Translational Oncology最新文献_第9页

Prognostic prediction for inflammatory breast cancer patients using random survival forest modeling 随机生存森林模型用于炎性乳腺癌患者的预后预测。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102246

Yiwei Jia , Chaofan Li , Cong Feng , Shiyu Sun , Yifan Cai , Peizhuo Yao , Xinyu Wei , Zeyao Feng , Yanbin Liu , Wei Lv , Huizi Wu , Fei Wu , Lu Zhang , Shuqun Zhang , Xingcong Ma

Background

Inflammatory breast cancer (IBC) is an aggressive and rare phenotype of breast cancer, which has a poor prognosis. Thus, it is necessary to establish a novel predictive model of high accuracy for the prognosis of IBC patients.

Methods

Clinical information of 1,230 IBC patients from 2010 to 2020 was extracted from the Surveillance, Epidemiology and End Results (SEER) database. Cox analysis was applied to identify clinicopathological characteristics associated with the overall survival (OS) of IBC patients. Random survival forest (RSF) algorithm was adopted to construct an accurate prognostic prediction model for IBC patients. Kaplan–Meier analysis was performed for survival analyses.

Results

Race, N stage, M stage, molecular subtype, history of chemotherapy and surgery, and response to neoadjuvant therapy were identified as independent predictive factors for the OS of IBC patients. The top five significant variables included surgery, response to neoadjuvant therapy, chemotherapy, breast cancer molecular subtypes, and M stage. The C-index of RSF model was 0.7704 and the area under curve (AUC) values for 1, 3, 5 years in training and validation datasets were 0.879–0.955, suggesting the excellent predictive performance of RSF model. IBC patients were divided into high-risk group and low-risk group according the risk score of RSF model, and the OS of patients in the low-risk group was significantly longer than those in the high-risk group.

Conclusion

In this study, we constructed a prognosis prediction model for IBC patients through RSF algorithm, which may potentially serve as a useful tool during clinical decision-making.

背景：炎性乳腺癌（IBC）是一种侵袭性的、罕见的乳腺癌表型，预后较差。因此，有必要建立一种新的、高精度的IBC患者预后预测模型。方法：从监测、流行病学和最终结果（SEER）数据库中提取2010 - 2020年1230例IBC患者的临床信息。应用Cox分析确定与IBC患者总生存期（OS）相关的临床病理特征。采用随机生存森林（RSF）算法构建IBC患者准确的预后预测模型。生存分析采用Kaplan-Meier分析。结果：种族、N期、M期、分子亚型、化疗和手术史、对新辅助治疗的反应是IBC患者OS的独立预测因素。前五个显著变量包括手术、对新辅助治疗的反应、化疗、乳腺癌分子亚型和M分期。RSF模型的c指数为0.7704，训练和验证数据集1、3、5年的曲线下面积（AUC）值为0.879 ~ 0.955，表明RSF模型具有良好的预测性能。根据RSF模型的风险评分将IBC患者分为高危组和低危组，低危组患者的OS明显长于高危组。结论：在本研究中，我们通过RSF算法构建了IBC患者的预后预测模型，该模型可能为临床决策提供有用的工具。

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引用次数: 0

Cross-Talk between NOK and EGFR: Juxtamembrane and Kinase domain interactions enhancing STAT3/5 signaling in breast cancer tumorigenesis NOK 与表皮生长因子受体之间的交叉对话：在乳腺癌肿瘤发生过程中，并膜和激酶结构域的相互作用增强了 STAT3/5 信号的传递。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2025.102276

Yinyin Wang , Bingdong Zhang , Chunhua He , Bo Tian , Sihan Liu , Jianghua Li , Jiayu Wang , Shigao Yang , Bingtao Zhu , Xiaoguang Wang , Zhijie Chang , Chenxi Cao

