Clinical and Translational Medicine最新文献

{"title":"Deciphering the pseudouridine nucleobase modification in human diseases: From molecular mechanisms to clinical perspectives","authors":"Shiheng Jia,&nbsp;Xue Yu,&nbsp;Na Deng,&nbsp;Chen Zheng,&nbsp;Mingguang Ju,&nbsp;Fanglin Wang,&nbsp;Yixiao Zhang,&nbsp;Ziming Gao,&nbsp;Yanshu Li,&nbsp;Heng Zhou,&nbsp;Kai Li","doi":"10.1002/ctm2.70190","DOIUrl":"10.1002/ctm2.70190","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>RNA pseudouridylation, a dynamic and reversible post-transcriptional modification found in diverse RNA species, is crucial for various biological processes, including tRNA homeostasis, tRNA transport, translation initiation regulation, pre-mRNA splicing, enhancement of mRNA translation, and translational fidelity. Disruption of pseudouridylation impairs cellular homeostasis, contributing to pathological alterations. Recent studies have highlighted its regulatory role in human diseases, particularly in tumourigenesis. Cellular stresses trigger RNA pseudouridylation in organisms, suggesting that pseudouridylation-mediated epigenetic reprogramming is essential for maintaining cellular viability and responding to stress. This review examines the regulatory mechanisms and pathological implications of pseudouridylation in human diseases, with a focus on its involvement in tumourigenesis. Additionally, it explores the therapeutic potential of targeting pseudouridylation, presenting novel strategies for disease treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Methods to detect pseudouridine were introduced from classic mass spectrometry-based methods to newer approaches such as nanopore-based technologies and BID sequencing, each with its advantages and limitations.</li>\u0000 \u0000 <li>RNA pseudouridylation is crucial for various biological processes, including tRNA homeostasis, tRNA transport, translation initiation regulation, pre-mRNA splicing, enhancement of mRNA translation, and translational fidelity.</li>\u0000 \u0000 <li>Increased pseudouridylation is frequently associated with tumour initiation, progression, and poor prognosis, whereas its reduction is predominantly implicated in non-tumour diseases.</li>\u0000 \u0000 <li>A comprehensive understanding of the inducing factors for RNA pseudouridylation will be essential for elucidating its role in diseases. Such insights can provide robust evidence for how pseudouridylation influences disease progression and offer new avenues for therapeutic strategies targeting pseudouridylation dysregulation.</li>\u0000 \u0000 <li>The therapeutic potential of RNA pseudouridylation in diseases is enormous, including inhibitors targeting pseudouridine synthases, the application of RNA pseudouridylation in RNA therapeutics, and its role as a biological marker.</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/PMC11746961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001094","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":"Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition","authors":"Hui Luo,&nbsp;Jianhua Chen,&nbsp;Cao Li,&nbsp;Tian Wu,&nbsp;Siyue Yin,&nbsp;Guangping Yang,&nbsp;Yipin Wang,&nbsp;Zhihan Guo,&nbsp;Saifei Hu,&nbsp;Yanni He,&nbsp;Yingnan Wang,&nbsp;Yao Chen,&nbsp;Youqiang Su,&nbsp;Congxiu Miao,&nbsp;Yun Qian,&nbsp;Ruizhi Feng","doi":"10.1002/ctm2.70193","DOIUrl":"10.1002/ctm2.70193","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Numerous pathogenic variants causing human oocyte maturation arrest have been reported on the primate-specific TUBB8 gene. The main etiology is the dramatic reduction of tubulin α/β dimer, but still large numbers of variants remain unexplained.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using microinjection mRNA and genome engineering to reintroduce the conserved pathogenic missense variants into oocytes or in generating TUBB8 variant knock-in mouse models, we investigated that the human deleterious variants alter microtubule nucleation and spindle assembly during meiosis. Live-cell imaging and immunofluorescence were utilised to track the dynamic expression of microtubule plus end-tracking proteins in vivo and analysed microtubule nucleation or spindle assembly in vitro, respectively. Immunoprecipitation-mass spectrometry and ultramicro-quantitative proteomics were performed to identify the differential abundance proteins and affected interactome of TUBB8 protein.