Translational Oncology最新文献_第2页

Five-year survival of patients with non-small cell lung cancer treated with alkalization therapy 碱化治疗非小细胞肺癌患者的5年生存率。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-21 DOI: 10.1016/j.tranon.2026.102677

Shion Kachi , Kazuyuki Suzuki , Reo Hamaguchi , Ryoko Narui , Hiromasa Morikawa , Hiromi Wada

Acidic tumor microenvironments promote malignant progression, immune evasion, and drug resistance. This single-center retrospective cohort study evaluated whether, among patients with stage IV non-small cell lung cancer (NSCLC) who participated in a pragmatic “alkalization therapy”—defined as a low potential renal acid load diet plus oral sodium bicarbonate and/or potassium/sodium citrate—urinary pH was associated with long-term survival, and whether these associations differed by EGFR/ALK mutation status. Urinary pH was used as a surrogate marker of systemic alkalization. All consecutive patients with stage IV NSCLC who first attended Karasuma Wada Clinic between January 2014, and December 2019 were included (n = 203; EGFR/ALK mutation-negative, n = 100; EGFR/ALK mutation-positive, n = 103). All outpatients received standardized instruction in alkalization therapy. For each patient, a mean urine pH value (excluding the first visit) was calculated. Survival was analyzed using Kaplan–Meier methods with log-rank and Gehan–Breslow–Wilcoxon tests, and Cox proportional hazards regression models incorporating recurrence status and urine pH. Overall, the 5-year survival rate was 49·0 % and was similar by mutation status (EGFR/ALK mutation-positive, 49·9 %; EGFR/ALK mutation-negative, 48·6 %). Among EGFR/ALK mutation-negative patients, postoperative recurrence was associated with a more favorable outcome than de novo stage IV disease at initial diagnosis (5-year survival 65·5 % vs 42·0 %; log-rank p = 0·02). In this subgroup, a mean urine pH ≥7·5 was associated with superior 5-year survival (70·0 % vs 39·3 %; log-rank p = 0·04). Given potential confounding, this shows association—not a causal benefit. Urinary pH may serve as a pragmatic marker of acid–base status, particularly in EGFR/ALK-mutation-negative disease.

酸性肿瘤微环境促进恶性进展、免疫逃避和耐药。这项单中心回顾性队列研究评估了IV期非小细胞肺癌（NSCLC）患者参加实用的“碱化治疗”（定义为低潜在肾酸负荷饮食加口服碳酸氢钠和/或柠檬酸钾/钠）尿液pH是否与长期生存相关，以及这些关联是否因EGFR/ALK突变状态而异。尿液pH值作为全身碱化的替代指标。纳入2014年1月至2019年12月期间首次就诊的所有连续IV期NSCLC患者（n = 203； EGFR/ALK突变阴性，n = 100； EGFR/ALK突变阳性，n = 103）。所有门诊患者均接受标准化的碱化治疗指导。计算每位患者的平均尿液pH值（不包括第一次就诊）。采用Kaplan-Meier法、log-rank检验和Gehan-Breslow-Wilcoxon检验，以及纳入复发状态和尿ph的Cox比例风险回归模型分析生存率。总体而言，5年生存率为49.0%，突变状态相似（EGFR/ALK突变阳性，49.9%；EGFR/ALK突变阴性，48.6%）。在EGFR/ALK突变阴性的患者中，术后复发比初始诊断时的新发IV期疾病更有利（5年生存率为65.5% vs 42.0%; log-rank p = 0.02）。在该亚组中，平均尿液pH≥7.5与较好的5年生存率相关（70% vs 39.3%; log-rank p = 0.04）。考虑到潜在的混淆，这显示了关联，而不是因果关系。尿pH值可以作为酸碱状态的实用标记，特别是在EGFR/ alk突变阴性的疾病中。

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引用次数: 0

Integrated multi-omics analysis of prognostic model and immune microenvironment in intrahepatic cholangiocarcinoma 肝内胆管癌预后模型和免疫微环境的综合多组学分析。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-19 DOI: 10.1016/j.tranon.2026.102675

Xi Li , Yixian Wang , Xiangbao Yin , Junwen Hu , Hongcheng Lu , Die Li , Mingming Wu

Background

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy originating from the epithelial lining of second-order bile ducts. Despite advances in immunotherapy, which underscore the pivotal roles of T-cell dynamics and tumor microenvironment (TME) remodeling in anti-tumor immunity, iCCA remains a clinical challenge due to its rapid progression. Consequently, there is a pressing need for integrated multi-omics approaches to elucidate the immune landscape of iCCA and guide effective precision immunotherapy.

