MedComm最新文献

{"title":"Bending and Scission: When the Membraneless Condensates Meet Endosome Membrane","authors":"Zhengkun Zhang, Feng Xie, Long Zhang","doi":"10.1002/mco2.70165","DOIUrl":"https://doi.org/10.1002/mco2.70165","url":null,"abstract":"<p>In a recent study reported in <i>Nature</i>, Xiaofeng Fang's group from Tsinghua University and a team led by Roland Knorr from the University of Cologne in Germany discovered that the plant protein FREE1 can form condensates through phase separation, which drive endosomal membrane invagination and instability via wetting phenomenon [<span>1</span>]. This study highlights biomolecular condensates' critical role in physiological processes, particularly in mediating endosomal sorting complex required for transport (ESCRT) and adenosine triphosphate (ATP) independent intraluminal vesicle (ILV) formation.</p><p>Multivesicular bodies (MVBs) are vital organelles within cells that are primarily responsible for delivering cargo molecules from the endocytic pathway to lysosomes for degradation and recycling and for regulating biological processes such as nutrient uptake, immunity, and signal transduction [<span>2</span>]. The MVB membrane forms ILVs through invagination and scission; these ILVs then sort protein cargo and require the consumption of ATP by the ESCRT protein complex. Biomolecular condensates result from liquid–liquid phase separation (LLPS) and typically exhibit the characteristics of liquid droplets or gel-like aggregates, performing various functions within cells. Previous studies have shown that condensates interact with membranes, leading to “wetting” and capillary phenomena. However, the biological significance of wetting-related capillary forces in cellular processes remains largely unknown [<span>3</span>]. In the study led by Xiaofeng Fang and colleagues, the authors used in vitro reconstitution, computer simulations, and genetic experimental analysis to discover that FREE1 condensates can induce membrane curvature and invagination independently of the ESCRT protein complex and ATP. Notably, the ATP-independent membrane scission mediated by FREE1 condensates was primarily supported by in vitro reconstitution and computer simulations, whereas the genetic experimental analysis (e.g., vps2.1 knockout complementation) indirectly supports ESCRT-independence. The study first used biotinylated isoxazole (b-isox) compounds to precipitate and screen proteins with phase-separation capabilities [<span>4</span>], revealing that FREE1 possesses robust phase-separation abilities both in vivo and in vitro. This phase separation ability is unaffected by salt concentration, and the intrinsically disordered region (IDR) at the N-terminus of FREE1 is required for phase separation. In addition, FREE1 contains an FYVE domain capable of binding to the membrane lipid phosphatidylinositol 3-phosphate (PI3P), enabling its localization to the MVB membrane. Further research revealed that the formation of condensates significantly enhances the membrane-binding capacity of FREE1. Moreover, FREE1 condensates served as scaffolds, recruiting other ESCRT components, particularly the ESCRT-I subcomplex (including VPS23, VPS28, and VPS37), as client molecules into","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic Alterations in DNA Methylation of CD4+ T Cells and Macrophages in a Murine Model of Tuberculous Pleural Infection Induced by BCG Vaccination","authors":"Ming-Ming Shao,&nbsp;Qing-Yu Chen,&nbsp;Xin Zhang,&nbsp;Shu-Feng Dong,&nbsp;Rui-Qi Wei,&nbsp;Huan-Zhong Shi,&nbsp;Feng-Shuang Yi","doi":"10.1002/mco2.70166","DOIUrl":"https://doi.org/10.1002/mco2.70166","url":null,"abstract":"<p>Tuberculous pleural effusion (TPE) is a prevalent form of extrapulmonary tuberculosis, and immune abnormalities play a crucial role in promoting its development. However, the dynamic changes and regulatory characteristics of immune cells during TPE progression remain incompletely understood. This study analyzed DNA methylation and transcriptome data from macrophages and CD4⁺ T cells