Clinical and Translational Medicine最新文献

{"title":"Oestrogen suppresses the adipogenesis of fibro/adipogenic progenitors through reactivating the METTL3–ESR1-mediated loop in post-menopausal females","authors":"Hao Zhou, Shujing Feng, Jinkui Cai, Xiexiang Shao, Siyuan Zhu, Han Zhou, Yongmin Cao, Ru Wang, Xingzuan Lin, Jianhua Wang","doi":"10.1002/ctm2.70206","DOIUrl":"10.1002/ctm2.70206","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Post-menopausal women experience more severe muscular fatty infiltration, though the mechanisms remain unclear. The decline in estrogen levels is considered as a critical physiological alteration during post-menopause. Fibro/adipogenic progenitors (FAPs) are identified as major contributors to muscular fatty infiltration. This study aimed to investigate the detailed mechanism underlying the excessive muscular fatty infiltration in postmenopausal females.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Supraspinatus muscle samples were collected from female patients with or without menopause, and from mice with or without ovariectomy (OVX), to evaluate muscular fatty infiltration and isolated FAPs. The expressions of (estrogen receptor 1) ESR1, methyltransferase-like 3 (METTL3), and adipogenesis ability in FAPs from post-menopausal women and OVX mice were investigated. RNA sequencing (RNA-Seq) was performed to explore the gene expression profiles and potential mechanisms in FAPs from Pdgfrα-CreERT2; Esr1 knockout (Esr1 KO) mice and Esr1 flox/flox (Esr1 f/f) mice. The interplay of the METTL3-ESR1 mediated loop and its role in regulating adipogenesis in FAPs were investigated using dual luciferase reporter assays, chromatin immunoprecipitation (ChIP), and protein and RNA stability assays. The effects of estrogen supplementation on muscular fatty infiltration and locomotor function in OVX mice were evaluated by immunofluorescent staining and functional analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Decreased expression of ESR1/METTL3 and increased adipogenesis ability in FAPs was found in post-menopausal female. METTL3-mediated m6A methylation promoted ESR1 mRNA stability at the post-transcriptional level in FAPs. METTL3-mediated m6A modification promoted ESR1 expression by stabilizing ESR1 mRNA, while ESR1 acted as a transcription factor that enhanced METTL3 transcription in turn. ESR1 also suppressed the transcription of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), thereby inhibiting adipogenesis in FAPs. Reactivation of the METTL3-ESR1 mediated loop by estrogen alleviated excessive adipogenesis in FAPs from post-menopausal women, and it also reduced muscular fatty infiltration, and improved locomotor function in OVX mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Excessive muscular fatty infiltration in post-menopausal women arose from the disruption of the METTL3-ESR1 mediated loop of FAPs due to estrogen deficiency. Reactivation of the METTL3-ESR","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057966","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":"Proteomic profiling of the serum of patients with COVID-19 reveals key factors in the path to clinical improvement","authors":"Hye Seong, Chae-Hyeon Lee, Seo-Gyu Park, Kyoung-Min Choi, Su-Min Lee, Jisoo Han, Ha-Song Bae, Su-Bhin Han, Sung-Jin Kim, Eunjung Kim, Jae-Young Kim, Joon Young Song","doi":"10.1002/ctm2.70201","DOIUrl":"10.1002/ctm2.70201","url":null,"abstract":"<p>Dear Editor,</p><p>This study uncovers new molecular insights into the coronavirus disease (COVID-19) remission process and identifies potential predictive markers through proteomic profiling of patient serum, potentially guiding clinical decision making.</p><p>COVID-19 caused by the SARS-CoV-2 virus has triggered a global health crisis. Many proteomic studies using patient sera have been conducted to understand the host's response to this disease and identify potential therapeutic target.