Clinical and Translational Medicine最新文献

{"title":"Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: 3-year survival update and multi-omics analysis","authors":"Jie Dai, Tianxiao Xu, Lifeng Li, Meiyu Fang, Jing Lin, Jun Cao, Xue Bai, Caili Li, Xiaoting Wei, Junjie Gu, Yaoyao Liu, Xuan Gao, Xuefeng Xia, Jun Guo, Yu Chen, Lili Mao, Lu Si","doi":"10.1002/ctm2.70169","DOIUrl":"10.1002/ctm2.70169","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Atezolizumab plus bevacizumab has shown promising efficacy in advanced mucosal melanoma in the multi-centre phase II study. This report updates 3-year survival outcomes and multi-omics analysis to identify potential response biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Forty-three intention-to-treat (ITT) patients received intravenous administration of atezolizumab and bevacizumab every 3 weeks. Available samples underwent whole exome sequencing, transcriptome sequencing and targeted bisulphite sequencing to assess correlations with clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>With a median follow-up of 40.3 months, the median overall survival (mOS) was 23.7 months (95% confidence interval [CI], 15.1–34), and the 3-year OS rate was 28.7% (95% CI, 17.6%–46.8%). Patients with upper site melanoma exhibited longer progression-free survival (PFS), higher tumour neoantigen burden (TNB) and greater copy number variations (CNVs) burden compared to those with lower site melanoma. <i>NRAS</i> mutations were associated with enhanced angiogenesis, with five of six patients achieving partial response. Inflammatory cell infiltration, angiogenic status and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This 3-year updated analysis confirms the sustained efficacy of atezolizumab in combination of bevacizumab in patients with advanced mucosal melanoma. Inflammatory cell infiltration and angiogenic status were associated with therapeutic response. Furthermore, mucosal melanoma of upper site and <i>NRAS</i> mutation appear to be good predictors of response to immune checkpoint inhibitor and anti-angiogenic combination treatment. Targeting SMAD2 and p38 MAPK pathways may further improve the outcome of mucosal melanoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>3-year follow-up study confirmed the therapeutic efficacy of atezolizumab combined with bevacizumab</li>\u0000 \u0000 <li>Tumors in the upper site and NRAS mutations are more sensitive to treatment</li>\u0000 \u0000 <li>Inflammatory cell infiltration, angiogenic status, and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators</li>\u0000 </ul>\u0000 </div>\u0000 </section>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930663","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":"Disrupting EDEM3-induced M2-like macrophage trafficking by glucose restriction overcomes resistance to PD-1/PD-L1 blockade","authors":"Shaoyong Peng, Minshan Wu, Qian Yan, Gaopo Xu, Yumo Xie, Guannan Tang, Jinxin Lin, Zixu Yuan, Xiaoxia Liang, Ze Yuan, Jingrong Weng, Liangliang Bai, Xiaolin Wang, Huichuan Yu, Meijin Huang, Yanxin Luo, Xiaoxia Liu","doi":"10.1002/ctm2.70161","DOIUrl":"10.1002/ctm2.70161","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immunotherapy is beneficial for some colorectal cancer (CRC) patients, but immunosuppressive networks limit its effectiveness. Cancer-associatedfibroblasts (CAFs) are significant in immune escape and resistance toimmunotherapy, emphasizing the urgent need for new treatment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Flow cytometric, Western blotting, proteomics analysis, analysis of public database data, genetically modified cell line models, T cell coculture, crystal violetstaining, ELISA, metabonomic and clinical tumour samples were conducted to assess the role of EDEM3 in immune escape and itsmolecular mechanisms. We evaluated theeffects of FMD plus 2-DG on antitumour immunity using multipleximmunofluorescence, flow cytometry, cytokine profiling, TUNEL assays, xenografttumours, and in vivo studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We show thatCAFs upregulate PD-L1 glycosylation and contribute to immune evasion byglycosyltransferase EDEM3. Additionally, EDEM3 plays a role in tumour immunityduring tumour progression. However, the EDEM3-mediated upregulation of PD-L1 expression underpins PD-1/PD-L1 blockade resistance in vivo. This finding contradictsthe previous trend that positive PD-L1 expression indicates a strong responseto PD-1/PD-L1 blockade. Mechanistically, high-EDEM3 expression