Epidermal growth factor receptor (EGFR) plays an important role in the regulation of cell proliferation and migration [1]. It forms a homodimer or heterodimer with other ErbB receptor family members to activate downstream signaling. Emerging evidence indicates that the EGFR activity and downstream signaling are regulated by other proteins except its family members during tumorigenesis. Hence, investigating the diverse partnership profiles of EGFR is crucial for elucidating the mechanisms underlying EGFR-mediated actions in tumors, which in turn can guide the development of targeted therapeutic strategies. Here we report that NOK (also known as STYK1), a novel tyrosine kinase cross-talks with EGFR to promote tumorigenesis and metastasis of breast cancer cells. We found that NOK directly interacted with EGFR and formed a heterodimer complex in a manner of cross interaction via their juxtamembrane (JM) domains and kinase domains. Depletion of NOK impaired, but over-expression of NOK increased, the phosphorylation of EGFR. NOK enhanced EGF-induced phosphorylation of STAT3 and STAT5 via its juxtamembrane (JM) domain in promoting the proliferation and migration of breast cancer cells. Overexpression of NOK and EGFR synergistically induced the tumorigenesis of NIH-3T3 normal cells. We demonstrated that co-expression of NOK and EGFR correlated with tumor malignant stages in breast cancer patients. Our finding introduces a new cross interaction manner of EGFR-NOK via juxtamembrane (JM) domains and kinase domains, uncovers a mechanism by which NOK coordinates EGFR to enhance EGF-STAT3/5 signaling during tumorigenesis and metastasis, and proposes a potential strategy for targeting NOK-EGFR in breast cancer treatment.

表皮生长因子受体（Epidermal growth factor receptor， EGFR）在细胞增殖和迁移过程中起着重要的调控作用。它与其他ErbB受体家族成员形成同二聚体或异二聚体来激活下游信号。越来越多的证据表明，EGFR活性和下游信号在肿瘤发生过程中受到除其家族成员外的其他蛋白的调节。因此，研究EGFR的不同伙伴关系对于阐明EGFR在肿瘤中介导作用的机制至关重要，这反过来又可以指导靶向治疗策略的发展。在这里，我们报道了NOK（也称为STYK1），一种新型酪氨酸激酶与EGFR交叉对话，促进乳腺癌细胞的肿瘤发生和转移。我们发现NOK直接与EGFR相互作用，并通过它们的近膜结构域和激酶结构域以交叉相互作用的方式形成异源二聚体复合物。NOK的缺失损害了EGFR的磷酸化，但NOK的过表达增加了。NOK通过近膜结构域（JM）增强egf诱导的STAT3和STAT5的磷酸化，促进乳腺癌细胞的增殖和迁移。NOK和EGFR的过表达可协同诱导NIH-3T3正常细胞的肿瘤发生。我们证明了NOK和EGFR的共同表达与乳腺癌患者的肿瘤恶性分期相关。我们的发现介绍了EGFR-NOK通过近膜（JM）结构域和激酶结构域的一种新的交叉相互作用方式，揭示了NOK在肿瘤发生和转移过程中协调EGFR增强EGF-STAT3/5信号的机制，并提出了靶向NOK-EGFR治疗乳腺癌的潜在策略。

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引用次数: 0

Lysyl oxidase inhibitors in colorectal cancer progression 赖氨酸氧化酶抑制剂在结直肠癌进展中的作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102233

Muxian Liu, Jie Wang, Meihong Liu

The lysine oxidase (LOX) family, consisting of LOX and LOX-like-1–4 (LOXL1–LOXL4), catalyses the cross-linking reaction of collagen and elastin in the extracellular matrix (ECM). Numerous studies have demonstrated that LOX family members are dysregulated in a variety of cancers, including colorectal cancer (CRC), and play a key role in cancer cell migration, proliferation, invasion and metastasis. Targeting LOX family proteins with specific inhibitors has therefore been developed as a new therapeutic strategy for cancer. In this paper, we review the role of LOX enzymes in the development and progression of CRC. In addition, we address recent advances in the development of LOX/LOXL inhibitors, highlighting the potential use of this inhibitor as an effective and complementary treatment for CRC.

赖氨酸氧化酶（LOX）家族由LOX和LOX样-1-4 （LOXL1-LOXL4）组成，在细胞外基质（ECM）中催化胶原和弹性蛋白的交联反应。大量研究表明，LOX家族成员在包括结直肠癌（CRC）在内的多种癌症中都存在异常，并在癌细胞迁移、增殖、侵袭和转移中发挥关键作用。因此，利用特异性抑制剂靶向LOX家族蛋白已成为一种新的癌症治疗策略。本文就LOX酶在结直肠癌发生发展中的作用作一综述。此外，我们讨论了LOX/LOXL抑制剂的最新进展，强调了该抑制剂作为结直肠癌有效和补充治疗的潜在用途。

引用次数: 0

TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers TNG908是一种脑渗透，mta协同PRMT5抑制剂，用于治疗mtap缺失的癌症。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102264

Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Alice Tsai, Minjie Zhang, Douglas A. Whittington, Wenhai Zhang, Steven A. Lombardo, Satoshi Yoda, Erik W. Wilker, Samuel R. Meier, Yi Yu, Teng Teng, Alan Huang, John P. Maxwell

TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10–15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478).