<span><sup>1-4</sup></span> However, the precise mechanisms underlying the diverse clinical presentations of patients with SARS-CoV-2 infection remain unclear. Additionally, only a few studies have investigated the molecular factors or biomarkers that may influence clinical improvement of patients who have already exhibited severe symptoms. In this study, proteomic analysis of serum samples from a unique patient cohort, including individuals whose COVID-19 symptoms worsened and those who improved from moderate or severe conditions, identified 14 differentially expressed proteins (DEPs). Pathway and network analysis of these proteins revealed potential biological processes central to COVID-19 remission, particularly complement regulation. Remarkably, elevated levels of complement C2 in the patient serum could be an early marker for detecting clinical deterioration in patients with COVID-19.</p><p>The study design, patient clinical data, and the proteomics analysis, including statistical and bioinformatics analysis, are detailed in the Supporting Information (Section 1). Briefly, proteomic analyses were conducted using sera collected from a cohort of 20 patients with COVID-19 and five healthy individuals as controls. Patients with COVID-19 were categorised into different prognostic groups based on the National Institute of Allergy and Infectious Disease Ordinal Scale score (Table S1): those who improved from mild COVID-19 (G1), individuals with deteriorating COVID-19 symptoms (G2), individuals who improved from moderate to mild COVID-19 (G3), and those who improved from severe to mild COVID-19 (G4). Table S2 presents the baseline characteristics of patients with COVID-19 and healthy controls, and Table S3 presents a comparison of the laboratory test results across the subject groups. After depleting high-abundance proteins using High-Select HSA/Immunoglobulin Depletion Resin (Thermo Scientific), sera from patients were processed for proteomic analysis via in-gel trypsin digestion and liquid chromatography‒mass spectrometry/mass spectrometry (LC‒MS/MS). The study design is illustrated in Figure 1. Using this proteomics approach, a total of 181 proteins were identified and quantified (Figure S1 and Dataset S1). Protein intensities were normalised,<span><sup>5</sup></span> and DEPs (fold-change > 2, <i>p</i> < .05) were identified using MaxQuant software and statistical tools. Pathway enrichment and interaction networks of DEPs were analysed using STRING dat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051714","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":"Neutrophil extracellular traps promote growth of lung adenocarcinoma by mediating the stability of m6A-mediated SLC2A3 mRNA-induced ferroptosis resistance and CD8(+) T cell inhibition","authors":"Li Xu,&nbsp;Yi Kong,&nbsp;Kang Li,&nbsp;Jia Li,&nbsp;Fang Xu,&nbsp;Yan Xu,&nbsp;Shuzhi Liang,&nbsp;Bolin Chen","doi":"10.1002/ctm2.70192","DOIUrl":"10.1002/ctm2.70192","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>To investigate the potential mechanisms underlying neutrophil extracellular traps (NETs) confer ferroptosis resistance and CD8(+) T cell inhibition in lung adenocarcinoma (LUAD). By the intravenous injection of LLC cells into the tail vein, a LUAD mouse model was created. Phorbol-12-myristate-13-acetate (PMA) stimulated neutrophils to facilitate NETs formation and combined with NETs inhibitor DNase I to explore NETs mechanism on LLC cell proliferation, migration, ferroptosis resistance, and CD8(+) T cell activity. CitH3, myeloperoxidase (MPO), cell-free DNA, and MPO-DNA levels in LUAD were increased, indicating an increase in NETs formation in LUAD. PMA promoted NETs formation in tumours of mice, increased the number of CD3(+)CD4(+) T cells, decreased perforin, granzyme A, granzyme B, IFNγ, and TNF-α levels, and promoted LUAD growth and the number of lung tumour nodules, indicating that PMA promoted NETs formation, reduced the activity of CD8(+)T cells, and promoted LUAD growth. DNase I partially reversed the effects of PMA. NETs promoted LLC cell proliferation and migration, while DNase I reversed NETs effects. Erastin inhibited LLC cell proliferation and migration and promoted ferroptosis. NETs partially reversed Erastin effects. Further results showed that NETs promoted LLC cell proliferation and migration and inhibited ferroptosis by promoting YTHDF2-mediated SLC2A3 mRNA degradation. Sh-YTHDF2 partially reversed the effect of NETs on LLC cells, whereas si-SLC2A3 partially reversed sh-YTHDF2 effects on LLC cells. In addition, NETs inhibited LLC cell ferroptosis by inhibiting CD8(+) T cell activity. Sh-YTHDF2 and DNase I inhibited