IF 14.1

MedComm Pub Date : 2026-10-06 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71013

引用次数: 0

Hypothalamus Participates in Peripheral Sympathetic Hyperactivity After Acute Brain Injury by Regulating Trhr M⁶A Modification. 下丘脑通过调节Trhr M6A修饰参与急性脑损伤后外周交感神经亢进。

IF 14.1

MedComm Pub Date : 2026-10-05 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71036

Maoxing Fei, Handong Wang, Chaochao Gao, Shiqiao Luo, Xiwen Huang, Yanling Han, Mengliang Zhou, Zhenxing Li

{"title":"Hypothalamus Participates in Peripheral Sympathetic Hyperactivity After Acute Brain Injury by Regulating Trhr M6A Modification.","authors":"Maoxing Fei, Handong Wang, Chaochao Gao, Shiqiao Luo, Xiwen Huang, Yanling Han, Mengliang Zhou, Zhenxing Li","doi":"10.1002/mco2.71036","DOIUrl":"https://doi.org/10.1002/mco2.71036","url":null,"abstract":"Sympathetic hyperactivity following acute brain injury (ABI) impedes recovery, yet effective treatments are lacking. Recently, N6-methyladenosine (m6A) modified by fat mass and obesity-associated gene (FTO) has been demonstrated to play critical roles in multiple neurological diseases. Here, we found that sympathetic hyperactivity occurred in traumatic brain injury and intracerebral hemorrhage patients and mouse models in vivo. In mouse ABI models, the RNA demethylase FTO was upregulated in hypothalamic neurons. Through m6A methylation sequencing, we found that FTO mediated m6A demethylation of Trhr mRNA, enhancing its stability by inhibiting YTHDF2-dependent decay. This increased neuronal TRHR expression and sensitivity to TRH, culminating in sympathetic hyperactivity. Conversely, restoring hypothalamic FTO or TRHR levels alleviated this condition. We further mapped and functionally validated a monosynaptic projection from lateral hypothalamic TRHR neurons to the rostral ventrolateral medulla (RVLM), demonstrating that modulating these neurons controls sympathetic tone. Collectively, our findings elucidate a novel FTO-Trhr axis in post-ABI autonomic dysfunction and highlight a promising therapeutic target.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71036"},"PeriodicalIF":14.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120997","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}

引用次数: 0

Alveolar Macrophages: Development, Respiratory Homeostasis, Signal Pathways, Diseases, and Therapeutic Opportunities. 肺泡巨噬细胞：发育、呼吸稳态、信号通路、疾病和治疗机会。

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71031

Sihan Yang, Ruomeng Li, Chuanjiang Yu, Jing Li, Xikun Zhou

{"title":"Alveolar Macrophages: Development, Respiratory Homeostasis, Signal Pathways, Diseases, and Therapeutic Opportunities.","authors":"Sihan Yang, Ruomeng Li, Chuanjiang Yu, Jing Li, Xikun Zhou","doi":"10.1002/mco2.71031","DOIUrl":"https://doi.org/10.1002/mco2.71031","url":null,"abstract":"Alveolar macrophages (AMs), as primary immune sentinels in the respiratory tract, are uniquely adapted to tissue-specific demands shaped by local factors and the physiological environment, maintaining airway homeostasis through the clearance of surfactants and particulates. While AMs exhibit remarkable plasticity shaped by dynamic microenvironmental cues, the traditional M1/M2 paradigm fails to adequately capture this complex heterogeneity, and the specific role of AMs in the pathogenesis of pulmonary diseases, as well as AM-centric therapies, remain to be fully elucidated. This review systematically synthesizes the current understanding of AM ontogeny, homeostatic regulation, and their signaling pathways in lung homeostasis and pathologies. Furthermore, we propose a refined conceptual framework categorizing AMs into five distinct functional subtypes to better capture their in vivo plasticity. Then, pathological shifts in the lung microenvironment that drive the pathogenesis of diverse pulmonary disorders, including asthma, chronic obstructive pulmonary disease, acute lung injury, and pulmonary fibrosis, and trigger dysregulated transcriptional and metabolic reprogramming in AMs, are comprehensively discussed. Finally, we explore emerging therapeutic avenues, including metabolic modulation, trained immunity, and autophagy-apoptosis balance restoration. By addressing challenges in precisely regulating AM function, this overview provides a concise yet comprehensive framework for advancing AM-centric therapies in respiratory medicine.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71031"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120976","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}

引用次数: 0

G Protein-Coupled Receptor in High-Altitude Diseases: Mechanistic Insights and Therapeutic Opportunities. 高原疾病中的G蛋白偶联受体：机制见解和治疗机会。