Methods

To comprehensively characterize iCCA, we integrated single-cell RNA-seq data for microenvironment analysis and bulk RNA-seq cohorts for prognostic model construction using machine learning, followed by external validation and functional experimental verification of key genes.

Results

Integrated single-cell and spatial transcriptomic analysis of iCCA uncovered interacting epithelial-fibroblast subpopulations and guided the machine learning-based derivation of a five-gene prognostic signature. Furthermore, spatial transcriptomics confirmed the physical co-localization between SPP1+ Macrophage and NDRG1+ CAF. Finally, functional experiments established that MT1X, a gene highly expressed in iCCA, drives tumor proliferation, migration, and invasion.

Conclusion

This study establishes a prognostic model based on five key genes and elucidates their role in the immunosuppressive TME. MT1X was validated as a pro-tumorigenic factor, highlighting its potential as a therapeutic target.

背景：肝内胆管癌（iCCA）是一种起源于二级胆管上皮的侵袭性恶性肿瘤。尽管免疫治疗的进步强调了t细胞动力学和肿瘤微环境（TME）重塑在抗肿瘤免疫中的关键作用，但由于其快速进展，iCCA仍然是一个临床挑战。因此，迫切需要整合多组学方法来阐明iCCA的免疫景观并指导有效的精确免疫治疗。方法：为了全面表征iCCA，我们整合了单细胞RNA-seq数据进行微环境分析，并利用机器学习整合了大量RNA-seq队列进行预后模型构建，随后对关键基因进行外部验证和功能实验验证。结果：iCCA的综合单细胞和空间转录组学分析揭示了相互作用的上皮-成纤维细胞亚群，并指导了基于机器学习的五基因预后标记的推导。此外，空间转录组学证实了SPP1+巨噬细胞和NDRG1+ CAF之间的物理共定位。最后，功能实验证实，在iCCA中高表达的MT1X基因驱动肿瘤增殖、迁移和侵袭。结论：本研究建立了基于5个关键基因的TME预后模型，并阐明了它们在免疫抑制性TME中的作用。MT1X被证实是一种促肿瘤因子，突出了其作为治疗靶点的潜力。

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引用次数: 0

Tumor-stroma contributes to immunotherapeutic resistance in non-small cell lung cancer via SEMA3C-mediated immunosuppressive tumor microenvironment 肿瘤基质通过sema3c介导的免疫抑制肿瘤微环境促进非小细胞肺癌的免疫治疗耐药。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-19 DOI: 10.1016/j.tranon.2026.102679

Huanyan Zhang , Hongxin Lin , Jian Wang , Di Wu , Qian Wang , Jie Mei , Qing Li , Yichao Zhu , Yun Cai

Background

The tumor-stroma proportion (TSP) was a critical factor influencing clinical outcomes in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms driving TSP-associated aggressiveness and its contribution to immune checkpoint blockade (ICB) resistance remained poorly understood.

Methods

Using H&E staining data from the TCGA-NSCLC cohort, patients were stratified into TSP-high and low groups. Transcriptomic profiling and single-cell RNA sequencing (scRNA-seq) were employed to identify the TSP signatures. Functional validation was conducted to investigate the role of SEMA3C in cancer-associated fibroblasts (CAFs) and its influence to tumor cells and T cells.

Results

TSP-high status independently predicted worse overall survival (OS) and correlated with ICB resistance. Transcriptomic analysis identified seven TSP-related genes enriched in stromal fibroblasts. Among these signatures, SEMA3C emerged as the key TSP biomarker associated with an immunosuppressive tumor microenvironment (TME) and ICB resistance in NSCLC. Functionally, SEMA3C knockdown in CAFs suppressed their migratory capacity and collagen production. Co-culture experiments demonstrated that compared to SEMA3C-knockdown CAFs, control CAFs significantly enhanced tumor cell migration and invasion while suppressing the activation and proliferation of CD8⁺ T cells. Strikingly, in vivo targeting of SEMA3C inhibited tumor growth.