from pleural lavage fluid of BCG-induced tuberculous pleurisy mouse models at specific time points (Days 0, 1, 7, and 14). The results revealed substantial alterations in DNA methylation patterns associated with inflammatory factors and interferon genes. Notably, macrophages exhibited the most pronounced differences in DNA methylation profiles on Day 1, while CD4⁺ T cells demonstrated gradual changes over time. The investigation further indicated that DNA methylation primarily regulated the differentiation of Th1, Th17, and Th22 cells but not Th9 cells. Additionally, single-cell RNA sequencing analysis revealed an increasing expression of C1q during infection, which was regulated by DNA methylation. Importantly, C1q⁺ and C1q⁻ macrophages demonstrated distinct roles in modulating immune responses during infection. This research provides valuable insights into the DNA methylation profile of immune cells during <i>Mycobacterium bovis</i> infection–induced pleurisy in a mouse model, enhancing our understanding of the upstream regulatory mechanisms underlying immune response development in TPE.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT3 Signaling Pathway in Health and Disease","authors":"Md Abdus Samad,&nbsp;Iftikhar Ahmad,&nbsp;Aakifah Hasan,&nbsp;Mohammad Hassan Alhashmi,&nbsp;Arusha Ayub,&nbsp;Fahad A. Al-Abbasi,&nbsp;Ajoy Kumer,&nbsp;Shams Tabrez","doi":"10.1002/mco2.70152","DOIUrl":"https://doi.org/10.1002/mco2.70152","url":null,"abstract":"<p>Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor involved in multiple physiological and pathological processes. While STAT3 plays an essential role in homeostasis, its persistent activation has been implicated in the pathogenesis of various diseases, particularly cancer, bone-related diseases, autoimmune disorders, inflammatory diseases, cardiovascular diseases, and neurodegenerative conditions. The interleukin-6/Janus kinase (JAK)/STAT3 signaling axis is central to STAT3 activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, and therapy resistance. Despite extensive research, the precise mechanisms underlying dysregulated STAT3 signaling in disease progression remain incompletely understood, and no United States Food and Drug Administration (USFDA)-approved direct STAT3 inhibitors currently exist. This review provides a comprehensive evaluation of STAT3's role in health and disease, emphasizing its involvement in cancer stem cell maintenance, metastasis, inflammation, and drug resistance. We systematically discuss therapeutic strategies, including JAK inhibitors (tofacitinib, ruxolitinib), Src Homology 2 domain inhibitors (S3I-201, STATTIC), antisense oligonucleotides (AZD9150), and nanomedicine-based drug delivery systems, which enhance specificity and bioavailability while reducing toxicity. By integrating molecular mechanisms, disease pathology, and emerging therapeutic interventions, this review fills a critical knowledge gap in STAT3-targeted therapy. Our insights into STAT3 signaling crosstalk, epigenetic regulation, and resistance mechanisms offer a foundation for developing next-generation STAT3 inhibitors with greater clinical efficacy and translational potential.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoration of Transgelin 2 Expression Reverses Immune Escape in Ovarian Cancer: A Dawn for Immunotherapy","authors":"Zhiqiang Wang,&nbsp;Ge Lou,&nbsp;Mingzhu Yin","doi":"10.1002/mco2.70164","DOIUrl":"https://doi.org/10.1002/mco2.70164","url":null,"abstract":"&lt;p&gt;In a seminal study published in &lt;i&gt;Nature&lt;/i&gt;, Hwang et al. recently revealed for the first time that Transgelin 2 (TAGLN2) regulates lipid metabolism and antitumor function through interaction with fatty acid binding protein 5 (FABP5) in CD8+ T cells [&lt;span&gt;1&lt;/span&gt;]. The mechanism by which TAGLN2 is inhibited by endoplasmic reticulum (ER) stress in the microenvironment of ovarian cancer (OC) leading to T-cell dysfunction was clarified, providing a new target and a potential strategy for improving immunotherapy for solid tumors.