facilitates M2-like This finding contradictsthe previous trend that positive PD-L1 expression indicates a strong responseto PD-1/PD-L1 blockade.Mechanistically, polarizationand chemotactic migration of macrophages, which are enriched in theperipheral region of tumours compared to thecore region, precluding access of CD8+ T cells to tumourfoci. Furthermore, we EDEM3 predominantly activates the recruited M2-like macrophagesvia a glucose metabolism-dependent mechanism. Manipulationof glucose utilization by a fasting-mimicking diet(FMD) plus 2-DG treatmentsynergistically with PD-1 antibody elicits potent antitumour activity byeffectively decreasing tumour glycosylated PD-L1 expression, augmenting the CD8+effector T cell infiltration and activation while concurrently reducing the infiltration.TheCAFs-EDEM3-M2-like macrophage axis plays a critical role in promotingimmunotherapy resistance. infiltration.TheCAFs-EDEM3-M2-like macrophage axis plays a critical role in promotingimmunotherapy resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study suggests that blocking EDEM3-induced M2-like macro phage trafficking by FMD plus 2-DG is a promising and effective strategy to overcomeresistance to c","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926577","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 the prognostic and operative role of intratumoural microbiota in non-small cell lung cancer: Insights from 16S rRNA and RNA sequencing","authors":"Fuling Mao, Zixuan Hu, Ruifeng Shi, Hongbing Zhang, Zihe Zhang, Yongwen Li, Xuanguang Li, Penghu Gao, Jinhui Li, Minghui Liu, Hongyu Liu, Jun Chen","doi":"10.1002/ctm2.70156","DOIUrl":"10.1002/ctm2.70156","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Complex interrelationships between the microbiota and cancer have been identified by several studies. However, despite delineating microbial composition in non-small cell lung cancer (NSCLC), key pathogenic microbiota and their underlying mechanisms remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed <i>16S rRNA</i> V3–V4 amplicon and transcriptome sequencing on cancerous and adjacent normal tissue samples from 30 patients with NSCLC, from which clinical characteristics and prognosis outcomes were collected. We used <i>16S rRNA</i> sequencing to dissect microbial composition and perform prognosis correlations, and in conjunction with transcriptome sequencing, we determined potential mechanisms underpinning significant microbiota actions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In comparing different sample types, we identified more pronounced beta diversity disparity between NSCLC, lung squamous cell carcinoma (LUSC) and corresponding paired normal tissues. Concurrently, LUSC and lung adenocarcinoma exhibited distinct microbial composition traits at genus levels. Subsequently, four phyla, five classes, nine orders, 17 families and 36 genera were filtered out and were related to prognosis outcomes. Intriguingly, a protective microbial cluster was identified encompassing nine genera associated with delayed disease recurrence, with functional analyses suggested that these microbiota predominantly exerted metabolism-related functions. Additionally, a harmful microbial cluster (HMC) was identified, including three genera. In this HMC and subsequent prognosis model analyses, harmful intratumoural microbiota were potentially implicated in infection, inflammation and immune regulation. Crucially, we identified a microbial genus, <i>Peptococcus</i>, which was as an independent, detrimental NSCLC prognostic factor and potentially impacted prognosis outcomes via tumour necrosis factor (TNF) signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified a substantial connection between intratumoural microbiota and NSCLC prognosis outcomes. Protective microbiota primarily exerted metabolic functions, whereas harmful microbiota were mainly implicated in infection, inflammation and immune modulation. Furthermore, <i>Peptococcus</i> may be significant in adverse NSCLC prognoses and serve as a potential biomarker for patient management and cancer screening.