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71033

Qing Zhao, Changliang Liu, Lu Dai, Kun Zheng, Kun Liang, Chuanling Pan, Lianhua Liu, Ling Chen, Xuefei He, Hui Yan, Lei Chen, Huaping Zheng, Cheng Deng, Fengming Luo

{"title":"G Protein-Coupled Receptor in High-Altitude Diseases: Mechanistic Insights and Therapeutic Opportunities.","authors":"Qing Zhao, Changliang Liu, Lu Dai, Kun Zheng, Kun Liang, Chuanling Pan, Lianhua Liu, Ling Chen, Xuefei He, Hui Yan, Lei Chen, Huaping Zheng, Cheng Deng, Fengming Luo","doi":"10.1002/mco2.71033","DOIUrl":"https://doi.org/10.1002/mco2.71033","url":null,"abstract":"High-altitude diseases (HADs) encompass a spectrum of acute and chronic disorders-including acute mountain sickness, high-altitude cerebral edema, high-altitude pulmonary edema, high-altitude polycythemia, high-altitude pulmonary hypertension, and high-altitude heart disease-that arise from insufficient adaptation to hypobaric hypoxia. Despite their heterogeneous clinical manifestations, these conditions represent a continuum from acute adaptive stress to chronic maladaptive compensation, unified by persistent oxygen deprivation and dysregulated systemic homeostasis. G protein-coupled receptors (GPCRs), the largest superfamily of membrane receptors, have emerged as central regulators of hypoxia sensing, ventilatory control, vascular tone, barrier integrity, erythropoiesis, immune activation, and metabolic reprogramming. However, how specific GPCR subtypes and their downstream signaling networks coordinate adaptation versus maladaptation across distinct organ systems and disease stages remains incompletely defined. This review synthesizes recent mechanistic insights into GPCR-mediated pathways that govern neural, pulmonary, vascular, and hematologic responses to hypoxia. We examine the transition from protective to pathological signaling, highlight receptor-level divergence that enables therapeutic selectivity, and evaluate translational prospects for GPCR-targeted strategies, including biased agonism, receptor-specific modulation, and sex-based interventions. These advances establish a framework for precision therapies tailored to high-altitude populations.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71033"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120926","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}

引用次数: 0

Envonalkib Versus Crizotinib in Treatment-Naive ALK-Positive Non-Small Cell Lung Cancer: Final Efficacy and Biomarker Analyses of the Randomized Phase III Study. 环境alkib与克唑替尼治疗初治alk阳性非小细胞肺癌：随机III期研究的最终疗效和生物标志物分析

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.70998

Jie Huang, Yuanyuan Wang, Haishuang Sun, Jie Min, Nong Yang, Qitao Yu, Ying Cheng, Yanqiu Zhao, Manxiang Li, Hong Chen, Shouan Ren, Jianying Zhou, Wu Zhuang, Xintian Qin, Lejie Cao, Yan Yu, Jian Zhang, Jianxing He, Jifeng Feng, Hao Yu, Lin Zhang, Xinyuan Zhao, Wenfeng Fang, Jing Li, Li Zhang, Yunpeng Yang

{"title":"Envonalkib Versus Crizotinib in Treatment-Naive ALK-Positive Non-Small Cell Lung Cancer: Final Efficacy and Biomarker Analyses of the Randomized Phase III Study.","authors":"Jie Huang, Yuanyuan Wang, Haishuang Sun, Jie Min, Nong Yang, Qitao Yu, Ying Cheng, Yanqiu Zhao, Manxiang Li, Hong Chen, Shouan Ren, Jianying Zhou, Wu Zhuang, Xintian Qin, Lejie Cao, Yan Yu, Jian Zhang, Jianxing He, Jifeng Feng, Hao Yu, Lin Zhang, Xinyuan Zhao, Wenfeng Fang, Jing Li, Li Zhang, Yunpeng Yang","doi":"10.1002/mco2.70998","DOIUrl":"https://doi.org/10.1002/mco2.70998","url":null,"abstract":"This study reports efficacy and biomarker results from a multicenter, randomized, open-label Phase III study (NCT04009317). Treatment-naive anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients were centrally randomized 1:1 to envonalkib or crizotinib, stratified by brain metastases and chemotherapy lines. The primary endpoint was progression-free survival (PFS) assessed by independent review committee. This analysis updated investigator-assessed PFS. A total of 264 patients were randomized (envonalkib: 131, crizotinib: 133). Median follow-up was 46.5 and 46.8 months for envonalkib and crizotinib, respectively. Envonalkib significantly improved PFS over crizotinib (median PFS: 30.4 vs. 12.0 months, p < 0.0001; hazard ratio [HR] = 0.48, 95% CI: 0.35-0.65). Overall survival (OS) data remained immature. In the envonalkib group, circulating tumor DNA (ctDNA) analysis revealed poor prognosis for patients with co-mutations in p53 pathway genes (TP53, CDKN2A, MDM2, MDM4) or other concurrent oncogenic drivers (median PFS: 15.7 and 8.3 months). Among 52 patients with post-progression ctDNA data, putative resistance mechanisms were identified in 14 (26.9%), including secondary ALK mutations (n = 9) and/or bypass pathway activations (n = 9). Final follow-up confirms the robust benefit of envonalkib over crizotinib, supporting its role as a first-line option for ALK-positive NSCLC. Biomarker analyses validate the prognostic impact of genomic co-alterations and delineate resistance mechanisms.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e70998"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121010","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}