NETs formation in tumours, increased the activity of CD8(+) T cells and inhibited LUAD growth. Our results suggested that NETs promoted the growth of LUAD through inhibiting ferroptosis and CD8(+) T cell activity by promoting YTHDF2-mediated SLC2A3 mRNA degradation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11769710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045035","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":"Engineering the future of medicine: Natural products, synthetic biology and artificial intelligence for next-generation therapeutics","authors":"Emre F. Bülbül,&nbsp;Helge B. Bode,&nbsp;Steven Schmitt,&nbsp;Kenan A. J. Bozhüyük","doi":"10.1002/ctm2.70146","DOIUrl":"10.1002/ctm2.70146","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The e<b><i>X</i></b>change <b><i>U</i></b>nit between <b><i>T</i></b>hiolation domains approach and artificial intelligence (AI)-driven tools like <i>Synthetic Intelligence</i> are transforming nonribosomal peptide synthetase and polyketide synthase engineering, enabling the creation of novel bioactive compounds that address critical challenges like antibiotic resistance and cancer. These innovations expand chemical space and optimize biosynthetic pathways, offering precise and scalable therapeutic solutions. Collaboration across synthetic biology, AI, and clinical research is essential to translating these breakthroughs into next-generation treatments and revolutionizing drug discovery and patient care.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037462","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":"Transcriptome profiles of human preimplantation blastocysts related to mosaicism, developmental speed and competence","authors":"Song Li,&nbsp;Bing Cai,&nbsp;Jialiu Liu,&nbsp;Yan Xu,&nbsp;Chenhui Ding,&nbsp;Muhua Lai,&nbsp;Canquan Zhou,&nbsp;Yanwen Xu","doi":"10.1002/ctm2.70196","DOIUrl":"10.1002/ctm2.70196","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;By taking advantage of parallel sequencing of genome and transcriptome (G&amp;T-seq),&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; we demonstrated the distinct transcriptome profiles of human preimplantation blastocysts in perspectives of embryo digital karyotype, developmental speed and implantation competence. Our study provided valuable information for further research in the physiology behind human embryo development and laid the foundation for embryo selection from the view of the transcriptome.&lt;/p&gt;&lt;p&gt;Preimplantation genetic test for aneuploidy (PGT-A) serves as an important invasive method to select euploid embryos. However, even PGT-A cannot guarantee a successful pregnancy,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; for almost 50% of euploid blastocysts could not result in a live birth. It means that there is still a big room to improve the capability of embryo selection besides aneuploidy screening. RNA sequencing might have the potential for assessing embryo competence.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Here we investigated the distinct transcriptome profiles in human pre-implantation blastocysts with the application of G&amp;T-seq (Figure 1A). We have verified this method in biopsied samples from 41 donated blastocysts in terms of the transcriptome consistency of samples from the same blastocyst, the prediction value of aneuploidies by transcriptome (Figure S1), as well as the lineage characteristic of inner cell mass (ICM) and trophectoderm (TE) (Figure S2), indicating the clinical safety and reproducibility of this method.&lt;/p&gt;&lt;p&gt;G&amp;T-seq is a unique technology for studying the transcriptome of chromosomal mosaicism, taking advantage of separate genome sequencing and RNA sequencing. In comparisons of transcriptomes of 28 TE few-cell samples from eight mosaic embryos with 17 TE few-cell samples from five euploidies (Figure 1B), we identified 79 genes upregulated and 37 genes downregulated (Figure 1C). Notably, ectoderm and primitive endoderm genes, including &lt;i&gt;KLF4&lt;/i&gt;, &lt;i&gt;TGFBR1&lt;/i&gt;, &lt;i&gt;ITGB5&lt;/i&gt; and &lt;i&gt;GATA6&lt;/i&gt;, were significantly upregulated in TE of mosaic blastocysts (Figure 1D). Furthermore, upregulated genes were mainly enriched in embryonic development, stem cell proliferation, endoderm development and other pathways (Table S1), implying that there might be a lineage separation disorder in TE cells with chromosomal mosaicism, and the inadequately developed trophoblast may contribute to the adverse pregnancy outcomes of mosaic embryos.