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926554","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":"A new peptide inhibitor of C1QBP exhibits potent anti-tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair","authors":"Xingxing Li,&nbsp;Yue Wu,&nbsp;Min Zhang,&nbsp;Fengliang Wang,&nbsp;Hong Yin,&nbsp;Yanrong Zhang,&nbsp;Shuli Zhao,&nbsp;Jiehua Ma,&nbsp;Mingming Lv,&nbsp;Cheng Lu","doi":"10.1002/ctm2.70162","DOIUrl":"10.1002/ctm2.70162","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>C1QBP exhibits heightened expression across a spectrum of tumours, thereby fostering their proliferation and metastasis, rendering it a pivotal therapeutic target. Nevertheless, to date, no pharmacological agents capable of directly targeting and inducing the degradation of C1QBP have been identified. In this study, we have unveiled a new peptide, PDBAG1, derived from the precursor protein GPD1, employing a peptidomics-based drug screening strategy. PDBAG1 has demonstrated substantial efficacy in suppressing triple-negative breast cancer (TNBC) both in vitro and in vivo. Its mechanism of action involves mitochondrial impairment and the inhibition of oxidative phosphorylation (OXPHOS), achieved through direct binding to C1QBP, thereby promoting its ubiquitin-dependent degradation. Concomitantly, due to metabolic adaptability, we have observed an up-regulation of glycolysis to compensate for OXPHOS inhibition. We observed an aberrant phenomenon wherein the hypoxia signalling pathway in tumour cells exhibited significant activation under normoxic conditions following PDBAG1 treatment. Through size-exclusion chromatography (SEC) and isothermal titration calorimetry (ITC) assays, we have validated that PDBAG1 is capable of binding C1QBP with a <i>K</i>_d value of 334 nM. Furthermore, PDBAG1 inhibits homologous recombination repair proteins and facilitates synergism with poly-ADP-ribose polymerase inhibitors in cancer therapy. This underscores that PDBAG1 ultimately induces insurmountable survival stress through multiple mechanisms while concurrently engendering therapeutic vulnerabilities specific to TNBC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The newly discovered peptide PDBAG1 is the first small molecule substance found to directly target and degrade C1QBP, demonstrating significant tumour inhibitory effects and therapeutic potential.</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":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920698","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":"Exosome-derived long non-coding RNA AC010789.1 modified by FTO and hnRNPA2B1 accelerates growth of hair follicle stem cells against androgen alopecia by activating S100A8/Wnt/β-catenin signalling","authors":"Shaojun Chu,&nbsp;Lingling Jia,&nbsp;Yulong Li,&nbsp;Jiachao Xiong,&nbsp;Yulin Sun,&nbsp;Qin Zhou,&nbsp;Dexiang Du,&nbsp;Zihan Li,&nbsp;Xin Huang,&nbsp;Hua Jiang,&nbsp;Baojin Wu,&nbsp;Yufei Li","doi":"10.1002/ctm2.70152","DOIUrl":"10.1002/ctm2.70152","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 increased incidence of androgenic alopecia (AGA) causes adverse physiological and psychological effects on people of all genders. The hair follicle stem cells (HFSCs) have displayed clinical improvements on AGA. However, the molecular mechanism of HFSCs against AGA remains elusive.&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;The expression and prognosis of lncRNA AC010789.1 in AGA hair follicle tissues were assessed by qRT-PCR analysis. CCK-8, EdU and Transwell analysis were utilized to assess cell growth. The specific binding between AC010789.1 and FTO mediated m&lt;sup&gt;6&lt;/sup&gt;A modification or the effect of AC010789.1 on hnRNPA2B1, S100A8 and Wnt/β-catenin signaling expression was confirmed by bioinformatic analysis, RIP, RNA pull-down and Western blot assay. The effects of Exosome-loaded AC010789.1 prompted HFSCs proliferation and hair follicle regeneration were confirmed in hairless mice.&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 herein found that the mRNA levels of lncRNA AC010789.1 were decreased in AGA tissue samples but increased in HFSCs of surrounding normal tissue samples. Overexpression (OE) of AC010789.1 promoted HFSC proliferation, DNA synthesis and migration as well as K6HF and Lgr5 upregulation, whereas knockdown of AC010789.1 showed the opposite effects. The total or AC010789.1 m&lt;sup&gt;6&lt;/sup&gt;A levels were reduced and FTO demethylase was upregulated in AGA tissue samples, but these indicated the reverse results in HFSCs of surrounding normal tissue samples. FTO OE decreased AC010789.1 m&lt;sup&gt;6&lt;/sup&gt;A levels and its mRNA levels in HFSCs and abolished AC010789.1-induced HFSCs proliferation. In addition, AC010789.1 was identified to bind to m&lt;sup&gt;6&lt;/sup&gt;A reader hnRNPA2B1, which was downregulated in AGA but upregulated in HFSCs of surrounding normal tissue samples. hnRNPA2B1 OE attenuated AC010789.1 knockdown-induced inhibition of HFSCs proliferation. Moreover, AC010789.1 could bind to and enhance downstream S100A8 protein expression, which mediated Wnt/β-catenin signaling to accelerate HFSCs proliferation. Exosome-loaded AC010789.1 prompted HFSCs proliferation and hair follicle regeneration 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 findings demonstrated that exosome-derived lncRNA AC010789.1 modified by FTO and hnRNPA2B1 facilitated the proliferation of human HFSCs against AGA by activating S100A8/Wnt/β-catenin signaling.