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>First, we observed a significant depletion of the EB1 signal upon microinjection of mutated TUBB8 mRNA (including R262Q, M300I, and D417N missense variants), indicating disruption of microtubule nucleation caused by these introduced TUBB8 missense variants. Mechanically, we demonstrated that the in vivo TUBB8-D417N missense variant diminished the affinity of EB1 and microtubules. It also harmed the interaction between microtubules and CKAP5/TACC3, which are crucial for initiating microtubule nucleation. Attenuated Ran-GTP pathway was also found in TUBB8-D417N oocytes, leading to disrupted spindle assembly. Stable microtubule was largely abolished on the spindle of TUBB8-D417N oocytes, reflected by reduced tubulin acetylation and accumulated HDAC6. More importantly, selective inhibition of HDAC6 by culturing TUBB8-D417N oocytes with Tubacin or Tubastatin A showed morphologically normal spindle and drastically recovered polar-body extrusion rate. These rescue results shed light on the strategy to treat meiotic defects in a certain group of TUBB8 mutated patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study provides a comprehensive mechanism elucidating how TUBB8 missense variants cause oocyte maturation arrest and offers new therapeutic avenues for treating female infertility in the clinic.</p>\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/PMC11746963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001102","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":"How the brain produces generalized fear","authors":"Hui-Quan Li,&nbsp;Nicholas C. Spitzer","doi":"10.1002/ctm2.70124","DOIUrl":"10.1002/ctm2.70124","url":null,"abstract":"&lt;p&gt;Fear alerts us to threats and is essential to survival. Acquired fear that is associated with a specific stimulus is defined as conditioned fear. However, fear can frequently generalize to other stimuli and contexts, and this generalized fear to harmless situations is a key component of anxiety that can result from acute stress. Generalized fear that is inappropriate to the stimuli that provoke it can be disadvantageous, destructive and even dangerous. Understanding how fear generalization occurs and how it can be controlled may suggest directions for the development of novel therapies to treat or even cure fear disorders.&lt;/p&gt;&lt;p&gt;In our study, we investigated the effect of footshock, a form of acute stress, which causes freezing behaviour that is a measure of fear in rodents. We found that a mild footshock given to mice produced only conditioned fear, but a strong footshock produced both conditioned and generalized fear (Figure 1A). We also found that footshock produced conditioned fear immediately, but generalized fear was present only after a three-day delay. The production of generalized fear was tightly associated with a change in co-transmitter identity from excitatory neurotransmitter glutamate to inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in serotonergic neurons in the dorsal raphe (Figure 1B).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; No change in birth or death of neurons was detected that could account for changes in neurotransmitter expression.&lt;/p&gt;&lt;p&gt;Using a stable genetic marker to track the neurons, the change in co-transmitter was seen to occur in single cells—thus revealing a co-transmitter switch. There was no gender difference identified for the production of either conditioned or generalized fear or for the induction of the transmitter switch. The switching neurons made connections to neurons in the central amygdala and lateral hypothalamus, which are regions of the brain that mediate fear responses.&lt;/p&gt;&lt;p&gt;To learn whether the findings in rodents were translatable to humans, we then examined the postmortem brains of individuals with and without posttraumatic stress disorder (PTSD) provided by the National Institutes of Health NeuroBioBank. We observed a change in co-transmitter expression in the brains of individuals with PTSD, but not in the brains of age-, gender-, and postmortem interval-matched control subjects. The changes seen in PTSD individuals are consistent with those observed in footshocked mice that exhibited generalized fear.