Conclusion

TSP served as an independent prognostic biomarker and predictor of ICB resistance in NSCLC. SEMA3C was identified as a crucial mediator within this axis, promoting tumor malignancy and fostering an immunosuppressive TME characterized by stromal remodeling and excluded anti-tumor immunity. This study established TSP as a clinically relevant stratification tool and revealed stromal-immune crosstalk.

背景：肿瘤-间质比例（TSP）是影响非小细胞肺癌（NSCLC）临床预后的关键因素。然而，驱动tsp相关侵袭性的潜在分子机制及其对免疫检查点阻断（ICB）抗性的贡献仍然知之甚少。方法：利用TCGA-NSCLC队列的H&E染色数据，将患者分为tsp高组和低组。利用转录组学分析和单细胞RNA测序（scRNA-seq）来鉴定TSP的特征。通过功能验证研究SEMA3C在癌症相关成纤维细胞（CAFs）中的作用及其对肿瘤细胞和T细胞的影响。结果：tsp高状态独立预测较差的总生存期（OS），并与ICB耐药相关。转录组学分析鉴定了间质成纤维细胞中富集的7个tsp相关基因。在这些特征中，SEMA3C成为与非小细胞肺癌免疫抑制肿瘤微环境（TME）和ICB耐药相关的关键TSP生物标志物。功能上，CAFs中SEMA3C的下调抑制了它们的迁移能力和胶原蛋白的产生。共培养实验表明，与sema3c敲低的CAFs相比，对照CAFs显著增强了肿瘤细胞的迁移和侵袭，同时抑制了CD8 + T细胞的活化和增殖。引人注目的是，在体内靶向SEMA3C抑制肿瘤生长。结论：TSP可作为非小细胞肺癌ICB耐药的独立预后生物标志物和预测因子。SEMA3C被认为是该轴上的一个关键介质，促进肿瘤恶性并促进以基质重塑和排除抗肿瘤免疫为特征的免疫抑制性TME。本研究确立了TSP作为临床相关的分层工具，并揭示了基质-免疫串扰。

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引用次数: 0

RHOJ-induced chemotherapy resistance through epithelial–mesenchymal transition in drug-tolerant persister cells of head and neck cancer rhoj通过上皮-间质转化诱导头颈癌耐药持久细胞的化疗耐药

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-17 DOI: 10.1016/j.tranon.2026.102673

Hang Huong Ling , Chih-Ming Huang , Ming-Shou Hsieh , Vijesh Kumar Yadav , Iat-Hang Fong , Kuang-Tai Kuo , Chi-Tai Yeh , Jo-Ting Tsai

Background: Building on our previous identification of TXNRD1 and RHOJ as mediators of immunotherapy resistance in head and neck squamous cell carcinoma (HNSCC), this study investigates the role of RHOJ in regulating endothelial markers and signaling pathways in drug-tolerant persister (DTP) cells, as well as its contribution to immune suppression within the resistant tumor microenvironment. Methods: We examined the role of RHOJ in regulating tumor-associated macrophage polarization and enhancing M1 antitumor activity and evaluated the therapeutic potential of targeting the RHOJ/Rho kinase axis in an HNSCC DTP mouse model. Results: RHOJ expression was significantly upregulated in HNSCC DTP cells. RHOJ contributes to chemoresistance by increasing oxidative stress and initiating the DNA damage response. RNA sequencing revealed that the IPO9/EpCAM signaling pathway positively regulates RHOJ expression. Knockdown of RHOJ with shRNA suppressed HNSCC DTP cell migration and downregulated IPO9/EpCAM signaling. Gene enrichment analysis revealed high RHOJ expression in tumor-associated endothelial cells. Treatment with the RHOJ-dependent F-actin inhibitor Latrunculin B (HY-101,848) impaired actin polymerization and increased the chemosensitivity of HNSCC DTP cells. Silencing RHOJ inhibited M2 tumor-associated macrophage activation. RHOJ overexpression promoted M2 macrophage proliferation. Conclusion: RHOJ plays a critical role in modulating immunosuppressive signaling in both tumor and endothelial cells. RHOJ promotes the function of tumor-associated endothelial cells and drives EMT through its interaction with the IPO9/EpCAM signaling pathway, thereby increasing cell survival and drug resistance. Additionally, RHOJ may limit immune cell infiltration into the tumor core and promote immune evasion by contributing to vascular abnormalities and impaired barrier function.