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920701","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":"Titin gene mutations enhance radiotherapy efficacy via modulation of tumour immune microenvironment in rectum adenocarcinoma","authors":"Hengchang Liu,&nbsp;Jialiang Liu,&nbsp;Xu Guan,&nbsp;Zhixun Zhao,&nbsp;Pu Cheng,&nbsp;Haipeng Chen,&nbsp;Zheng Jiang,&nbsp;Xishan Wang","doi":"10.1002/ctm2.70123","DOIUrl":"10.1002/ctm2.70123","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study investigates the impact of Titin (TTN) gene mutations on radiotherapy sensitivity in rectum adenocarcinoma (READ) by examining changes in the tumour immune microenvironment.&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;Data on gene expression and mutations in READ were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Bioinformatics analysis explored the correlation between TTN mutations and immune cell infiltration. In vitro, lentiviral vectors were used to assess TTN mutations' effects on ANKRD1 expression in two READ cell lines. ANKRD1 was overexpressed, and clonogenic assays evaluated radiotherapy sensitivity. Flow cytometry, immunofluorescence, and comet assays examined mutations' impact on cell cycle, apoptosis, and DNA damage response (DDR). An in vivo mouse model and formalin-fixed paraffin-embedded samples from locally advanced rectal cancer (LARC) patients before and after radiotherapy were analyzed, followed by prognostic evaluation.&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;Bioinformatics revealed that TTN mutations increase radiation sensitivity in LARC by slowing cell proliferation, promoting apoptosis, and reducing DDR. TTN mutations also inhibit ANKRD1 expression via JUN disruption and enhance CD4/CD8 T-cell infiltration, improving anti-tumour immunity and outcomes. Observations from the clinical study showed a substantial decline in ANKRD1 expression levels alongside a notable surge in the counts of CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T cells after undergoing radiotherapy. Patients with TTN mutations, low ANKRD1 expression, and high densities of CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T cells had longer 3-year disease-free survival in READ.&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 reveal that TTN mutations can serve as biomarkers for enhanced radiotherapy sensitivity in READ. By altering the tumour's immune microenvironment, these mutations may provide a novel target for personalized radiotherapy strategies, potentially improving therapeutic outcomes in patients with READ.&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;ol&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The association between TTN mutations and tumour mutation burden, as well as immune cell infiltration in READ, is examined.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920736","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":"Identification of taste cells and reduced taste-related proteins in saliva correlate with the impaired taste sensitivity in long-coronavirus disease","authors":"Parul Patel,&nbsp;Shveta Jaishankar,&nbsp;Mythily Srinivasan","doi":"10.1002/ctm2.70165","DOIUrl":"10.1002/ctm2.70165","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Although transient chemosensory impairments in viral infections are common, the unique features of the recent severe acute respiratory coronavirus-2 (CoV2) pandemic are subjective reports of taste dysfunction (TD) and TD without olfactory disturbance.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Further, TD lasting for months to years has been observed with varied prevalence amongst post-CoV2 symptoms. Persistent dysgeusia even in adolescents who were asymptomatic during primary infection is an emerging concern that could impact the overall health.