&lt;/p&gt;&lt;p&gt;When we suppressed the synthesis of GABA in footshock mice using adeno-associated virus (AAV)-based gene transfer tools to interfere with the expression of GABA synthase, we prevented the appearance of generalized fear in response to footshock. This result suggested that the transmitter switch is necessary for the acquisition of generalized fear. Re-establishing the function of glutamatergic transmission, by restoring the lost glutamate transporters using AAV tools, was not as effective ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001099","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":"Advanced mutant receptor activator of nuclear factor kappa-Β ligand development with low affinity for osteoprotegerin","authors":"Yuria Jang,&nbsp;Yongjin Cho,&nbsp;Youngjong Ko,&nbsp;Yeonhee Moon,&nbsp;Chang-Moon Lee,&nbsp;Wonbong Lim","doi":"10.1002/ctm2.70195","DOIUrl":"10.1002/ctm2.70195","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;As a new receptor for receptor activator of nuclear factor kappa-Β ligand (RANKL), Leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) was recently introduced. Unlike RANKL–RANK signalling, RANKL-LGR4 inhibits the NFATc1 translocation, thereby inhibiting osteoclastic activity.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; Novel mutant RANKL has been introduced in site-directed mutations at critical RANKL-RANK binding sites; it avoids RANK and binds to the LGR4, thereby inhibiting osteoclastogenesis.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; However, a structure similar to that of RANKL has a weakness in the way that it can be scavenged by osteoprotegerin (OPG).&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; As OPG is an effective substance that removes RANKL, mutant RANKL can also be scavenged.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Therefore, an advanced RANKL mutation was performed for the LGR4 signalling trigger to inhibit osteoclast activity without affinity for OPG, and its applicability as a treatment for osteoporosis was investigated.&lt;/p&gt;&lt;p&gt;The previous mutant RANKL (001) containing transformants at K180R, D189I, R190K, H223F and H224Y and advanced mutant RANKL containing transformants at Q236D (011) or F269L (012), F269Y (013) and F269H (014) in the 011 and were generated for low affinity with OPG in wild type RANKL (WT) (Figure 1A and Figure S1).&lt;span&gt;&lt;sup&gt;9, 10&lt;/sup&gt;&lt;/span&gt; To determine the candidate with the lowest binding affinity to RANK and OPG (Figures S2 and S3), microscale thermophoresis (MST) was performed between RANK or OPG and mutant RANKL candidates in comparison to wild-type RANKL (WT) (Figure 1B,C). The binding affinity of 011 and 013 did not show with OPG. The binding affinity between RANK and 011/013 was about 17.1 µM and that between LGR4 and 013 showed the highest (about 8.59 µM and Figure S4). These results indicated 013 to be the potential candidates. To determine which mutant RANKL has the most inhibitory effect on osteoclast differentiation and activities, we stained tartrate-resistant acid phosphatase (TRAP) and analyzed resorbing pits on mutant RANKL candidates- or OPG-, as a positive control, and treated bone marrow-derived macrophage cells (BMMs) in the presence of WT. As a result, 013 showed the strongest inhibitory effect on trap-positive BMMs (Figure 1D,E) and caused a considerable dose-dependent decrease in TRAP-positive BMMs (Figure 1F,G). Furthermore, 013 decreased the resorption pit area in WT-treated BMMs (Figure 1H,I). Therefore, 013 plays an inhibitory role against osteoclast and could be a potential advanced mutant RANKL.&lt;/p&gt;&lt;p&gt;To investigate the effects of advanced mutant RANKL on the RANK or LGR4 signalling cascade, TRAP staining was performed on BMMs treated with only 013. Compared with WT, 013 did not result in TRAP-positive BMMs, even after treatment with 400 ng/mL (Figure 2A,B). A marked decrease in TRAP, NFATc1 and OSCAR (markers of osteoclast differentiation and activity) mRNA expressions was noted in 013+WT compared to WT (","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001054","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":"RECQL4 affects MHC class II-mediated signalling and favours an immune-evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma","authors":"Sara Egea-Rodriguez,&nbsp;Renáta Váraljai,&nbsp;Thierry M. Nordmann,&nbsp;Restuan Lubis,&nbsp;Manuel Philip,&nbsp;Florian Rambow,&nbsp;Alexander Roesch,&nbsp;Michael Flaig,&nbsp;Susanne Horn,&nbsp;Raphael Stoll,&nbsp;Fang Zhao,&nbsp;Annette Paschen,&nbsp;Bert Klebl,&nbsp;Ian D. Hickson,&nbsp;Dirk Schadendorf,&nbsp;Matthias Mann,&nbsp;Iris