引用次数: 0

Maturation-Dependent Constraints in the Ability of Human Monocytes to Initiate Trained Immunity. 人类单核细胞启动训练免疫能力的成熟依赖性限制。

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.70939

Michael Eigenschink, Elsa Davogg, Manuel Pristner, David Seki, Marcus Arzmüller, Herbert Kiss, Alex Farr, Angelika Berger, David Berry, Benedikt Warth, Lukas Wisgrill

{"title":"Maturation-Dependent Constraints in the Ability of Human Monocytes to Initiate Trained Immunity.","authors":"Michael Eigenschink, Elsa Davogg, Manuel Pristner, David Seki, Marcus Arzmüller, Herbert Kiss, Alex Farr, Angelika Berger, David Berry, Benedikt Warth, Lukas Wisgrill","doi":"10.1002/mco2.70939","DOIUrl":"https://doi.org/10.1002/mco2.70939","url":null,"abstract":"The survival of nonvertebrate species that lack adaptive immunity has prompted the discovery of memory mechanisms in innate immune cells, termed trained immunity. Because infants depend on innate immunity to fight off pathogens, leveraging these mechanisms in neonatal care may hold clinical significance. Yet, this is constrained by limited understanding of innate immune memory development during early-life. By performing systems-level characterization of β-glucan-trained monocytes from adults, term infants, and preterm infants, we report maturation-dependent constraints in trained immunity. We corroborate these findings in a small cohort of premature infants with in utero pathogen exposure. Alongside limited stimulus-induced reprogramming of innate immune responses in the clinical cohort, monocytes from premature infants exhibited metabolic alterations in glutaminolysis and tricarboxylic acid cycle metabolism, pathways central to trained immunity. They also displayed a treatment-robust long noncoding RNA landscape and transcriptional alterations in enzymes relevant to epigenetic induction of innate immune memory. Finally, network-based analyses implicated SMAD5 and ARNT as potential drivers of differences and provided evidence for altered transcriptional regulation of chromatin organization across early-life development. Our results suggest that metabolic and transcriptomic immaturity constrains trained immunity in premature infants, highlighting a developmental mechanism that may affect host defense and guide future immunomodulatory strategies.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e70939"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120971","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}

引用次数: 0

Both Genetic Manipulation and Acupuncture Alleviate Depressive-Like Behavior Mediated by Astrocytic P2X7 Receptors. 基因操作和针刺均可缓解星形细胞P2X7受体介导的抑郁样行为。

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71042

Wen-Jing Ren, Muhammad Tahir Khan, Xing-Ying Ren, Xuan Li, Patrizia Rubini, Hai-Yan Yin, Alexei Verkhratsky, Peter Illes, Yong Tang