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Taste perception is mediated by continuously renewing specialized taste receptor cells (TRC) that are supported by non-gustatory epithelial cells. An optimal ratio of taste cell renewal and loss is tightly regulated to maintain taste function.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Chronic viral infections, even in the absence of continued presence of the virus could hamper progenitor cell renewal. A longitudinal study of CoV2-infected individuals with prolonged TD showed positive staining for spike protein and reduced number taste cells in tongue papillae as late as seventeen weeks post-infection.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Further, concomitant dysbiosis and inflammation could accelerate the loss of taste cells contributing to TD.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Saliva acts as a conduit of substances to taste cells that mediate specific taste perception. Consistently, proteins that facilitate the transport of tastants are reduced in the saliva of individuals with TD. Some salivary proteins also contribute to the cellular turnover and homeostasis. Gustin, an enzymatic protein may directly influence taste perception as a trophic factor, or by modulating the buffering environment around taste receptors.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Sonic hedgehog (SHH) is a morphogenic protein, signalling through which promotes proliferation and differentiation of taste progenitor cells. Disruption of SHH pathways in viral infections could impair TRC proliferation and differentiation, and thereby interfere with taste perception.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; In this pilot study, we correlated the objective measures of taste sensitivity with the salivary proteins involved in taste perception and investigated the presence of taste cells in saliva to explore the biological indicators of TD in long-coronavirus disease (long-COVID) individuals.&lt;/p&gt;&lt;p&gt;We invited respondents from our survey amongst individuals with subjective complaints of TD following the CoV2+ test and with records of the initial date of positive testing. Figure 1A shows the demographic features of our study cohort of individuals with a history of CoV2+ test once (long-COVID) or more than once (long-COVID reinfection). All individuals completed the Waterless Empirical Taste Test (WETT) which consists of 53 paper strips, with four strips of increasing concentrations each of sucrose, citric acid, sodium chloride, caffeine, and monosodium glutamate or ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920735","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":"A new paradigm for cancer immunotherapy: Orchestrating type 1 and type 2 immunity for curative response","authors":"Bing Feng,&nbsp;Li Tang","doi":"10.1002/ctm2.70154","DOIUrl":"10.1002/ctm2.70154","url":null,"abstract":"&lt;p&gt;The immune system serves a vital function in safeguarding the body against external pathogens and eradicating cancerous cells. Depending on the nature of pathogens encountered, the immune system orchestrates distinct immunological strategies: type 1 immunity primarily targets intracellular pathogens, including viruses and certain bacteria; type 2 immunity is adept at combating parasites within mucosal tissues and the dermis; while type 3 immunity is instrumental in the clearance of extracellular fungi and bacteria.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Nevertheless, the mechanisms by which the immune system influences cancer initiation, progression, and therapeutic intervention remain partially elucidated. Traditionally, type 1 immunity has been regarded as the foremost defence against cancers, and current immunotherapeutic approaches including immune checkpoint blockade (ICB)&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; and chimeric antigen receptor T-cell (CAR-T) therapy&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; are crafted to activate or enhance type 1 immune responses against cancer. Despite the clinical success, the curative response of type 1-centric immunotherapies has been limited, frequently resulting in a low patient response rate or high relapse rate with diminished durability of response.&lt;/p&gt;&lt;p&gt;CAR-T therapy targeting CD19 has exhibited exceptional initial response rates in various malignancies derived from B-cell lineages; however, relapse remains a formidable challenge. To elucidate the underlying factors contributing to relapse, we conducted a comprehensive single-cell multi-omics analysis of over one million pre-infusion CAR-T cells sourced from 82 pediatric patients with B-acute lymphoblastic leukaemia (B-ALL) and six healthy donors.