&lt;/p&gt;&lt;p&gt;Human blastocysts have different developmental speeds. It may take 5–7 days for an embryo to develop to the grade 4 stage according to the Gardner grading system, which is the stage allowing TE biopsy. Clinically, blastocysts biopsied on day 6 or day 7 (named D6 or D7 blastocyst) are defined as growth-retarded blastocysts with lower implantation potential compared with day 5 blastocysts. The reason for retarded development speed remains to be clarified. To investigate the transcriptome related to blastocyst ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037478","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":"Spatial distribution of immune cells and their proximity to STING+ cells are associated with survival in glioblastoma","authors":"Hanwool Jeon,&nbsp;Hayeong Kang,&nbsp;Jihyun Im,&nbsp;Suin Jo,&nbsp;Hyunchul Jung,&nbsp;Moinay Kim,&nbsp;Jae Hyun Kim,&nbsp;Eunyeup Lee,&nbsp;Soyoung Kim,&nbsp;Jeong Hoon Kim,&nbsp;Chang-Ki Hong,&nbsp;Young-Hoon Kim,&nbsp;Sang Woo Song,&nbsp;Jinha Park,&nbsp;Sang-Yeob Kim,&nbsp;Seungjoo Lee","doi":"10.1002/ctm2.70187","DOIUrl":"10.1002/ctm2.70187","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Glioblastoma (GBM), the most aggressive malignant tumour, is increasingly treated with immunotherapy.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; The stimulator of interferon genes (STING) pathway&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; is key to tumour immunity and a studied target for immunotherapy.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; This study explores the immune landscape of GBM, focusing on spatial relationships between tumour-associated immune cells (TAICs)&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; and STING-expressing cells, uncovering patterns linked to prognosis.&lt;/p&gt;&lt;p&gt;We studied 14 recurrent GBM patients using protein composition and Gene Ontology (GO) analysis and analyzed immune pathways in 69 newly diagnosed GBM patients undergoing standard therapy. Spatial analysis of cells was performed using QuPath, CytoMAP, and R, as illustrated in Figure 1A. From our proteomic analysis, we identified protein groups with marked upregulation in patients with favourable responses. A total of 99 proteins were highly upregulated in the favourable group, while 170 were more pronounced in the unfavourable group (Figure 1B). Clusters of downregulated and upregulated proteins were identified using the Benjamini-Hochberg False Discovery Rate. The expression of &lt;b&gt;TMEM173&lt;/b&gt;, the gene encoding STING, was significantly elevated in the favourable group, as measured by protein expression using a mass spectrometer. The results were represented as an abundance ratio, and statistical significance was confirmed using the adjusted p-value. (Figure 1C). GO analysis showed that upregulated proteins in the favourable group were mainly linked to immune response activation. (Figure 1D). Pathways such as ‘regulation of innate immune response’ and ‘phagocytic respiratory burst’ were strongly linked to innate immune activation (Figure 1E). Additionally, pathways like ‘cell surface receptor signalling in immune response’, ‘T cell migration’ and ‘positive regulation of T cell receptor signalling’ were significantly linked to immune response activation (Figure 1F). &lt;i&gt;p&lt;/i&gt;-Values were transformed to -log10 for statistical significance, with values above 1.3 considered significant. Table S1 provides the GO categories associated with immune response activation.&lt;/p&gt;&lt;p&gt;We used multiplex immunohistochemistry (IHC) to analyze immune cell distribution and protein markers in the TME. Markers included CD4&lt;sup&gt;+&lt;/sup&gt; (helper T cells), CD8&lt;sup&gt;+&lt;/sup&gt; (cytotoxic T cells), CD11c&lt;sup&gt;+&lt;/sup&gt; (dendritic cells), TCRγ/δ&lt;sup&gt;+&lt;/sup&gt; (γ/δ T cells), ATRX&lt;sup&gt;+&lt;/sup&gt; (tumour cells) and DAPI&lt;sup&gt;+&lt;/sup&gt; (nuclei), with STING as a primary marker of interest.