{"title":"Both Genetic Manipulation and Acupuncture Alleviate Depressive-Like Behavior Mediated by Astrocytic P2X7 Receptors.","authors":"Wen-Jing Ren, Muhammad Tahir Khan, Xing-Ying Ren, Xuan Li, Patrizia Rubini, Hai-Yan Yin, Alexei Verkhratsky, Peter Illes, Yong Tang","doi":"10.1002/mco2.71042","DOIUrl":"https://doi.org/10.1002/mco2.71042","url":null,"abstract":"Major depressive disorder (MDD) has been associated with P2X7 receptors (P2X7Rs), yet the contribution of astrocytic P2X7Rs to neuronal dysfunction remains unclear. We investigated the role of astrocytic P2X7Rs in depression-like behaviors using a chronic unpredictable mild stress (CUMS) mouse model and further examined whether electroacupuncture (EA) exerts antidepressant effects by modulating astrocytic P2X7Rs. Astrocytic P2X7Rs in the medial prefrontal cortex (mPFC) were selectively knocked down or overexpressed via gene manipulation. Depression-like behaviors were assessed after CUMS exposure and EA intervention, and in vivo fiber photometry was used to monitor calcium dynamics in excitatory and inhibitory neurons within the mPFC. CUMS markedly increased P2X7R expression in the mPFC and induced depression-like behaviors. Genetic deletion or knockdown of astrocytic P2X7Rs alleviated these abnormalities, whereas overexpression of astrocytic P2X7Rs exacerbated them and diminished the antidepressant efficacy of EA. Fiber photometry revealed that astrocytic P2X7Rs contributed to stress-induced dysregulation of neuronal calcium activity. EA restored the balance between excitatory and inhibitory neuronal activity in the mPFC, and this effect depended on appropriate regulation of astrocytic P2X7Rs. These findings suggest that astrocytic P2X7Rs are key mediators of stress-induced depressive phenotypes and may represent a promising therapeutic target for MDD.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71042"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121005","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}

引用次数: 0

Machine Learning-Driven Noninvasive Prediction of Liver Fibrosis in Unclassified Liver Disease. 机器学习驱动的无创预测未分类肝病肝纤维化。

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.70990

Ye Yang, Yirui Hu, Ting Wei, Yue Chen, Wenkang Gao, Yupin Tan, Yuanqing Zhu, Yonggang Yuan, Zhuang Cao, Yunfei Zhao, Zexuan Li, Jiake Che, Yue Yang, Xinyang Wang, Shengqi Yan, Weiyan Huang, Shuyan Wang, Fuyu Yang, Lijia Yin, Xiaotong Du, Jiahao Liu, Rong Lin, Ling Yang, Huikuan Chu

{"title":"Machine Learning-Driven Noninvasive Prediction of Liver Fibrosis in Unclassified Liver Disease.","authors":"Ye Yang, Yirui Hu, Ting Wei, Yue Chen, Wenkang Gao, Yupin Tan, Yuanqing Zhu, Yonggang Yuan, Zhuang Cao, Yunfei Zhao, Zexuan Li, Jiake Che, Yue Yang, Xinyang Wang, Shengqi Yan, Weiyan Huang, Shuyan Wang, Fuyu Yang, Lijia Yin, Xiaotong Du, Jiahao Liu, Rong Lin, Ling Yang, Huikuan Chu","doi":"10.1002/mco2.70990","DOIUrl":"https://doi.org/10.1002/mco2.70990","url":null,"abstract":"Chronic liver diseases (CLDs) frequently progress silently to advanced fibrosis or cirrhosis, yet existing predictive models have largely been developed for patients with clearly defined etiologies. Here, we asked whether a noninvasive machine-learning model based on routine clinical variables and liver stiffness measurement (LSM) could accurately identify significant liver fibrosis in patients with CLD of uncertain etiology, and whether such a model would add value beyond conventional fibrosis scores for clinical decision-making. We retrospectively analyzed 503 patients who underwent liver biopsy at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Twelve machine-learning algorithms were trained to predict significant hepatic fibrosis, and model interpretability was assessed using SHapley Additive exPlanations. The best-performing model was then compared with four established noninvasive tools: FIB-4, GPR, Forns Index, and LSM alone. Among all candidate models, Categorical Boosting delivered the most favorable overall diagnostic performance, achieving the highest discriminative accuracy (AUC, 0.827; 95% CI, 0.754-0.900) and outperforming all conventional comparators across key classification metrics. We therefore establish an interpretable and clinically applicable panel integrating serological markers, age, LSM for noninvasive fibrosis assessment in patients with undefined or clinically ambiguous liver disease, with potential to reduce unnecessary biopsy and enable earlier intervention.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e70990"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120974","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}

引用次数: 0

TRIM28 Increases RFC4 Protein Expression to Promote Triple-Negative Breast Cancer Progression. TRIM28增加RFC4蛋白表达促进三阴性乳腺癌进展

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71043

Cheng Guo, Li Liu, Lixiang Sun, Litong Liu, Han Wei, Yutong Yan, Fei Yu, Guangming Fu, Xianning Dong, Ceshi Chen, Chengqin Wang