Helfrich","doi":"10.1002/ctm2.70094","DOIUrl":"10.1002/ctm2.70094","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;Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ-like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains 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;We analysed whole exome and bulk RNA sequencing data from a pan-cancer cohort of 25 775 patients and cutaneous melanoma cohorts (untreated: &lt;i&gt;n&lt;/i&gt; = 471, anti-progressive disease [PD]-1 treated: &lt;i&gt;n&lt;/i&gt; = 212). &lt;i&gt;RECQL4&lt;/i&gt; copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4-dependent signalling pathways and explored the association between &lt;i&gt;RECQL4&lt;/i&gt; levels and immunoscores. We evaluated the interplay of ICI response and &lt;i&gt;RECQL4&lt;/i&gt; expression in melanoma cohorts of 95 responders and 85 non-responders prior to and after ICI-targeted therapy and tested the prognostic power of &lt;i&gt;RECQL4&lt;/i&gt;. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi-omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights.&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 identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti-PD-1 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune-related pathways robustly suppressed in tumours with high &lt;i&gt;RECQL4&lt;/i&gt; levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4-mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation.&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 unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982844","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 and spatial transcriptomic analysis reveal a distinct population of APOE− cells yielding pathological lymph node metastasis in papillary thyroid cancer","authors":"Guohui Xiao,&nbsp;Rongli Xie,&nbsp;Jianhua Gu,&nbsp;Yishu Huang,&nbsp;Min Ding,&nbsp;Dongjie Shen,&nbsp;Jiqi Yan,&nbsp;Jianming Yuan,&nbsp;Qiong Yang,&nbsp;Wen He,&nbsp;Siyu Xiao,&nbsp;Haizhen Chen,&nbsp;Dan Xu,&nbsp;Jian Wu,&nbsp;Jian Fei","doi":"10.1002/ctm2.70172","DOIUrl":"10.1002/ctm2.70172","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Thyroid cancer is one of the most common endocrine tumors worldwide, especially among women and the metastatic mechanism of papillary thyroid carcinoma remains poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Thyroid cancer tissue samples were obtained for single-cell RNA-sequencing and spatial transcriptomics, aiming to intratumoral and antimetastatic heterogeneity of advanced PTC. The functions of <i>APOE</i> in PTC cell proliferation and invasion were confirmed through in vivo and in vitro assays. Pseudotime analysis and CellChat were performed to explore the the molecular mechanisms of the <i>APOE</i> in PTC progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified a subpopulation of tumor cells with lower expression levels of <i>APOE</i>, associated with advanced stages of PTC and cervical metastasis. <i>APOE</i> overexpression significantly reduced tumor cell proliferation and invasion, both in vitro and in vivo, by activating the <i>ABCA1-LXR</i> axis. <i>APOE⁻</i> tumor cells may promote tumor growth by interacting with dendritic cells and CD4⁺ T cells via <i>CD99</i>- rather than CD6-regulated signaling. We established a machine learning-based scRNA-seq data, 13-gene signature predictive of lymph node metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified a distinct <i>APOE⁻</i> tumor cell population associated with cervical metastasis and poor prognosis. Our results and models have potential clinical, prognostic, and therapeutic implications for advanced PTC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A subpopulation of tumor cells with lower expression levels of <i>APOE</i> was strongly associated with more advanced stages and metastasis of PTC.</li>\u0000 \u0000 <li><i>APOE</i>-negative (<i>APOE</i>⁻) cellsoverall exhibited weaker interactions with immune cells.</li>\u0000 \u0000 <li>A machine-learning bioinformatics model based on scRNA-seq data of in-situ thyroid cancer tissue was established to predict lymph node metastasis.