Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;BCL2 activated IRF4 by enhancing its nuclear activity to induce sex-determining region Y (SRY)-box 9 protein (SOX9) aberrant expression, which is a critica","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/ctm2.70336","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938942","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":"Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy","authors":"Ying Xie,&nbsp;Qiaoyuan Li,&nbsp;Xiyun Bian,&nbsp;Yan Yin,&nbsp;Zhuo Liang,&nbsp;Xu Liu,&nbsp;Tao Zhang,&nbsp;Xiaozhi Liu,&nbsp;Xin Quan,&nbsp;Yunlong Wang","doi":"10.1002/ctm2.70318","DOIUrl":"https://doi.org/10.1002/ctm2.70318","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Ischemic cardiomyopathy (ICM) is characterised by the insufficient capacity of the heart to effectively pump blood, which ultimately contributes to heart failure (HF). In this study, the down regulation of SENP1 is identified in the cardiomyocyte of ICM mouse models and in patients. The depletion of SENP1 exacerbates hypoxia-induced apoptosis of cardiomyocytes in vitro and deteriorated cardiomyocyte injury of ICM mice in vivo. Mechanistically, SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for stabilising protein stability. Moreover, the interaction with SENP1 controls the nuclear condensation of MEF2C to promote the expression of genes critical for cardiomyocyte function. When rescuing SENP1 expression using adeno-associated virus serotype 9, the attenuation of cardiomyocyte injury is discerned in the mouse model of ICM. Therefore, these finding elicits a previously unrecognised role and mechanism of SENP1 in safeguarding cardiomyocyte in ICM progression while establishing a basis for the development of SENP1 as a potential marker for ICM diagnosis and treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>SNEP1 is downregulated in the cardiomyocyte of ICM mouse models and in patients.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for protein stability.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>The interaction with SENP1 controls the nuclear condensation of MEF2C to promote cardiomyocyte function.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Cardiac rescue of SENP1 alleviates ischemic heart injury in ICM mouse models by AAV9.</p>\u0000 </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":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919375","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":"Unravelling tumour spatiotemporal heterogeneity using spatial multimodal data","authors":"Chunman Zuo,&nbsp;Junchao Zhu,&nbsp;Jiawei Zou,&nbsp;Luonan Chen","doi":"10.1002/ctm2.70331","DOIUrl":"https://doi.org/10.1002/ctm2.70331","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Analysing the genome, epigenome, transcriptome, proteome, and metabolome within the spatial context of cells has transformed our understanding of tumour spatiotemporal heterogeneity. Advances in spatial multi-omics technologies now reveal complex molecular interactions shaping cellular behaviour and tissue dynamics. This review highlights key technologies and computational methods that have advanced spatial domain identification and their pseudo-relations, as well as inference of intra- and inter-cellular molecular networks that drive disease progression. We also discuss strategies to address major challenges, including data sparsity, high-dimensionality, scalability, and heterogeneity. Furthermore, we outline how spatial multi-omics enables novel insights into disease mechanisms, advancing precision medicine and informing targeted therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Advancements in spatial multi-omics facilitate our understanding of tumour spatiotemporal heterogeneity.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>AI-driven multimodal models uncover complex molecular interactions that underlie cellular behaviours and tissue dynamics.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Combining multi-omics technologies and AI-enabled bioinformatics tools helps predict critical disease stages, such as pre-cancer, advancing precision medicine, and informing targeted therapeutic strategies.</p>\u0000 </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":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919378","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":"USP22 promotes the proliferation and Sorafenib resistance of hepatocellular carcinoma cells via its deubiquitinase activity","authors":"Xiaochen Wang,&nbsp;Yijie Su,&nbsp;Bei Lan,&nbsp;Xuanyuan Li,&nbsp;Bodi Zhang,&nbsp;Liang Zhang,&nbsp;Yingmei Wang,&nbsp;Chunze Zhang,&nbsp;Chenghao Xuan","doi":"10.1002/ctm2.70324","DOIUrl":"https://doi.org/10.1002/ctm2.70324","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;Hepatocellular carcinoma remains one of the most lethal cancers, characterized by poor prognosis and low life expectancy. Unfortunately, there are very few molecular therapeutic options available for it. Sorafenib is a current standard first-line treatment for advanced hepatocellular carcinoma, however, drug resistance significantly limits its therapeutic efficacy.&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;Ubiquitin-specific protease 22 (USP22) expression level and its prognostic significance in hepatocellular carcinoma were analyzed using The Cancer Genome Atlas (TCGA) database. A series of cellular experiments related to cell proliferation and ferroptosis, and mouse tumor-bearing experiments were performed to investigate the role of USP22 in hepatocellular carcinoma cell growth and Sorafenib resistance. Flag affinity purification coupled with mass spectrometry, co-immunoprecipitation, and ubiquitination assays were conducted to identify direct substrates of USP22. Spike-in chromatin-immunoprecipitation (ChIP)-seq, RNA-seq, and ChIP assays were employed to explore the transcriptional substrates of USP22 as an H2BK120ub deubiquitinase.