TNG908是一种临床阶段的PRMT5抑制剂，具有mta协同结合机制，旨在利用PRMT5抑制和MTAP缺失之间的合成致死相互作用。MTAP缺失发生在代表多种组织学的所有人类癌症的10- 15%中。MTA是PRMT5的负调节因子，由于MTAP缺失而积累。在这项研究中，我们证明了TNG908选择性结合PRMT5·MTA复合物，在mtap缺失的癌症中驱动PRMT5的选择性抑制，这一机制相对于具有非肿瘤选择性的替代结合机制的第一代PRMT5抑制剂创造了一个大的治疗指数。在多种mtap缺失的异种移植物模型中具有很强的临床前活性，以及在临床前模型中显示的脑外显性，支持TNG908在mtap缺失的实体瘤（包括中枢神经系统恶性肿瘤）中具有组织学不可知的临床发展潜力。TNG908正在一项I/II期临床试验中对mtap缺失肿瘤（包括胶质母细胞瘤）患者进行临床测试（NCT05275478）。

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引用次数: 0

ConvXGB: A novel deep learning model to predict recurrence risk of early-stage cervical cancer following surgery using multiparametric MRI images ConvXGB：利用多参数MRI图像预测早期宫颈癌术后复发风险的新型深度学习模型。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2025.102281

Ji Wu , Jian Li , Bo Huang , Sunbin Dong , Luyang Wu , Xiping Shen , Zhigang Zheng

Background

Accurate estimation of recurrence risk for cervical cancer plays a pivot role in making individualized treatment plans. We aimed to develop and externally validate an end-to-end deep learning model for predicting recurrence risk in cervical cancer patients following surgery by using multiparametric MRI images.

Methods

The clinicopathologic data and multiparametric MRI images of 406 cervical cancer patients from three institutions were collected. We designed a novel deep learning model called “ConvXGB” for predicting recurrence risk by combining the convolutional neural network (CNN) and eXtreme Gradient Boost (XGBoost). The predictive performance of the ConvXGB model was evaluated using time-dependent area under curve (AUC), compared with the deep learning radio-clinical model, clinical model, conventional radiomics nomogram and an existing histology-specific tool. The potential of the ConvXGB model in predicting the recurrence-free survival (RFS) and overall survival (OS) was assessed.

Results

The ConvXGB model outperformed other models in predicting recurrence risk, with AUCs for 1 and 3 year-RFS of 0.872(95% CI, 0.857–0.906) and 0.882(95% CI, 0.860–0.904) respectively in the test cohort. This model showed better discrimination, calibration and clinical utility. Grad-CAM analysis was adopted to help clinicians better understand the predictive results. Moreover, Kaplan–Meier survival analysis revealed that patients who were stratified into high-risk group by the ConvXGB model were significantly susceptible to higher cumulative recurrence risk rates and worse outcome.

Conclusion

The ConvXGB model allowed for predicting postoperative recurrence risk in cervical cancer patients and for stratifying the risk of RFS and OS.

背景：准确估计宫颈癌复发风险对制定个体化治疗方案具有关键作用。我们的目标是开发和外部验证端到端深度学习模型，通过使用多参数MRI图像预测宫颈癌患者术后复发风险。方法：收集3所医院406例宫颈癌患者的临床病理资料及多参数MRI影像。结合卷积神经网络（CNN）和极限梯度增强（XGBoost），设计了一种新的深度学习模型“ConvXGB”，用于预测复发风险。与深度学习放射-临床模型、临床模型、常规放射组学图和现有的组织学特异性工具相比，使用随时间变化的曲线下面积（AUC）来评估ConvXGB模型的预测性能。评估ConvXGB模型在预测无复发生存期（RFS）和总生存期（OS）方面的潜力。结果：ConvXGB模型在预测复发风险方面优于其他模型，在测试队列中，1年和3年rfs的auc分别为0.872（95% CI, 0.857-0.906）和0.882（95% CI, 0.860-0.904）。该模型具有较好的鉴别性、校正性和临床实用性。采用Grad-CAM分析来帮助临床医生更好地理解预测结果。此外，Kaplan-Meier生存分析显示，被ConvXGB模型分层为高危组的患者，其累积复发风险率较高，预后较差。结论：ConvXGB模型可以预测宫颈癌患者术后复发风险，并对RFS和OS的风险进行分层。