&lt;/p&gt;&lt;p&gt;We explored correlations between immune cell populations identified by multiplex IHC and patient survival (Figure 2A). Tumour specimens were stained with multiplex immunofluorescence, and a pathologist selected regions of interest (ROIs), which were scanned at high magnification and analyzed with markers including ATRX, CD8, STING, DAPI, CD4, CD11c and TCRγ/δ. (Figure 2B","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037473","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":"Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer","authors":"Sally E. Claridge,&nbsp;Shalini Nath,&nbsp;Anneliese Baum,&nbsp;Richard Farias,&nbsp;Julie-Ann Cavallo,&nbsp;Nile M. Rizvi,&nbsp;Lamberto De Boni,&nbsp;Eric Park,&nbsp;Genesis Lara Granados,&nbsp;Matthew Hauesgen,&nbsp;Ruben Fernandez-Rodriguez,&nbsp;Eda Nur Kozan,&nbsp;Evgeny Kanshin,&nbsp;Khoi Q. Huynh,&nbsp;Peng-Jen Chen,&nbsp;Kenneth Wu,&nbsp;Beatrix Ueberheide,&nbsp;Juan Miguel Mosquera,&nbsp;Fred R. Hirsch,&nbsp;Robert J. DeVita,&nbsp;Olivier Elemento,&nbsp;Chantal Pauli,&nbsp;Zhen-Qiang Pan,&nbsp;Benjamin D. Hopkins","doi":"10.1002/ctm2.70078","DOIUrl":"10.1002/ctm2.70078","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;The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high-throughput drug screening platform, our functional genomics pipeline inverts the common paradigm to identify patient populations that are likely to benefit from novel therapeutic strategies.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Approach&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Utilizing drug screening data across a panel of 46 cancer cell lines from 11 tumor lineages, we identified an ovarian cancer-specific sensitivity to the first-in-class CRL4 inhibitors KH-4-43 and 33-11. CRL4 (i.e., Cullin-4 RING E3 ubiquitin ligase) is known to be dysregulated in a variety of cancer contexts, making it an attractive therapeutic target. Unlike proteasome inhibitors that are associated with broad toxicity, CRL4 inhibition offers the potential for tumor-specific effects.&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;We observed that CRL4 inhibition negatively regulates core gene signatures that are upregulated in ovarian tumors and significantly slowed tumor growth as compared to the standard of care, cisplatin, in OVCAR8 xenografts. Building on this, we performed combination drug screening in conjunction with proteomic and transcriptomic profiling to identify ways to improve the antitumor effects of CRL4 inhibition in ovarian cancer models. CRL4 inhibition consistently resulted in activation of the mitogen-activated protein kinase (MAPK) signaling cascade at both the transcriptomic and protein levels, suggesting that survival signaling is induced in response to CRL4 inhibition. These observations were concordant with the results of the combination drug screens in seven ovarian cancer cell lines that showed CRL4 inhibition cooperates with MEK inhibition. Preclinical studies in OVCAR8 and A2780 xenografts confirmed the therapeutic potential of the combination of KH-4-43 and trametinib, which extended overall survival and slowed tumor progression relative to either single agent or the standard of care.&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;Together, these data demonstrate the prospective utility of functional modeling pipelines for therapeutic development and underscore the clinical potential of CRL4 inhibition in the ovarian cancer context.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;A precision medicine pipe","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037468","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":"Vitamin K-dependent gamma-carboxyglutamic acid protein 1 promotes pancreatic ductal adenocarcinoma progression through stabilizing oncoprotein KRAS and tyrosine kinase receptor EGFR","authors":"Zheng Wu,&nbsp;Qing Ye,&nbsp;Shan Zhang,&nbsp;Li-Peng Hu,&nbsp;Xiao-Qi Wang,&nbsp;Lin-Li Yao,&nbsp;Lei Zhu,&nbsp;Shu-Yu Xiao,&nbsp;Zong-Hao Duan,&nbsp;Xue-Li Zhang,&nbsp;Shu-Heng Jiang,&nbsp;Zhi-Gang Zhang,&nbsp;De-Jun Liu,&nbsp;Dong-Xue Li,&nbsp;Xiao-Mei Yang","doi":"10.1002/ctm2.70191","DOIUrl":"10.1002/ctm2.70191","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;Vitamin K-dependent γ-glutamic acid carboxylation (Gla) proteins are calcium-binding and membrane-associated, participating in coagulation, bone turnover, and cancer biology. The molecular function of transmembrane proline-rich Gla proteins (PRRGs) remains unexplored.