&lt;/p&gt;&lt;p&gt;Lipid metabolism plays an indispensable role in the activation, proliferation, and execution of effector functions in T cells [&lt;span&gt;2&lt;/span&gt;]. As a critical regulator of lipid metabolism, FABP5 efficiently coordinates lipid uptake and transport, providing sufficient energy substrates for mitochondrial respiration in T cells, thereby ensuring their optimal bioenergetic status during antitumor immunity [&lt;span&gt;3, 4&lt;/span&gt;]. However, significant gaps remain in understanding the regulatory mechanisms of FABP5 in T-cell lipid metabolism, particularly within tumor-related contexts. Metastatic OC, a refractory immunosuppressive tumor resistant to multiple therapeutic approaches—including T cell-based immunotherapies, exerts a microenvironment that drives functional impairment in tumor-infiltrating T cells [&lt;span&gt;5&lt;/span&gt;]. Consequently, elucidating the molecular mechanisms underlying immune evasion in OC and identifying potential therapeutic targets capable of reversing T cell dysfunction is paramount for enhancing the efficacy of OC immunotherapy and improving patient prognosis.&lt;/p&gt;&lt;p&gt;The exact way tumor microenvironment (TME) inhibits T cell lipid metabolism is unclear. Hwang et al. demonstrated that TAGLN2 expression in CD8+ T cells was significantly downregulated in both ascites and solid tumors of OC patients. In addition, CD8+ T cell surface FABP5 expression was decreased in ascites from OC patients compared to peripheral CD8+ T cells from cancer-free individuals, although total intracellular FABP5 levels were comparable. These results suggest that the OC microenvironment may affect the lipid metabolism and function of intratumoral T cells by repressing TAGLN2 expression. Further experiments showed that the interaction of TAGLN2 with FABP5 is critical for the localization and function of FABP5 on the surface of activated CD8+ T cells. This allows the cells to efficiently take up extracellular fatty acids to fuel mitochondrial respiration, thereby maintaining the energy requirements of CD8+ T cells. These results emphasize the central role of TAGLN2 in T-cell lipid metabolism, particularly in promoting FABP5-mediated lipid uptake.&lt;/p&gt;&lt;p&gt;What molecular pathways link TME stress signals to TAGLN2 suppression?​ The authors discovered that the ER stress response inhibits TAGLN2 expression through the IRE1α-XBP1s signaling pathway. The active form of XBP1s can bind directly to the promoter region of the &lt;i&gt;TAGLN2&lt;/i&gt; ge","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming Growth Factor Beta2 Promotes Migration and Inhibits the Proliferation of Gastric Cancer Cells by Regulating the pSmad2/3-NDRG1 Signaling Pathway","authors":"Feng-Jun He,&nbsp;Xiao-Long Chen,&nbsp;Yun-Feng Zhu,&nbsp;Hua-Yang Pang,&nbsp;Ze-Dong Li,&nbsp;Pan-Ping Liang,&nbsp;Tao Jin,&nbsp;Zheng-Wen Chen,&nbsp;Ze-Hua Chen,&nbsp;Jian-Kun Hu,&nbsp;Kun Yang","doi":"10.1002/mco2.70148","DOIUrl":"https://doi.org/10.1002/mco2.70148","url":null,"abstract":"<p>Transforming growth factor beta2 (TGFβ2) is upregulated in gastric cancer (GC), playing a crucial role in driving its progression. However, the biological effects of TGFβ2 in GC metastasis and proliferation remain not fully understood. Our study reveals that TGFβ2 enhances N-myc downstream-regulated gene 1 (NDRG1) protein expression by activating the TGFβR/Smad2/3-dependent pathway, accelerating GC progression. TGFβ2 knockdown downregulates NDRG1 by inhibiting the TGFβR/Smad2/3 signaling pathway, which in turn inhibits GC cell migration and epithelial–mesenchymal transition (EMT) but stimulates proliferation. Both TGFβ2 upregulation and NDRG1 upregulation enhance GC cell migration in vitro and promote lung metastasis in mouse models. Interfering with NDRG1 reverses TGFβ2-induced migration, and inhibiting Smad2/3 or TGFβR reverses TGFβ2-induced NDRG1 upregulation and GC cell migration. Clinical sample analysis shows high TGFβ2 and NDRG1 expression in GC, associated with poor prognosis. Our study reveals that