背景：在我们之前确定TXNRD1和RHOJ是头颈部鳞状细胞癌（HNSCC）免疫治疗耐药的介质的基础上，本研究探讨了RHOJ在调节耐药持续性（DTP）细胞内皮标志物和信号通路中的作用，以及它在耐药肿瘤微环境中的免疫抑制作用。方法：研究RHOJ在调节肿瘤相关巨噬细胞极化和增强M1抗肿瘤活性中的作用，并在HNSCC DTP小鼠模型中评估靶向RHOJ/Rho激酶轴的治疗潜力。结果：RHOJ在HNSCC DTP细胞中表达显著上调。RHOJ通过增加氧化应激和启动DNA损伤反应来促进化学耐药。RNA测序结果显示，ip9 /EpCAM信号通路正调控RHOJ的表达。shRNA敲低RHOJ抑制HNSCC DTP细胞迁移，下调ip9 /EpCAM信号。基因富集分析显示RHOJ在肿瘤相关内皮细胞中高表达。rhoj依赖性f -肌动蛋白抑制剂Latrunculin B （hy - 101848）抑制了肌动蛋白聚合，增加了HNSCC DTP细胞的化学敏感性。沉默RHOJ抑制M2肿瘤相关巨噬细胞活化。RHOJ过表达促进M2巨噬细胞增殖。结论：RHOJ在肿瘤和内皮细胞免疫抑制信号的调节中起关键作用。RHOJ通过与ip9 /EpCAM信号通路的相互作用，促进肿瘤相关内皮细胞的功能，驱动EMT，从而提高细胞存活率和耐药能力。此外，RHOJ可能通过导致血管异常和屏障功能受损来限制免疫细胞浸润到肿瘤核心并促进免疫逃避。

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引用次数: 0

Advances in FLASH radiation therapy: A review on biological foundations and clinical prospects FLASH放射治疗的生物学基础和临床前景综述

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-16 DOI: 10.1016/j.tranon.2026.102676

Yupeng Di , Lingling Meng , Yingjie Wang , Jing Li

This paper provides a comprehensive review of the fundamental theories, clinical practices, technological advancements, current status, and future prospects of FLASH radiation therapy (FLASH-RT). As an emerging technique, FLASH-RT offers the potential to enhance therapeutic efficacy while minimizing damage to healthy tissues. We elaborate on the physical principles of the “FLASH effect” in radiation biology and its dose-distribution characteristics, describe clinical applications in tumor treatment, and evaluate protective effects on normal tissues. Furthermore, the review discusses technical advancements in equipment, dosimetry, and imaging, while analyzing current research hotspots and technical bottlenecks. We also examine pathological mechanisms, future applications, and prevailing controversies regarding safety, efficacy uncertainty, and ethics. This comprehensive discussion provides a valuable reference for deepening the understanding of FLASH-RT’s translational journey.

本文就FLASH放射治疗（FLASH- rt）的基本理论、临床实践、技术进展、现状及未来展望等方面进行了综述。作为一种新兴技术，FLASH-RT提供了提高治疗效果的潜力，同时最大限度地减少对健康组织的损害。我们阐述了辐射生物学中“FLASH效应”的物理原理及其剂量分布特征，描述了在肿瘤治疗中的临床应用，并评估了对正常组织的保护作用。此外，本文还讨论了设备、剂量学和成像方面的技术进展，同时分析了当前的研究热点和技术瓶颈。我们还研究了病理机制，未来的应用，以及关于安全性，疗效不确定性和伦理的普遍争议。这一全面的讨论为加深对FLASH-RT的转化之旅的理解提供了有价值的参考。