&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;Analysis of TCGA database reveals that USP22 is highly expressed in hepatocellular carcinoma tissues, which is closely associated with poor patient prognosis. Our data further indicates that USP22 promotes the proliferation of hepatocellular carcinoma cells via deubiquitinating and stabilizing cyclin-dependent kinase 11B (CDK11B). Additionally, USP22 acts as a novel inducer of Sorafenib resistance and suppresses Sorafenib-triggered ferroptosis in hepatocellular carcinoma cells. It reduces the transcription of transferrin receptor (TFRC) by decreasing H2BK120ub occupancy at &lt;i&gt;TFRC&lt;/i&gt; transcription start site (TSS) downstream region, thereby inhibiting ferroptosis upon Sorafenib treatment. Finally, animal experiments confirm the role of USP22 in promoting hepatocellular carcinoma cell growth and Sorafenib resistance in vivo. Taken together, this study demonstrates that USP22 promotes hepatocellular carcinoma growth and inhibits Sorafenib-induced ferroptosis by deubiquitinating non-histone substrate CDK11B and histone H2B, respectively.&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;Our findings suggest USP22 as a promising prognostic biomarker and therapeutic target for hepatocellular carcinoma patients, particularly those with Sorafenib resistance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70324","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919374","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":"Changes in plasma lipid composition upon glucocorticoid treatment in patients with primary immune thrombocytopenia","authors":"Lili Ji,&nbsp;Yanxia Zhan,&nbsp;Shanshan Qin,&nbsp;Jianjun Jin,&nbsp;Mengjia Qian,&nbsp;Bijun Zhu,&nbsp;Yang Ou,&nbsp;Pengcheng Xu,&nbsp;Xia Shao,&nbsp;Hao Chen,&nbsp;Yunfeng Cheng","doi":"10.1002/ctm2.70321","DOIUrl":"https://doi.org/10.1002/ctm2.70321","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Approximately one-third of patients with primary immune thrombocytopenia (ITP) failed to glucocorticoid treatment and currently no biomarker can predict the response.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Lipidomics, a branch of metabolomics, offers a powerful approach to elucidate disease mechanisms and to discover disease-specific biomarkers for diagnosis or therapy.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Here, we investigate the lipid portraits of ITP, in particular, illustrate the lipid metabolic characteristics and analyse the changes of lipids in ITP patients before and after glucocorticoid treatment. The study also sought to determine specific lipid species that could allow response prediction to glucocorticoid treatment.&lt;/p&gt;&lt;p&gt;The study was approved (approval no. B2020-279R) by the Ethics Committee of Zhongshan Hospital, Fudan University. First, to investigate the lipid portraits of ITP, we used an internal standards kit containing nine-lipid subclass (5040156, SCIEX) and the AB SCIEX QTRAP 5500 system to measure plasma lipids of 53 patients with ITP (newly diagnosed without treatment) and 20 healthy controls (HCs) matched by gender and age. Characteristics and clinical data of the patients and HC are included in Table S1. Recent studies have revealed the association of low high-density lipoprotein cholesterol (HDL-C) with high risk of autoimmune diseases, including ITP.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The level of HDL-C in the study showed significantly decreased in ITP (&lt;i&gt;p &lt;/i&gt;= .001), similar to previous studies.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Signalling lipids control multiple important cellular processes through signal transduction. Abnormality of lipid metabolism is considered a risk factor in many diseases. In our study, a total of 783 lipids was detected in plasma samples and 570 lipids were observed in quality control samples with relative standard deviation less than 30%. Partial least squares discrimination analysis model showed no very clear separation between ITP and HC (Figure 1A,B), indicating that ITP does not globally alter lipid composition. Analysis of the nine lipid subclasses, we found that cholesteryl ester, triacylglycerol (TAG), sphingomyelin (SM), phosphatidylcholine (PC), diacylglycerol (DAG), lysophosphatidylcholine (LPC) and phosphatidylethanolamine (PE) have no significant differences (Figure 1C). However, ITP patients showed an increase in ceramide (CER, &lt;i&gt;p &lt;/i&gt;= .033) and lysophosphatidylethanolamine (LPE, &lt;i&gt;p &lt;/i&gt;= .026). CER is an important bioactive lipid and involved in a variety of important cellular processes.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; The increased CER in ITP patients indicated that activation of inflammatory signalling could increase ITP CER biosynthesis, consistent with previously report. The increased CER could further affect cells apoptosis, autophagy and proliferation, leading to immune disorders in ITP patients. Several studies demonstrated that LPE are involved in the cell signalling process, act","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919376","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":"CRISPRi screening identifies PIKfyve as a co-therapeutic target for obinutuzumab","authors":"Yerim Kim,&nbsp;Jinkyung Oh,&nbsp;Jeong Ryeol Kim,&nbsp;Donghyuk Lee,&nbsp;Joo Young Kim","doi":"10.1002/ctm2.70333","DOIUrl":"https://doi.org/10.1002/ctm2.70333","url":null,"abstract":"&lt;p&gt;Dear Editor:&lt;/p&gt;&lt;p&gt;Combining monoclonal antibodies with targeted agents is a promising yet mechanistically underexplored strategy for B-cell lymphoma therapy.