{"title":"TRIM28 Increases RFC4 Protein Expression to Promote Triple-Negative Breast Cancer Progression.","authors":"Cheng Guo, Li Liu, Lixiang Sun, Litong Liu, Han Wei, Yutong Yan, Fei Yu, Guangming Fu, Xianning Dong, Ceshi Chen, Chengqin Wang","doi":"10.1002/mco2.71043","DOIUrl":"https://doi.org/10.1002/mco2.71043","url":null,"abstract":"Replication factor C subunit 4 (RFC4) dysregulation has been implicated in tumor progression and poor prognosis across multiple cancer types. Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor outcomes, underscoring the need for effective therapeutic targets. However, the role of RFC4 in TNBC progression and metastasis remains unclear. In the present study, integrated bioinformatics analyses, together with validation in 80 clinical TNBC samples, showed that RFC4 was markedly upregulated in TNBC. In vitro functional assays and experiments in nude mouse models further demonstrated that elevated RFC4 expression contributed to TNBC progression (p < 0.05). Mechanistically, the upstream transcription factor TRIM28 (Tripartite motif-containing 28) bound to the BS2 and BS3 sites within the RFC4 promoter region, thereby activating RFC4 transcription and increasing its expression. Furthermore, TRIM28 interacted with RFC4 and assembled K29-linked ubiquitin chains at K205 and K217, enhancing RFC4 ubiquitination and protein stability in a manner dependent on TRIM28 ubiquitin ligase activity (p < 0.05). Finally, we showed that RFC4 activates the Ras-associated protein 1 (Rap1)-PI3K-AKT pathway in a ubiquitination-dependent manner, thereby enhancing TNBC cell proliferation and metastasis. Together, these findings suggest that the TRIM28-RFC4 axis may represent a promising therapeutic target for TNBC.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71043"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121111","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}

引用次数: 0

TP53 Mutation Heterogeneity Refines Prognostic Stratification in IDH-Wildtype Glioma. TP53突变异质性改善了idh -野生型胶质瘤的预后分层。

IF 14.1

MedComm Pub Date : 2026-10-04 eCollection Date: 2026-10-01 DOI: 10.1002/mco2.71041

Kuilin Liao, Zhi Ye, Songtao Qi, Chang Xu, Yudi Huang, Zhiyong Li, Guozhong Yi, Yuou Qin, Qiuming Pan, Guiling Liu, Chao Chen, Zhuoyang Chen, Hongrui Li, Junxi Wang, Xi'an Zhang, Guanglong Huang, Shanqiang Qu

{"title":"TP53 Mutation Heterogeneity Refines Prognostic Stratification in IDH-Wildtype Glioma.","authors":"Kuilin Liao, Zhi Ye, Songtao Qi, Chang Xu, Yudi Huang, Zhiyong Li, Guozhong Yi, Yuou Qin, Qiuming Pan, Guiling Liu, Chao Chen, Zhuoyang Chen, Hongrui Li, Junxi Wang, Xi'an Zhang, Guanglong Huang, Shanqiang Qu","doi":"10.1002/mco2.71041","DOIUrl":"https://doi.org/10.1002/mco2.71041","url":null,"abstract":"Clinically, TP53 mutation (TP53-mut) has long been simplistically dichotomized as mutant versus wildtype, overlooking their structural and functional complexity. The prognostic significance of TP53‑mut in IDH‑wildtype (IDH‑wt) gliomas remains controversial. In 237 IDH‑wt gliomas, we integrated clinical, genomic, and follow‑up data to test whether mutation subtypes refine risk stratification. In this cohort, 73 patients (73/237, 30.8%) harbored TP53-mut, which was significantly associated with worse overall survival. Subgroup analysis further revealed that patients with mutations in the β‑strand region had a median outcome of only 12.0 months, markedly inferior to those with mutations in the α‑helix (22.5 months), loop (23.9 months), and turn/other regions (23.6 months). Multivariable Cox regression analysis showed that TP53-mut was an independent prognostic factor associated with worse outcome (HR = 1.91; 95%CI: 1.29-2.84; p = 0.001). Notably, TP53‑mut patients with variant allele frequency (VAF)≥10% showed significantly worse survival than those with VAF<10% (p = 0.030), whereas VAF<10% cases had survival comparable to TP53‑wt. In addition, p53 immunohistochemistry score≥4 yielded an area under the curve (AUC) of 0.79 for TP53-mut prediction. Collectively, TP53-mut in IDH‑wt gliomas are prognostically heterogeneous. A VAF≥ 10% identified a potential high‑risk subgroup, with β-strand mutations associated with the poorest survival in our cohort. p53 immunohistochemistry offers a cost‑effective surrogate screen.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 10","pages":"e71041"},"PeriodicalIF":14.1,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120991","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}

引用次数: 0

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