</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":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982852","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":"Major cell types in the coronary thrombosis of acute myocardial infarction patients revealed by scRNA-seq","authors":"Zhiyao Wei,&nbsp;Cheng Cui,&nbsp;Zixuan Li,&nbsp;Jianping Li,&nbsp;Yibing Shao,&nbsp;Jizheng Wang,&nbsp;Jincheng Guo,&nbsp;Lei Song","doi":"10.1002/ctm2.70181","DOIUrl":"10.1002/ctm2.70181","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Intracoronary thrombosis, resulting from the rupture or erosion of atherosclerotic plaques, is the main cause of acute myocardial infarction (AMI). The role of immune cells in thrombosis has garnered attention as a central contributor to this catastrophic event.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; To further our understanding, we conducted single-cell RNA sequencing to picture a cellular atlas of aspired intracoronary thrombus.&lt;/p&gt;&lt;p&gt;Our dataset comprised a total of 10 456 cells, and a median of 2786 genes were detected per cell (Figure 1). Unsupervised clustering revealed that the largest part of cells in the intracoronary thrombus were monocytes (29.3%). We further subclustered monocytes and identified eight subclusters (Figure 2A). Cluster 6 was identified as conventional dendritic cells, for the high expression levels of HLA-DRB1 and HLA-DRA. The remaining clusters were categorized based on the relative expression levels of CD14 and FCGR3A, leading to three classifications: classical (CD14&lt;sup&gt;++&lt;/sup&gt;/FCGR3A&lt;sup&gt;−&lt;/sup&gt;; clusters 0, 2, 4), intermediate (CD14&lt;sup&gt;++&lt;/sup&gt;/FCGR3A&lt;sup&gt;+&lt;/sup&gt;; clusters 1, 3) and non-classical monocytes (CD14&lt;sup&gt;+&lt;/sup&gt;/FCGR3A&lt;sup&gt;++&lt;/sup&gt;; clusters 5, 7) (Figure 2B,C). Marker genes and functional heterogeneity for each cluster are presented in Figure 2D,E. Besides, among the monocytes, 14 modules of co-regulated genes were identified by weighted gene co-expression network analysis (WGCNA) (Figure 2F).&lt;/p&gt;&lt;p&gt;Classical monocytes comprised the largest proportion of the monocyte population (60.1%) and exhibited diverse functions. Cluster 0 (30.1%) demonstrated significant activation in response to non-infectious stimuli during AMI, characterized by elevated expression levels of NLRP3, IL-1B and NFKBIA. Module brown (TNF and NF-kappa signalling pathway) displayed a strong correlation with cluster 0 (Figure S1A). Cluster 2 (21.8%) displayed heightened expression of inflammatory mediators including S100A9, S100A8, CTSS and phagocytosis receptor CD36 (Figure 2G). Figure 2H,I proved its presentation. This cluster had a strong correlation with module tan, which is linked to phagosome and leukocyte trans-endothelial migration (Figure S2B). Cluster 4 (6.6%) exhibited elevated expression of T cell activation genes (CD247, NKG7, GNLY) and was associated with module black (nature killer [NK]-mediated cytotoxicity) (Figure S1C).&lt;/p&gt;&lt;p&gt;Intermediate monocytes represented 35.7% of the total monocyte population and comprised two distinct clusters. Cluster 1 (26.9%) showed a pro-fibrotic and anti-inflammatory profile, characterized by high expression levels of genes associated with fibrosis (FN1, SPP1), cardiac protection (CTSL, ANGPTL4), T cell activation (ALCAM), oxidized low-density lipoprotein-induced cell injury (ANGPTL4) and phagocytosis (MERTK). Four modules were predominantly expressed in cluster 1. Notably, module pink facilitated substrate adhesion-dependent cell spreading and endocytosis (Figure S1D), while m","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968848","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":"Predictive nomogram integrating radiomics and multi-omics for improved prognosis-model in cholangiocarcinoma","authors":"Yunlu Jia,&nbsp;Mingyu Wan,&nbsp;Yifei Shen,&nbsp;Junli Wang,&nbsp;Xiao Luo,&nbsp;Mengye He,&nbsp;Ruiliang Bai,&nbsp;Wenbo Xiao,&nbsp;Xiaochen Zhang,&nbsp;Jian Ruan","doi":"10.1002/ctm2.70171","DOIUrl":"10.1002/ctm2.70171","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Intrahepatic cholangiocarcinoma (ICC) is a malignant tumour originating from the epithelial cells of the intrahepatic bile ducts. In recent years, its incidence has shown an upward trend globally. Notably, hepatitis B virus (HBV) infection is one of the significant risk factors for ICC.