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The patients were participants in two of the pioneering global clinical trials for pediatric B-ALL (NCT01626495 and NCT02906371), with a follow-up duration extending beyond ten years. While some patients experienced relapse within two years post-treatment, others achieved remarkable long-term cancer-free survival, enduring for up to eight years, thereby being considered cured of their malignancy. Clustering analysis revealed that the CAR-T cell products from patients who were cured demonstrated a significantly higher proportion of CAR-T cells characterized by type 2 immune signatures (type 2 high CAR-T cells); conversely, no noteworthy differences were observed in the proportion of CAR-T cells exhibiting type 1 immune signatures.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Furthermore, preclinical experiments indicated that the proliferative capacity of type 2 high CAR-T cells surpassed that of type 2 low CAR-T cells by more than tenfold, indicative of their superior memory characteristics and diminished signs of exhaustion.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; In a recurrent leukaemia model, type 2 high CAR-T cells effectively mitigated leukaemia relapse.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; These findings underscore the pivotal and previously underappreciated ro","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909170","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 sequencing analysis reveals cetuximab resistance mechanism and salvage strategy in colorectal cancer","authors":"Shiyun Chen,&nbsp;Zhaoli Tan,&nbsp;Xiaojie Wu,&nbsp;Yanli Lin,&nbsp;Xiang Li,&nbsp;Yumeng Cui,&nbsp;Weiling Man,&nbsp;Fang Pang,&nbsp;Yanghua Li,&nbsp;Faliang Shi,&nbsp;Lu Han,&nbsp;Miaomiao Gou,&nbsp;Li Zhou,&nbsp;Zhikuan Wang,&nbsp;Youliang Wang,&nbsp;Guanghai Dai","doi":"10.1002/ctm2.70151","DOIUrl":"10.1002/ctm2.70151","url":null,"abstract":"&lt;p&gt;Through single-cell sequencing analysis, we identified heterogeneity and evolutionary trends in tumour cell subsets, as well as key signalling pathways involved in acquired resistance to cetuximab. Our findings suggest that celecoxib, which simultaneously inhibits ERK and SMAD signalling pathways, could effectively counteract cetuximab resistance in treating colorectal cancer (CRC).&lt;/p&gt;&lt;p&gt;Cetuximab is the preferred treatment for &lt;i&gt;RAS/RAF&lt;/i&gt; wild-type metastatic CRC.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, its efficacy is significantly curtailed by the development of resistance, with up to 70% of patients developing resistance within one year of cetuximab therapy.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Our previous investigation highlighted that &lt;i&gt;PRSS&lt;/i&gt; is intricately linked to cetuximab resistance.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Furthermore, several key genes implicated in EGFR monoclonal antibody resistance have been identified, including &lt;i&gt;EGFR&lt;/i&gt;,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;KRAS&lt;/i&gt;,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;PIK3CA&lt;/i&gt;&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; and &lt;i&gt;MET&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Despite these findings, reversing cetuximab resistance remains challenging. Although no large-scale clinical research has confirmed that celecoxib reverses cetuximab resistance, it is deemed a promising candidate for combination therapy in light of its extensive antitumor efficacy across a spectrum of cancers and its prevalent application in clinical practice.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In this study, we systematically investigated the molecular mechanisms and evolutionary pathways of acquired resistance via single-cell RNA sequencing (scRNA-seq) analysis. Initially, we established two independent cetuximab resistance models in CRC cell lines DiFi and LIM1215 (Figure 1A,B and Figure S1). Utilizing scRNA-seq, underlying mechanisms of cetuximab resistance were explored. Our findings revealed that CRC cells generated multiple subsets of tumour cells during the transition period (DiFi-R-T and LIM-R-T) of acquired drug resistance (Figure 1C and Figure S2A). Each cellular subset exhibited distinct highly expressed marker genes (Figures S2B and S3).