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引用次数: 0

Molecular profiling of bladder cancer xenografts defines relevant molecular subtypes and provides a resource for biomarker discovery. 膀胱癌异种移植物的分子图谱分析确定了相关的分子亚型，并为生物标记物的发现提供了资源。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102269

Sharada Mokkapati , Ganiraju Manyam , Alexis R. Steinmetz , Côme Tholomier , Alberto Martini , Woonyoung Choi , Bogdon Czerniak , Byron H Lee , Colin P Dinney , David J McConkey

Bladder cancer (BLCA) genomic profiling has identified molecular subtypes with distinct clinical characteristics and variable sensitivities to frontline therapy. BLCAs can be categorized into luminal or basal subtypes based on their gene expression. We comprehensively characterized nine human BLCA cell lines (UC3, UC6, UC9, UC13, UC14, T24, SCaBER, RT4V6 and RT112) into molecular subtypes using orthotopic xenograft models. Patient-derived, luciferase-tagged BLCA cell lines were cultured in vitro and engrafted into bladders of NSG mice. Tumor growth was monitored using bioluminescence imaging and mRNA-based molecular classification was used to characterize xenografts into molecular subtypes. RNAseq analysis and basal, luminal, and epithelial-mesenchymal transition (EMT) marker expression revealed distinct patterns; certain cell lines expressed predominantly basal or luminal markers while others demonstrated mixed expression. SCaBER expressed high basal and EMT markers and low luminal markers, consistent with a true basal cell. RT4V6 was a true luminal cell line, displaying only high luminal makers. UC13, T24 and UC3 only showed increased expression of EMT markers. RT112, UC6, UC9 and UC14 expressed basal, luminal, and EMT markers. Immunohistochemical analysis validated our findings. Ki67 was assessed as a continuous percentage of positively stained cells. Morphological assessment of xenografts included H&E and α-SMA staining. These findings will allow for the rational use of appropriate models to develop targeted therapies to overcome or manipulate mechanisms of treatment resistance in BLCA.

膀胱癌（BLCA）基因组分析已经确定了具有不同临床特征和对一线治疗敏感性的分子亚型。根据基因表达的不同，blca可分为管状亚型和基底亚型。我们利用同种异种移植模型对9种人BLCA细胞系（UC3、UC6、UC9、UC13、UC14、T24、scer、RT4V6和RT112）进行了分子亚型的全面表征。患者来源的荧光素酶标记的BLCA细胞系在体外培养并移植到NSG小鼠的膀胱中。利用生物发光成像监测肿瘤生长，并利用基于mrna的分子分类将异种移植物划分为分子亚型。RNAseq分析和基底、腔内和上皮-间质转化（EMT）标记的表达显示出不同的模式；某些细胞系主要表达基底或腔内标记物，而其他细胞系则表现出混合表达。scer表达高基底和EMT标记物和低腔标记物，与真正的基底细胞一致。RT4V6是一个真正的荧光细胞系，只显示高荧光细胞。UC13、T24和UC3仅显示EMT标记物表达增加。RT112、UC6、UC9和UC14表达基础、luminal和EMT标记物。免疫组织化学分析证实了我们的发现。Ki67以阳性染色细胞的连续百分比进行评估。形态学评价采用H&E染色和α-SMA染色。这些发现将允许合理使用适当的模型来开发靶向治疗，以克服或操纵BLCA的治疗耐药机制。

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引用次数: 0

Potentialities and critical issues of liquid biopsy in clinical practice: An umbrella review 液体活检在临床实践中的潜力和关键问题：综述。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102172

Nicola Veronese , Claudio Luchini , Stefano Ciriminna , Katia Spinelli , Santo Fruscione , Paola Mattiolo , Miriam Belluzzo , Veronica Messina , Lee Smith , Mario Barbagallo , Walter Mazzucco

Background

Liquid biopsy (LB) is a laboratory test performed on a fluid sample aiming at analyzing molecular data derived from circulating cells and related entities, or from nucleic acids. This umbrella review aims to map and evaluate the evidence supporting the use of LB in medicine across different medical specialities and conditions.