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Despite significant advancements in medical imaging and molecular biology technologies, predicting the prognosis of HBV-associated ICC patients remains challenging. One major reason for this challenge is the complex interactions between HBV infection, genetic mutations and tumour behaviour, which increase the uncertainty of prognosis predictions. As a result, traditional single indicators are insufficient for comprehensively assessing patient outcomes. Radiomics is a technology that extracts a large number of quantitative features from medical images, capturing the spatial structure and morphological changes of tumours.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Genomics, on the other hand, focuses on deciphering DNA sequence information, revealing the contributions of genetic variations to disease development. This study aims to develop and validate a predictive model that integrates radiomic features with genomic information. By doing so, it seeks to overcome the limitations of existing biomarkers, better meet the needs for personalised treatment of HBV-associated ICC patients and provide valuable references for future research and clinical practice.&lt;/p&gt;&lt;p&gt;A total of 389 intrahepatic cholangiocarcinoma (ICC) patients were retrospectively included and divided into a training cohort (210 patients), an internal validation cohort (90 patients) and an external validation cohort (89 patients). Table S1 displayed the clinical and imaging characteristics. The results showed that most clinical characteristics did not differ significantly between the groups, including age (&lt;i&gt;p&lt;/i&gt; = .188), gender distribution (&lt;i&gt;p&lt;/i&gt; = .456), the proportion of ferritin ≤323 (&lt;i&gt;p&lt;/i&gt; = .282), the proportion of high PIVKA-II (&lt;i&gt;p&lt;/i&gt; = .988), HBV infection rate (&lt;i&gt;p&lt;/i&gt; = .158), perineural invasion (&lt;i&gt;p&lt;/i&gt; = .294) and AJCC 8th edition Classification of Malignant Tumors (TNM) staging (&lt;i&gt;p&lt;/i&gt; = .455). The only characteristic that showed a statistically significant difference was the presence of vessel cancer embolus (VCE), with the training cohort (19.8%) significantly higher than the internal validation cohort (7.4%) and the external validation cohort (10.4%), &lt;i&gt;p&lt;/i&gt; = .044. There were no extreme biases between the three cohorts in baseline data. Figure 1 showed the flow diagram of the exclusion criteria of the ICC radiomic datasets. A total of 972 features of magnetic resonance imaging (MRI) images were extracted from the ROIs using the PyRadiomics Python package,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and those with ICC values &gt; 0.8 on both intra- and inter-observer agreement analyses were retained. Table S2 comprehensively summarised the essential patient dem","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969018","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":"Translational inhalable extracellular vesicle-based mRNA therapy for the treatment of lung cancer","authors":"Mengrui Liu,&nbsp;Brian Henick,&nbsp;Ke Cheng","doi":"10.1002/ctm2.70186","DOIUrl":"10.1002/ctm2.70186","url":null,"abstract":"&lt;p&gt;Lung cancer remains the leading carcinoma type in morbidity and mortality, distinguished by one of the lowest five-year survival rates. Despite improvements with incorporation of immune checkpoint therapy in certain contexts, systemic immune-related adverse events and the immunosuppressive tumour microenvironment(TME) constrain their effectiveness. Consequently, cytokines have emerged as a next-generation immunotherapy that can convert immunologically ‘cold’ tumours into ‘hot’ ones.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Interleukin-12 (IL12), a potent cytokine, has demonstrated significant efficacy in stimulating interferon-γ (IFN-γ) production and enhancing the cytolytic activity of immune cells. However, current research on IL12 normally focuses on intratumour injection due to the off-target-induced toxicity in systemic delivery.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Therefore, developing targeted and localised delivery platforms for IL12 is critical for deep-organ tumours, especially lung cancer. Our research introduces IL12 messenger RNA (mRNA)-loaded exosomes (IL12-Exo), which are directly delivered into the lung TME through inhalation, providing a groundbreaking approach to lung cancer immunotherapy.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The efficacy and safety of IL12 therapy hinge on its successful local delivery, which depends on enhanced targeting to the lung tumours and minimised leakage into the blood circulation and off-target organs. The mRNA of IL12 serves as an ideal delivery cargo, with its intratumoural delivery already advancing to clinical trials since the mRNA ensures local translation.