TGFβ2 upregulates NDRG1 via the TGFβR/Smad2/3 pathway, driving GC progression and highlighting the potential role of the TGFβ2NDRG1 axis in GC-targeted therapies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calpain 2 Isoform-Specific Cleavage of Filamin A Enhances HIF1α Nuclear Translocation, Promoting Metastasis in Triple-Negative Breast Cancer","authors":"Kyung-Hwa Jeon,&nbsp;Seojeong Park,&nbsp;Eun Seon Pak,&nbsp;Jeong-Ahn Kim,&nbsp;Yi Liu,&nbsp;Soo-Yeon Hwang,&nbsp;Younghwa Na,&nbsp;Youngjoo Kwon","doi":"10.1002/mco2.70147","DOIUrl":"https://doi.org/10.1002/mco2.70147","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) remains a challenge due to its aggressive nature and limited therapeutic options. Calpain 2, a member of the calcium-dependent cysteine protease family, is particularly associated with poor prognosis in TNBC. This study explores the isoform-specific role of calpain 2 in TNBC, examining its correlation with prognosis and its mechanistic impact on metastasis. Bioinformatic analyses, including Kaplan–Meier survival plots, univariate Cox proportional analysis, and gene set enrichment analysis (GSEA), assessed <i>CAPN2</i> expression and its association with mesenchymal genes in TNBC. Results of cell-based experiments with <i>CAPN2</i> knockdown or overexpression indicate that elevated <i>CAPN2</i> expression correlates with poor clinical outcomes and enhanced metastatic potential in TNBC. <i>CAPN2</i> knockdown inhibited the epithelial–mesenchymal transition (EMT), reducing cancer cell proliferation, migration, and invasion. Calpain 2 downregulation reversed the EMT by reducing isoform-specific cleavage of filamin A, HIF1α nuclear localization and <i>TWIST1</i> transcription. CNa <b>29</b>, a calpain 2-specific inhibitor, reduced cancer cell proliferation, decreased filamin A cleavage, downregulated <i>TWIST1</i> expression, and significantly retarded metastasis,. In conclusion, calpain 2 plays a critical role in TNBC progression by modulating HIF1α and <i>TWIST1</i>, to promote the EMT and metastasis. Isoform-selective inhibition of calpain 2 with CNa <b>29</b> presents a promising therapeutic strategy for managing TNBC.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stable Expressed DNMT3A Mutants Predict a Poor Prognosis in Acute Myeloid Leukemia Patients Without Receiving Hematopoietic Stem Cell Transplantation","authors":"Xiang Zhang,&nbsp;Lixia Liu,&nbsp;Jiayue Qin,&nbsp;Xiong Ni,&nbsp;Jie Jin","doi":"10.1002/mco2.70151","DOIUrl":"https://doi.org/10.1002/mco2.70151","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;DNA methyltransferase 3A (&lt;i&gt;DNMT3A&lt;/i&gt;) is wildly recognized as a tumor suppressor gene. Its deficiency leads to expanded hematopoietic stem cells (HSCs) pool, blocked HSCs differentiation, genomic instability, and a risk of malignant transformation in clonal hematopoiesis [&lt;span&gt;1&lt;/span&gt;]. &lt;i&gt;DNMT3A&lt;/i&gt; mutation (&lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;) is prevalent in adults, particularly in monocytic, and cytogenetically normal cases, affecting 25% of acute myeloid leukemia (AML) patients [&lt;span&gt;1&lt;/span&gt;]. Although the distribution pattern of &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;s has been well characterized in AML, its prognostic significance remains controversial.&lt;/p&gt;&lt;p&gt;To better understand the reasons behind &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; prognostic heterogeneity, we conducted a retrospective study, as detailed in two previous studies [&lt;span&gt;2, 3&lt;/span&gt;]. Our findings show that &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;s with stable expressed mutants are associated with poor prognosis in AML patients without receiving hematopoietic stem cell transplantation (HSCT). In this study, we enrolled 485 adult &lt;i&gt;de novo&lt;/i&gt; AML patients, of whom 98 (20.2%) were found to have &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;s. Our results indicate the distribution pattern of &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;s and clinical characteristics of AML patients with these mutations were similar to previous reports. In our cohort, patients with &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;s showed a relatively shorter overall survival (OS), relapse-free survival (RFS) and disease-free survival (DFS) (Figure 1A).