引用次数: 0

Diagnostic efficacy of blood biomarkers for differentiating early-stage pancreatic cancer from chronic pancreatitis: A systematic review and network meta-analysis 血液生物标志物鉴别早期胰腺癌和慢性胰腺炎的诊断效果：系统综述和网络荟萃分析

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-16 DOI: 10.1016/j.tranon.2026.102674

Di Wu , Zeng-Kan Du , Yuan-Chen Wang , Yi-Zhou Zheng , Hang-Ming Qi , Yu-Ru-Chen Zhu , Yu Cao , Lei Wang , Wen-Bin Zou , Zhuan Liao

Background

Early diagnosis of pancreatic cancer (PC) remains challenging, particularly in patients with chronic pancreatitis (CP). Currently, imaging is often inaccurate and biopsy is inherently invasive. This is the first network meta-analysis (NMA) comparing blood-based biomarkers for differentiating PC from CP.

Methods

PubMed and EMBASE were searched for studies evaluating blood-based biomarkers for distinguishing PC from CP. Risk of bias was assessed with QUADAS-2. We conducted individual biomarker meta-analysis with generalized bivariate models. For the NMA, we applied a Bayesian inference approach via a Markov-chain Monte Carlo random effects model. The surface under the cumulative ranking curve was used to rank the diagnostic performance of the biomarkers.

Results

Across 139 enrolled studies, 49 biomarkers or panels were analyzed. For differentiating PC from CP, tumor polypeptide antigen (TPA) had the highest area under the summary receiver operating characteristic curve (AUSROC) (0.92). The NMA revealed that microRNA-196b (miR-196b) ranked highest in sensitivity (OR 3.74e+27), while the combination of carbohydrate antigen 19–9 (CA199) and a panel of eight extracellular vesicle long RNAs (exLRs) exhibited the highest specificity (OR 3.78). For early-stage (stage I and II) PC, the eight exLRs showed the highest relative sensitivity (OR 7.00), and carcinoembryonic antigen (CEA) demonstrated the highest specificity (OR 4.70).

Conclusion

CA199 demonstrated only moderate diagnostic discrimination between PC and CP, with reduced efficacy in early-stage PC. Combining CA199 and eight exLRs exhibited promising differential diagnostic efficacy with both high sensitivity and specificity.

背景胰腺癌（PC）的诊断仍然具有挑战性，特别是慢性胰腺炎（CP）患者。目前，成像通常是不准确的，活检本身就是侵入性的。方法检索spubmed和EMBASE中评估血液生物标志物区分PC和CP的研究，并使用QUADAS-2评估偏倚风险。我们使用广义双变量模型进行了个体生物标志物荟萃分析。对于NMA，我们通过马尔可夫链蒙特卡洛随机效应模型应用贝叶斯推理方法。累积排序曲线下的曲面用于对生物标志物的诊断性能进行排序。结果在139项入组研究中，分析了49种生物标志物或组。在鉴别PC与CP时，肿瘤多肽抗原（tumor polypeptide antigen， TPA）在总接受者工作特征曲线（AUSROC）下的面积最高（0.92）。NMA显示，microRNA-196b （miR-196b）的敏感性最高（OR 3.74e+27），而碳水化合物抗原19-9 （CA199）和一组8个细胞外囊泡长rna （exlr）的组合具有最高的特异性（OR 3.78）。对于早期（I期和II期）PC， 8个exlr的相对敏感性最高（OR 7.00），癌胚抗原（CEA）的特异性最高（OR 4.70）。结论ca199对PC和CP的诊断鉴别能力较弱，对早期PC的鉴别能力较弱。CA199联合8种exLRs具有较高的敏感性和特异性，具有良好的鉴别诊断效果。

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引用次数: 0

Obesity and cancer: Relevance of DNA damage response 肥胖和癌症：DNA损伤反应的相关性

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-15 DOI: 10.1016/j.tranon.2025.102657