&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;Analysis of pancreatic ductal adenocarcinoma (PDAC) datasets, including transcription profiles, clinical data, and tissue microarrays, was conducted to evaluate PRRG1 expression and its clinical relevance. PDAC cell lines with overexpressed, knockdown, and mutated PRRG1 were developed to study biological functions and pathways using RNA-seq, co-immunoprecipitation with mass spectrometry, Western blotting, and immunofluorescence. In vivo xenograft and orthotopic models assessed PRRG1's impact on PDAC progression, with and without warfarin treatment.&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;PRRG1 was significantly upregulated in PDAC compared to normal pancreas, correlating with poorer patient survival. PRRG1 knockdown reduced PDAC cell proliferation, anchorage-independent growth in vitro, and tumor growth in vivo. PRRG1 localized at the plasma membrane, interacted with the HECT E3 ligase NEDD4 via the C-terminal PPXY motif, and promoted NEDD4 self-ubiquitination, reducing its protein levels. PRRG1 knockdown elevated NEDD4, destabilizing the oncoprotein KRAS and receptor EGFR, and attenuating downstream signaling and macropinocytosis under nutrient deprivation. The vitamin K-dependent Gla modification of PRRG1 was crucial for its membrane localization and pro-tumorigenic effects, and was inhibited by low-dose warfarin, a clinical vitamin K antagonist.&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;This study identifies PRRG1 as a key regulator of pro-tumorigenic signaling in PDAC, suggesting the potential of repurposing the anticoagulant warfarin as a therapeutic strategy.&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;PRRG1 is identified as the transmembrane Gla protein mediating PDAC malignancy.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;PRRG1 recruits and induces self-ubiquitination of membrane-anchoring E3 ligase NEDD4.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;PRRG1 exerts a protective role toward KRAS and EGFR by inhibiting NEDD4.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The anticoagul","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022302","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":"Annexin A8 deficiency delays atherosclerosis progression","authors":"Carmen Gutiérrez-Muñoz,&nbsp;Rafael Blázquez-Serra,&nbsp;Irene San Sebastian-Jaraba,&nbsp;Sandra Sanz-Andrea,&nbsp;Maria J. Fernández-Gómez,&nbsp;Gonzalo Nuñez-Moreno,&nbsp;Pablo Mínguez,&nbsp;Joan Carles Escolá-Gil,&nbsp;Paula Nogales,&nbsp;Veronique Ollivier,&nbsp;Jose L. Martín-Ventura,&nbsp;Benoit Ho-Tin Noe,&nbsp;Ursula Rescher,&nbsp;Nerea Méndez-Barbero,&nbsp;Luis M. Blanco-Colio","doi":"10.1002/ctm2.70176","DOIUrl":"10.1002/ctm2.70176","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;Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and leukocytes within the arterial wall. By studying the aortic transcriptome of atherosclerosis-prone apolipoprotein E (&lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;)&lt;/i&gt; mice, we aimed to identify novel players in the progression of atherosclerosis.&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;RNA-Seq analysis was performed on aortas from &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; and wild-type mice. AnxA8 expression was assessed in human and mice atherosclerotic tissue and healthy aorta. &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice lacking systemic AnxA8 (&lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;AnxA8&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt;) were generated to assess the effect of AnxA8 deficiency on atherosclerosis. Bone marrow transplantation (BMT) was also performed to generate &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; lacking AnxA8 specifically in bone marrow-derived cells. Endothelial-specific AnxA8 silencing in vivo was performed in &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice. The functional role of AnxA8 was analysed in cultured murine cells.