&lt;/p&gt;&lt;p&gt;We analyzed how different therapeutic strategies, with or without HSCT, affected the prognosis of various subgroups of &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; patients. In the HSCT group, &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; patients exhibited comparable OS, RFS, and DFS with &lt;i&gt;DNMT3A&lt;/i&gt; wild-type (&lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;WT&lt;/sup&gt;) patients (Figure 1A). Conversely, &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; patients showed poorer OS, RFS, and DFS in the non-HSCT group, and the disparity between &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; and &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;WT&lt;/sup&gt; patients was more pronounced in the non-HSCT group compared to the overall cohort (Figure 1A). Therefore, HSCT overcame the poor prognosis of &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt;, indicating &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; patients without receiving HSCT were primarily responsible for the unfavorable outcomes.&lt;/p&gt;&lt;p&gt;To further explore key factors contributing to poor prognosis of &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; patients, we focused on &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; types in the non-HSCT group. Near 50% of &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;Mut&lt;/sup&gt; variants in AML are heterozygous &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;R882&lt;/sup&gt;, the hotspot mutation [&lt;span&gt;1&lt;/span&gt;]. As reported, &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;R882&lt;/sup&gt; played a dominant-negative role against &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;WT&lt;/sup&gt; via formatting dimers, leading to genome-wide hypomethylation [&lt;span&gt;1&lt;/span&gt;]. However, &lt;i&gt;DNMT3A&lt;/i&gt;&lt;sup&gt;non-R882&lt;/sup&gt; has been infrequently studied. Recently, Yung-Hsin Huang e","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying the Intergenic ALK Fusion LOC388942-ALK as a Driver of Non–Small Cell Lung Cancer","authors":"Xiaoqian Zhai,&nbsp;Manli Wang,&nbsp;Qi Zhang,&nbsp;Donglin Li,&nbsp;Yanmou Wu,&nbsp;ZuoYu Liang,&nbsp;Jiewei Liu,&nbsp;Weiya Wang,&nbsp;Yu Liu,&nbsp;Guowei Che,&nbsp;Qinghua Zhou,&nbsp;Chong Chen","doi":"10.1002/mco2.70154","DOIUrl":"https://doi.org/10.1002/mco2.70154","url":null,"abstract":"<p><i>ALK</i> fusions, such as the classic <i>EML4-ALK</i>, are known drivers of lung cancer and effective therapeutic targets. However, variant <i>ALK</i> fusions, including intergenic fusions like <i>LOC388942-ALK</i> (<i>LA</i>), have been detected in increasing numbers of patients, with their roles in tumorigenesis and ALK inhibitor resistance remaining unclear. Using CRISPR/Cas9, we generated the <i>LA</i> fusion in A549 and H441 cells, confirming elevated ALK expression via qRT-PCR and immunohistochemistry (IHC) staining. Functional analyses showed that <i>LA</i> significantly promoted tumor growth in vitro and in vivo while conferring increased resistance to alectinib. RNA-seq revealed upregulation of the <i>FOS</i> pathway in <i>LA</i> tumors, identifying <i>FOS</i> as a potential therapeutic target. Subsequently, we demonstrated that FOS disruption and inhibition sensitized <i>LA</i> tumors to treatment. RNA-seq profiling demonstrated that <i>FOS</i> depletion in <i>LOC388942-ALK</i> tumor significantly downregulated multiple oncogenic pathways related to cell cycle progression, DNA replication fidelity, and extracellular matrix remodeling, suggesting a pivotal role of <i>FOS</i> in maintaining tumor growth. These findings establish <i>LOC388942-ALK</i> as a novel oncogenic driver in lung cancer, highlighting its role in tumor growth and ALK inhibitor resistance. Targeting <i>FOS</i> may provide a promising therapeutic strategy for tumors harboring this intergenic fusion.