Bhavana Deshmukh , Amrendra Kumar Ajay , Manoj Kumar Bhat

Obesity is a non-communicable, multifactorial disorder that has steadily emerged as one of the major global health concerns. It significantly increases the risk of diabetes, cardiovascular diseases and cancer. In obesity, the accumulation of excess fat causes increase in the circulatory levels of adipose tissue-specific hormones (adipokines) and exacerbates carbohydrate-fuelled metabolic stress. These factors promote oxidative and genotoxic stress, resulting in chronic inflammation. Moreover, obesity-related factors contribute to increase in DNA damage and disrupt the DNA Damage Response (DDR), thereby promoting genomic instability. Consequently, obesity may facilitate a complex, multi-step process of cellular transformation and cancer progression. However, the mechanisms linking obesity-associated DDR alterations to cancer progression are active areas of investigation. Therefore, elucidating these aspects of DDR in obesity could enhance our understanding of the risk assessment and facilitate advancement in treatment strategies for patients with cancers and obesity.

肥胖是一种非传染性、多因素疾病，已逐渐成为全球主要健康问题之一。它大大增加了患糖尿病、心血管疾病和癌症的风险。在肥胖中，过量脂肪的积累导致脂肪组织特异性激素（脂肪因子）循环水平的增加，并加剧碳水化合物驱动的代谢压力。这些因素促进氧化应激和基因毒性应激，导致慢性炎症。此外，肥胖相关因素导致DNA损伤增加，破坏DNA损伤反应（DDR），从而促进基因组不稳定。因此，肥胖可能促进了一个复杂的、多步骤的细胞转化和癌症进展过程。然而，将肥胖相关的DDR改变与癌症进展联系起来的机制是研究的活跃领域。因此，阐明肥胖中DDR的这些方面可以增强我们对风险评估的理解，促进癌症和肥胖患者治疗策略的进步。

引用次数: 0

NEIL1 suppresses ROS accumulation to promote temozolomide resistance and malignant progression in glioma cells NEIL1抑制ROS积累，促进替莫唑胺耐药和胶质瘤细胞恶性进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-13 DOI: 10.1016/j.tranon.2026.102667

Shuo Li , Chenhao Fang , Qingyue Yuan , Xianzhen Chen

Background

Glioma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard first-line chemotherapy, but its efficacy is severely limited by acquired resistance. Understanding resistance mechanisms, especially beyond traditional DNA repair, is crucial for improving outcomes.

Methods

We integrated multi-database glioma transcriptomics (TCGA, GTEx, CGGA). Bioinformatics (differential expression, WGCNA, glycolipid metabolism gene screening) and machine learning (LASSO, random forest) identified key genes, focusing on the DNA glycosylase NEIL1. Its expression was assessed in U251 MG cells versus TMZ-resistant (U251 MG/TMZ) cells. Gain/loss-of-function studies (lentiviral knockdown/overexpression) and pharmacological inhibition (a 2-thioxanthine derivative, TX16) were used to evaluate NEIL1′s role in proliferation (CCK-8, EdU), migration, invasion, apoptosis (TUNEL), ROS, and TMZ sensitivity (IC50). A subcutaneous nude mouse model provided in vivo validation.

Results

NEIL1 was aberrantly expressed in glioma and enriched in PI3K-Akt/cAMP signaling, suggesting that it may promote the malignant behavior of U251 MG cells through these pathways. Its expression was significantly higher in TMZ-resistant cells (P < 0.001). NEIL1 overexpression promoted malignant phenotypes (proliferation, migration, invasion, P < 0.05), while its knockdown suppressed them. Critically, NEIL1 overexpression attenuated TMZ-induced ROS and DNA damage, increased cell viability and IC₅₀ (1.2-fold), and bolstered TMZ resistance. The NEIL1 inhibitor TX16 reversed these malignant behaviors and restored TMZ sensitivity (P < 0.05), reinstating ROS-driven apoptosis. In vivo, NEIL1 promoted tumor growth, which was suppressed by TX16.

Conclusion

NEIL1 drives glioma malignancy and TMZ resistance by mitigating oxidative stress and DNA damage, highlighting its role as a promising target to overcome chemoresistance.