&lt;/p&gt;&lt;p&gt;A pseudotime analysis using DiFi-R-T was conducted to investigate the evolutionary trajectory of cell subsets. The results indicated that the trajectory of cell subset evolution followed a path from initial subsets such as subset 6 and subset 1 to terminal subsets like subset 2 (Figure 1D,E). Similarly, a pseudotime analysis with LIM-R-T demonstrated a transition from initial cell subsets like subset 1 and subset 7 to terminal subset 8 (Figure S4). Copy number variation (CNV) analyses revealed significant CNV disparities in the terminal subsets of both cell lines compared to other subsets, suggesting that terminal subsets possess a higher degree of malignancy relative to other subsets. These terminal subsets likely represent the group of cells that successfully transitioned into a fully cetuximab-resistant subset during resis","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909327","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":"From general to specific: Tailoring large language models for real-world medical communications","authors":"Xinti Sun,&nbsp;Wenjun Tang,&nbsp;Zigeng Huang,&nbsp;Erping Long,&nbsp;Peixing Wan","doi":"10.1002/ctm2.70157","DOIUrl":"10.1002/ctm2.70157","url":null,"abstract":"&lt;p&gt;The development of generative artificial intelligence (AI), such as large language models (LLMs), has garnered significant attention due to their proficiency in interpreting instructions and generating human-resembled responses. Autoregressive LLMs, like GPT, are pre-trained on large-scale natural language corpora.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Subsequently, they are fine-tuned using human-provided instructions, endowing them with generalized application capabilities across various tasks.&lt;/p&gt;&lt;p&gt;However, these foundation models lack training in specialized medical corpora, which limits their capability to accurately interpret the critical aspects of patient-provider communications, leading to misinterpretation or inaccuracies in real-world applications.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Over the past 2 years, several medical LLMs have been developed or fine-tuned using medical corpora and professional knowledge. For example, among Chinese LLMs, Sunsimiao-7B was fine-tuned from Qwen2-7B with medical corpora, achieving &lt;i&gt;state-of-the-art&lt;/i&gt; performance in the Chinese Medical Benchmark test.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Similarly, HuatuoGPT-II, adopting a one-stage adaptive training approach showed outstanding performance in the 2023 Chinese National Pharmacist Examination.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Despite possessing extensive medical knowledge and excelling in medical examinations, these models have yet to be implemented in real-world healthcare settings. A primary barrier is the lack of “site-specific” knowledge, which refers to the unique protocols, workflows, and contextual information specific to each reception desk within a hospital. The indispensable site-specific knowledge underscores the need for further refinement of foundation models. Secondly, LLMs may generate hallucinations or fabricated facts, leading to misinformation. This not only undermines trust but also raises significant concerns about patient safety, posing a major barrier to their practical implementation in healthcare settings.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Third, randomized clinical trials (RCTs) on medical LLMs remained limited, necessitating rigorous validation to assess their practicality. As pointed out by David Ouyang&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;, “We need more RCTs or AI”.&lt;/p&gt;&lt;p&gt;To address these needs, we developed a site-specific prompt engineering chatbot (SSPEC) within the “Panoramic Data Collection-Knowledge Refinement-Algorithm Enhancement” framework&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; (Figure 1). This process began with panoramic data collection across each reception site. Next, we incorporated site-specific knowledge and fine-tuned the foundation model, GPT-3.5 Turbo, using a prompt template with three components: Role of SSPEC, Patient Query, and Site-Specific Knowledge. This approach enriches the foundation model with site-specific knowledge and enhances its logical reasoning, effectively adapting it to the heterogeneity of medical settings (Figure 2A). Furthermore, the model undergoes iterat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909318","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}