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Additionally, extracellular vesicles, especially exosomes, are natural vesicles derived from cells and offer tremendous therapeutic potential through their inherent cargos or external mRNA delivery platforms.&lt;span&gt;&lt;sup&gt;5-7&lt;/sup&gt;&lt;/span&gt; Notably, we have harnessed lung spheroid cells as a novel source of therapeutic exosomes,&lt;span&gt;&lt;sup&gt;8-10&lt;/sup&gt;&lt;/span&gt; now in a first-in-man clinical trial for patients with idiopathic pulmonary fibrosis. We have also innovated various exosome-mediated delivery systems for lung-specific diseases, including COVID-19,&lt;span&gt;&lt;sup&gt;7, 11, 12&lt;/sup&gt;&lt;/span&gt; demonstrating the effectiveness of inhalation as a non-invasive and localised administration route.&lt;span&gt;&lt;sup&gt;8, 13-19&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Upon nebulised inhalation in a mouse model with lung tumours, IL12-Exo achieved targeted delivery and localised expression of IL12 cytokine (Figure 1). Neutralised inhalation delivery of IL12-Exo showed superior accumulation in the lung compared to other off-target organs, and the exosome platform exhibited a specific affinity for tumour cells over the IL12 mRNA-loaded liposome (IL12-Lipo) control. These findings align with our previous research indicating superior delivery of mRNA and protein in healthy lungs when encapsulated in exosomes rather than liposomes.&lt;span&gt;&lt;sup&gt;20&lt;/sup&gt;&lt;/span&gt; As expected, the enhanced localisation led to susta","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969337","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":"CMPK2 promotes NLRP3 inflammasome activation via mtDNA-STING pathway in house dust mite-induced allergic rhinitis","authors":"YaoMing Zheng,&nbsp;YaDong Xie,&nbsp;JiaYing Li,&nbsp;YuJie Cao,&nbsp;Min Li,&nbsp;Qing Cao,&nbsp;MiaoMiao Han,&nbsp;HongFei Lou,&nbsp;YiLai Shu,&nbsp;Hui Xiao,&nbsp;HuaBin Li","doi":"10.1002/ctm2.70180","DOIUrl":"10.1002/ctm2.70180","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;House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although allergic sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, the molecular mechanisms driving this process remain incompletely elucidated.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study aimed to elucidate the molecular mechanisms underlying HDM-induced AR.&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;We examined the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and the NLRP3 inflammasome in both AR patients and mice. Additionally, we investigated the role of CMPK2 and STING in the activation of the NLRP3 inflammasome in AR.&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;The expression of CMPK2, STING and the NLRP3 inflammasome was significantly increased in the nasal mucosa of AR patients compared to non-AR controls. A positive correlation was found between CMPK2 expression and the levels of STING, NLRP3, ASC, CASP1 and IL-1β. HDM treatment up-regulated the expression of CMPK2, and CMPK2 overexpression enhanced NLRP3 inflammasome activation in human nasal epithelial cells (HNEPCs). Additionally, mitochondrial reactive oxygen species (mtROS) production following HDM exposure contributed to mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA), which activated the cyclic GMP-AMP synthase (cGAS)-STING pathway. Remarkably, depletion of mtDNA or inhibition of STING signalling reduced HDM-induced NLRP3 inflammasome activation in HNEPCs. In vivo, genetic knockout of CMPK2 or STING alleviated NLRP3 inflammasome activation and ameliorated clinical symptoms of AR in mice.&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 results suggest that HDM promotes the activation of NLRP3 inflammasome through the up-regulation of CMPK2 and ensuing mtDNA-STING signalling pathway, hence revealing additional therapeutic target for AR.&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;\u0000 &lt;p&gt;Cytidine/uridine monophosphate kinase 2 (CMPK2) expression is up-regulated in the nasal mucosa of patients and mice with allergic rhinitis (AR).&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;CMPK2 caused NLRP3 inflamma","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968843","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}