神经胶质瘤是最常见的原发性恶性脑肿瘤。替莫唑胺（TMZ）是标准的一线化疗药物，但其疗效受到获得性耐药的严重限制。了解耐药性机制，尤其是传统DNA修复机制之外的机制，对于改善治疗效果至关重要。方法整合多数据库胶质瘤转录组学（TCGA, GTEx， CGGA）。生物信息学（差异表达，WGCNA，糖脂代谢基因筛选）和机器学习（LASSO，随机森林）鉴定了关键基因，重点是DNA糖基化酶NEIL1。比较其在U251 MG细胞和TMZ耐药（U251 MG/TMZ）细胞中的表达。通过获得/丧失功能研究（慢病毒敲除/过表达）和药理学抑制（2-硫黄嘌呤衍生物TX16）来评估NEIL1在增殖（CCK-8, EdU）、迁移、侵袭、凋亡（TUNEL）、ROS和TMZ敏感性（IC50）中的作用。皮下裸鼠模型提供了体内验证。结果neil1在胶质瘤中异常表达，并在PI3K-Akt/cAMP信号通路中富集，提示其可能通过这些通路促进U251 MG细胞的恶性行为。其在tmz耐药细胞中的表达显著升高（P < 0.001）。NEIL1过表达促进恶性表型（增殖、迁移、侵袭，P < 0.05），而其敲低抑制这些表型。重要的是，NEIL1过表达减弱了TMZ诱导的ROS和DNA损伤，增加了细胞活力和IC50（1.2倍），并增强了TMZ抗性。NEIL1抑制剂TX16逆转了这些恶性行为，恢复了TMZ敏感性（P < 0.05），恢复了ros驱动的细胞凋亡。在体内，NEIL1促进肿瘤生长，而TX16抑制NEIL1的生长。结论neil1通过减轻氧化应激和DNA损伤驱动胶质瘤恶性和TMZ耐药，是克服化疗耐药的有希望的靶点。

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引用次数: 0

Spatial and single-cell multi-omics reveal pro-angiogenic THY1⁺ fibroblast subtypes predicting prognosis in prostate cancer 空间和单细胞多组学揭示促血管生成THY1 +成纤维细胞亚型预测前列腺癌预后

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-12 DOI: 10.1016/j.tranon.2026.102664

Yongqiang Huang , Chunping Xiang , Yu Wang , Wei Zhang , Leilei Du , Wenfeng Wang , Guohai Shi , Jianhua Wang

Background

Cancer-associated fibroblasts (CAFs) play a key role in prostate cancer (PCa) progression, though their heterogeneity and specific protumorigenic subsets remain poorly characterized. This study aimed to identify and validate a distinct THY1⁺ CAF subset associated with aggressive PCa.

Methods

Multiomics data from public (TCGA-PRAD, GEO) and prospective (FUSCC, n = 84) cohorts were analyzed. An 8-gene CAF-derived prognostic signature was constructed using LASSO Cox regression. THY1⁺ CAF clusters were identified via scRNA-seq. Primary CAFs were isolated from patient tissues, and THY1⁺/THY1⁻ subpopulations were purified via MACS/FACS. Angiogenic function and secretory profiles were assessed through tube formation assays, ELISA, and antibody arrays. THY1 knockdown and CXCR2 inhibition were used for mechanistic studies. Clinical relevance was evaluated via qPCR and multiplex immunohistochemistry on tissue microarrays.

Results

High CAF abundance correlated with aggressive clinicopathological features and poor prognosis in PCa. The 8-gene signature effectively predicted biochemical recurrence (BCR). scRNA-seq revealed THY1⁺ CAFs as a proangiogenic subpopulation. THY1⁺ CAFs enhanced angiogenesis via increased secretion of CXCL6 and VEGFA. CXCL6 promoted endothelial tube formation through CXCR2 activation, while THY1 knockdown downregulated VEGFA and impaired angiogenesis. High THY1⁺ CAF infiltration was associated with significantly worse recurrence-free survival.

Conclusion

THY1⁺ CAFs represent a proangiogenic subset that drives PCa progression via the CXCL6/CXCR2 axis and THY1-mediated VEGFA expression. These findings highlight stromal THY1 and the CXCL6/CXCR2 pathway as potential therapeutic targets.