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Through a CRISPR interference (CRISPRi) screen, we identify PIKfyve as a suppressor of obinutuzumab-induced lysosomal membrane permeabilisation (LMP) and direct cell death (DCD), highlighting its potential as a combinatorial therapeutic target.&lt;/p&gt;&lt;p&gt;Obinutuzumab (OBI), a next-generation anti-CD20 monoclonal antibody, is known to trigger DCD via LMP in B-cell malignancies.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, the cellular factors that regulate this pathway remain poorly defined.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; To systematically identify modulators of OBI-induced cytotoxicity, we conducted a customised CRISPRi screen in Raji B cells targeting 2318 druggable genes&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; (Figure 1A). Following iterative rounds of OBI treatment and selection, next-generation sequencing (NGS) analysis revealed genes whose knockdown either sensitised cells to or conferred resistance against OBI-induced LMP and DCD (Figure 1B). Using Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK, Table S1), we ranked genes based on their depletion or enrichment following OBI treatment, identifying key regulators of LMP and DCD (Figure 1C). Essential genes critical for cell survival were excluded, as their sgRNAs were predominantly depleted. To prioritise clinically relevant targets, we applied a selection strategy: (1) applying FDR cutoff of 25%, (2) excluding essential genes based on the DepMap database and Raji B-cell essential gene list, specifically selecting genes with DepMap gene essentiality scores &lt; –1 and at least three high-quality sgRNAs (resulting in 97 genes, Table S2), and (3) focus on druggable targets with available inhibitors. This yielded 15 candidate genes for further validation. The sgRNA enrichment profiles and their relative importance are summarised in a box plot (Figure 1D and E).&lt;/p&gt;&lt;p&gt;To validate this finding, we generated single-knockdown Raji cell lines for 14 candidate genes and confirmed their knockdown efficiency (Figure 2A, Tables S3 and S4; CDK12 was excluded due to the inability to establish a stable knockdown line). Among these, six genes (DCTD, SMS, ATP1A1, SLC16A1, ODC1, and PIKfyve) significantly increased LMP and DCD, reinforcing their potential as modulators of lysosomal disruption (Figure 2B–D). Apilimod, a selective PIKfyve inhibitor, showed the strongest enhancement of OBI-induced DCD with minimal cytotoxicity alone (Figure 2E and F). Additionally, Apilimod dose-dependently enhanced DCD induced by OBI and RTX, indicating that PIKfyve inhibition broadly amplifies anti-CD20-mediated cytotoxicity (Figure 2G–J). Further, Umbralisib (a PI3Kδ inhibitor) enhanced OBI-induced cytotoxicity, whereas Acalabrutinib (a BTK inhibitor) had no effect, suggesting that the PI3K pathway, including PIKfyve, contributes to OBI efficacy (Figure S4).&lt;/p","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70333","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919377","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":"Obesity: Next game changer of allergic airway diseases?","authors":"Wenlong Li,&nbsp;Noah Marx,&nbsp;Qintai Yang,&nbsp;Deyu Fang,&nbsp;Yana Zhang","doi":"10.1002/ctm2.70316","DOIUrl":"https://doi.org/10.1002/ctm2.70316","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Obesity and allergic diseases are global health concerns, both of which are seeing an increase in prevalence in recent years. Obesity has been recognised as an important comorbidity in subpopulations with allergic airway diseases, which represents a unique phenotype and endotype. Obesity-related allergic airway diseases are associated with exacerbated clinical symptom burden, altered immune response, increased disease severity and compromised predictive capability of conventional biomarkers for evaluating endotype and prognosis. Moreover, treatment of obesity-related allergic airway diseases is challenging because this unique endotype and phenotype is associated with poor response to standard therapeutic strategies. Therapeutic regimen that involves weight loss by non-surgical and surgical interventions, gut microbiome-targeted treatment, glucagon-like peptide-1 receptor agonist and other agents should be considered in this population. In this review, we outline the current knowledge of the impact of obesity on prevalence, endotypes, clinical symptom and management of allergic airway diseases. Increased understanding of the implications of obesity may contribute to better treatment options for the obesity-related refractory airway inflammation, particularly in precision medicine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Obesity can increase the prevalence of allergic airway diseases such as asthma, AR, and CRSwNP.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Obesity alters the immune endotype and exacerbates clinical symptoms of respiratory allergic diseases.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Obesity-related allergic airway diseases exhibit therapeutic resistance to standard treatment.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Obesity-related allergic airway diseases constitute a distinct category of endotypes and phenotypes, requiring further in-depth research and novel therapeutic approaches.</p>\u0000 </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":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914069","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}