&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;RNA-Seq unveiled &lt;i&gt;AnxA8&lt;/i&gt; as one of the most significantly upregulated genes in atherosclerotic aortas of &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; compared to wild-type mice. Moreover, AnxA8 was upregulated in human atherosclerotic plaques. Germline deletion of AnxA8 decreased the atherosclerotic burden, the size and volume of atherosclerotic plaques in the aortic root. Plaques of &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;AnxA8&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; were characterized by lower lipid and inflammatory content, smaller necrotic core, thicker fibrous cap and less apoptosis compared with those in &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;AnxA8&lt;sup&gt;+/+&lt;/sup&gt;&lt;/i&gt;. BMT showed that hematopoietic AnxA8 deficiency had no effect on atherosclerotic progression. Oxidized low-density lipoprotein (ox-LDL) increased AnxA8 expression in murine aortic endothelial cells (MAECs). In vitro experiments revealed that &lt;i&gt;AnxA8&lt;/i&gt; deficiency in MAECs suppressed P/E-selectin and CD31 expression and secretion induced by ox-LDL with a concomitant reduction in platelet and leukocyte adhesion. Intravital microscopy confirmed the reduction in leukocyte and platelet adhesion in &lt;i&gt;ApoE&lt;sup&gt;−/−&lt;/sup&gt;AnxA8&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice. Finally, endothelial-specific silencing of AnxA8 decreased atherosclerosis progression.&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;Our findings demonstrate that AnxA8 promotes the progression of atherosclerosis by modulating endothelial−leukocyte interactions. Interventions capable of reducing AnxA8 expre","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001058","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 landscape of the intrahepatic ecosystem in alcohol-related liver disease","authors":"Xiaofang Zhao,&nbsp;Senyan Wang,&nbsp;Qi Liu,&nbsp;Wenjuan Wei,&nbsp;Xiaoyan Sun,&nbsp;Hao Song,&nbsp;Jing Xu,&nbsp;Shuijun Zhang,&nbsp;Hongyang Wang,&nbsp;Jing Fu","doi":"10.1002/ctm2.70198","DOIUrl":"10.1002/ctm2.70198","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Alcohol-related liver disease (ALD) is a common chronic liver disease caused by long-term excessive alcohol consumption and responsible for more than half of all liver-related deaths worldwide. The molecular mechanisms associated with ALD were not fully understood. In this study, we performed single-cell RNA sequencing on liver tissues obtained from ALD patients and healthy liver donors. We identified an ALB⁺KRT7⁺ epithelial population that expressed both hepatocyte and biliary markers significantly expanded in ALD livers. The ALB⁺KRT7⁺ epithelial cells were demonstrated to have stem cell properties and malignant transformation potentials. Moreover, ALB⁺KRT7⁺ epithelium-derived ALD organoids promote the tumour growth by activating Wnt/β-catenin signalling of liver cancer cells. Most importantly, blocking the Wnt protein secretion or knockdown the Wnt receptor suppressed the tumour promoting effect of ALD organoids. Our study provides important insights that Wnt signalling can be targeted in patients with advanced alcohol-related cirrhosis to prevent malignant transformation. In addition, our results also uncovered the important alterations of nonparenchymal cells, especially macrophages and T/NK populations that responsible for active inflammation responses in alcohol-related hepatitis and immunosuppressive microenvironment in advanced cirrhosis livers, which likely facilitated the malignant progression of ALD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>This study provides single-cell landscape of human liver samples across different ALD stages.</li>\u0000 \u0000 <li>The ALB⁺ KRT7⁺ epithelium were enriched in ALD patients, and the function of this epithelial population varied significantly across ALD stages.</li>\u0000 \u0000 <li>ALB⁺KRT7⁺ epithelium from advanced alcohol-related cirrhosis had malignant transformation potential and tumour promotion activity.</li>\u0000 \u0000 <li>The comprehensive changes of parenchymal and nonparenchymal cells in the ALD livers lay a hidden danger for the further malignant progression.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001110","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}