背景：癌症相关成纤维细胞（CAFs）在前列腺癌（PCa）的进展中起着关键作用，尽管它们的异质性和特定的蛋白发生亚群仍然缺乏特征。这项研究旨在鉴定和验证与侵袭性PCa相关的THY1 + CAF亚群。方法：对来自公共队列（TCGA-PRAD， GEO）和前瞻性队列（FUSCC, n = 84）的多组学数据进行分析。使用LASSO - Cox回归构建8基因caf衍生的预后特征。通过scRNA-seq鉴定THY1 + CAF簇。从患者组织中分离出原代CAFs，通过MACS/FACS纯化THY1⁺/THY1⁻亚群。血管生成功能和分泌谱通过管形成试验、ELISA和抗体阵列进行评估。THY1敲除和CXCR2抑制用于机制研究。通过组织微阵列上的qPCR和多重免疫组化来评估临床相关性。结果：高CAF丰度与前列腺癌侵袭性临床病理特征和不良预后相关。8基因标记可有效预测生化复发（BCR）。scRNA-seq显示THY1 + CAFs是促血管生成亚群。THY1 + CAFs通过增加CXCL6和VEGFA的分泌增强血管生成。CXCL6通过激活CXCR2促进内皮管的形成，而THY1敲低则下调VEGFA并损害血管生成。高THY1 + CAF浸润与明显较差的无复发生存率相关。结论：THY1 + CAFs代表一个促血管生成亚群，通过CXCL6/CXCR2轴和THY1介导的VEGFA表达驱动PCa进展。这些发现强调基质THY1和CXCL6/CXCR2通路是潜在的治疗靶点。

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引用次数: 0

Advances on drug therapy for KRASG12C-mutant non-small-cell lung cancer krasg12c突变体非小细胞肺癌的药物治疗进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-12 DOI: 10.1016/j.tranon.2026.102668

Ting Tian, Wangping Li

Lung cancer has an extremely high mortality rate among malignant tumors, posing a significant threat to human health Among all lung cancer cases, non-small cell lung cancer (NSCLC) accounts for a significant proportion and has become a hot topic in clinical research and treatment. The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most common oncogenic drivers in NSCLC, closely associated with tumor initiation, treatment response, and prognosis. However, due to the relatively smooth surface of the KRAS protein and the lack of drug-binding pockets, it has long been regarded as an "undrugable target". With further research, recently, targeted drugs targeting the KRAS^G12C gene mutation have achieved significant breakthroughs in clinical trials, especially the application of KRAS^G12C-specific inhibitors adagrasib and sotorasib, which has changed the treatment landscape for NSCLC patients. To address challenges such as tumor heterogeneity, the complexity of the tumor microenvironment, interpatient variability, and acquired drug resistance mechanisms, combination therapy strategies involving KRAS^G12C inhibitors have emerged sequentially. This article systematically reviews the progress of targeted therapy for KRAS^G12C-mutant NSCLC and the results of related clinical trials, while exploring novel therapeutic strategies for patients with KRAS^G12C mutations, aiming to provide a reference for the selection of clinical treatment regimens.

肺癌是恶性肿瘤中死亡率极高的肿瘤，对人类健康构成重大威胁。在所有肺癌病例中，非小细胞肺癌（non-small cell Lung cancer， NSCLC）占了相当大的比例，已成为临床研究和治疗的热点。Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）是NSCLC中最常见的致癌驱动因子之一，与肿瘤起始、治疗反应和预后密切相关。然而，由于KRAS蛋白表面相对光滑，缺乏药物结合口袋，长期以来被认为是“不可磨灭的靶标”。随着研究的深入，近年来，针对KRASG12C基因突变的靶向药物在临床试验中取得了重大突破，尤其是KRASG12C特异性抑制剂阿达格拉西和索托拉西的应用，改变了NSCLC患者的治疗格局。为了应对诸如肿瘤异质性、肿瘤微环境复杂性、患者间变异性和获得性耐药机制等挑战，涉及KRASG12C抑制剂的联合治疗策略相继出现。本文系统综述KRASG12C突变型NSCLC靶向治疗进展及相关临床试验结果，同时探索KRASG12C突变患者的新治疗策略，旨在为临床治疗方案的选择提供参考。

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