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(−)-Epicatechin Rescues Memory Deficits by Activation of Autophagy in a Mouse Model of Tauopathies","authors":"Yanqing Wu,&nbsp;Ting Li,&nbsp;Xingjun Jiang,&nbsp;Jianmin Ling,&nbsp;Zaihua Zhao,&nbsp;Jiahui Zhu,&nbsp;Chongyang Chen,&nbsp;Qian Liu,&nbsp;Xifei Yang,&nbsp;Xuefeng Shen,&nbsp;Rong Ma,&nbsp;Gang Li,&nbsp;Gongping Liu","doi":"10.1002/mco2.70144","DOIUrl":"https://doi.org/10.1002/mco2.70144","url":null,"abstract":"<p>In tauopathies, defects in autophagy-lysosomal protein degradation are thought to contribute to the abnormal accumulation of aggregated tau. Recent studies have shown that (−)-Epicatechin (Epi), a dietary flavonoid belonging to the flavan-3-ol subgroup, improves blood flow, modulates metabolic profiles, and prevents oxidative damage. However, less research has explored the effects of Epi on tauopathies. Here, we found that Epi rescued cognitive deficits in P301S tau transgenic mice, a model exhibiting characteristics of tauopathies like frontotemporal dementia and Alzheimer's disease, and attenuated tau pathology through autophagy activation. Proteomic and biochemical analyses revealed that P301S mice exhibit deficits in autophagosome formation via modulating mTOR, consequently inhibiting autophagy. Epi inhibited the mTOR signaling pathway to promote autophagosome formation, which is essential for the clearance of tau aggregation. By using chloroquine (CQ) to inhibit autophagy in vivo, we further confirmed that Epi induced tau degradation via the autophagy pathway. Lastly, Epi administration was also found to improve cognition by reversing spine decrease and neuron loss, as well as attenuating neuroinflammation. Our findings suggest that Epi promoted tau clearance by activating autophagy, indicating its potential as a promising therapeutic candidate for tauopathies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Inoculation of Cationic Crosslinked Carbon Dots-Adjuvanted Respiratory Syncytial Virus F Subunit Vaccine Elicits Mucosal and Systemic Humoral and Cellular Immunity","authors":"Hong Lei,&nbsp;Aqu Alu,&nbsp;Jingyun Yang,&nbsp;Cai He,&nbsp;Jie Shi,&nbsp;Weiqi Hong,&nbsp;Dandan Peng,&nbsp;Yu Zhang,&nbsp;Jian Liu,&nbsp;Furong Qin,&nbsp;Xiya Huang,&nbsp;Chunjun Ye,&nbsp;Lijiao Pei,&nbsp;Xuemei He,&nbsp;Hong Yan,&nbsp;Guangwen Lu,&nbsp;Xiangrong Song,&nbsp;Xiawei Wei,&nbsp;Yuquan Wei","doi":"10.1002/mco2.70146","DOIUrl":"https://doi.org/10.1002/mco2.70146","url":null,"abstract":"<p>Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract infections, especially in infants and the elderly. Developing an RSV vaccine that promotes a robust mucosal immune response is necessary to successfully prevent viral transmission and the development of severe disease. We previously reported that crosslinked carbon dots (CCD) may be an excellent adjuvant candidate for intranasal (IN) protein subunit vaccines. Considering the strong immunogenicity of RSV prefused F protein (preF), we prepared an IN RSV vaccine composed of the CCD adjuvant and the preF protein as antigen (CCD/preF) and evaluated the induced antigen-specific humoral and cellular immunity. We found that IN immunization with the CCD/preF vaccine elicited strong serum IgG responses and mucosal immunity, including secreted IgA antibodies, tissue-resident memory T (T_RM) cells, and antigen-specific B cells, which lasted for at least 1 year. In addition, a combination of intramuscular and IN immunization with CCD/preF vaccine induced stronger systemic and mucosal immunity. Together, this study proved the high immunogenicity of the CCD/preF vaccines and supported the university of the mucosal CCD adjuvant, supporting further development of the CCD/preF vaccine in larger animal models and clinical studies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}