Methods

We searched three repositories from database inception up to October 1, 2023 and we included meta-analyses of observational studies reporting data on the use of LB, compared to gold standard, and its accuracy (area under the curve, AUC).

Results

Among 726 articles initially screened, 42 systematic reviews were included. Most of the outcomes explored (202/211) were related to cancer. We found that 75/211 had an excellent accuracy (AUC >0.90), with one comparison with an AUC equal to 1, i.e., Cell-Free Human Papillomavirus DNA (cfHPV-DNA) for HPV-positive oropharyngeal squamous cell carcinoma. However, considering published meta-analyses, all the outcomes were graded as very low on the GRADE criteria, and the heterogeneity was never reported.

Discussion

The literature about LB is rapidly increasing and some promising data about precision oncology are now available. However, this umbrella review on existing meta-analyses highlighted some critical issues for providing quantitative estimations on the different roles of LB.

背景：液体活检（LB）是一种对液体样本进行的实验室检测，旨在分析来自循环细胞和相关实体或核酸的分子数据。本综述旨在绘制和评估支持在不同医学专业和条件下使用LB的证据。方法：我们检索了三个数据库，从数据库建立到2023年10月1日，我们纳入了观察性研究的荟萃分析，报告了与金标准相比使用LB的数据，及其准确性（曲线下面积，AUC）。结果：在最初筛选的726篇文章中，纳入了42篇系统评价。大多数研究结果（202/211）与癌症有关。我们发现75/211具有极好的准确性（AUC为0.90），其中一个与AUC等于1的比较，即hpv阳性口咽鳞状细胞癌的无细胞人乳头瘤病毒DNA （cfHPV-DNA）。然而，考虑到已发表的荟萃分析，所有结果在GRADE标准上的评分都很低，并且从未报道过异质性。讨论：关于LB的文献正在迅速增加，现在有一些关于精确肿瘤学的有希望的数据。然而，这篇对现有荟萃分析的综述强调了一些关键问题，以提供对LB不同作用的定量估计。

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引用次数: 0

Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia 修饰的CD15/CD16-CLL1抑制性CAR-T细胞在急性髓性白血病治疗中减轻粒细胞减少毒性

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102225

Rui Zhang , Yifan Zhao , Xiao Chai , Yingshuai Wang , Mohan Zhao , Shujing Guo , Yu Zhang , Mingfeng Zhao

CLL1 Chimeric antigen receptor T-cell (CAR-T) therapy, as a promising immunotherapeutic approach, has demonstrated its potential to enhance the prognosis of patients diagnosed with acute myeloid leukemia (AML). However, due to the overexpression of CLL1 on neutrophils, CAR-T cells not only eliminated tumor cells but also eradicated neutrophils simultaneously, resulting in severe granulocytopenia and subsequent infections. Considering the distinct expression levels of CD15/CD16 on neutrophils and AML blasts, we have devised novel modified CD15 /CD16-CLL1 iCAR structures incorporating diverse inhibitory elements. Through extensive screening of structural optimization, we have successfully identified CD16-CLL1 iCAR-T cells that combine PD1 and 2B4 blockade, as well as a single VHH fragment replacing the entire CD16 scFv recognition domain. These modified cells demonstrate enhanced cytotoxicity against blasts while minimizing neutrophil elimination. Furthermore, their functionality has been effectively validated through both in vitro and in vivo experiments. In conclusion, we have successfully engineered innovative CD16-CLL1 iCAR-T cells, which preserves the cytotoxicity against tumor cells while preventing elimination of neutrophils, thereby significantly reducing the incidence of granulocytopenia during CAR-T therapy. Furthermore, our future objectives encompass the meticulous validation of both the efficacy and safety profile of this groundbreaking CAR-T therapy in clinical trials, as well as a comprehensive assessment of its potential to enhance the prognosis of patients diagnosed with AML.

CLL1嵌合抗原受体t细胞（CAR-T）疗法作为一种很有前途的免疫治疗方法，已被证明具有改善急性髓性白血病（AML）患者预后的潜力。然而，由于CLL1在中性粒细胞上的过度表达，CAR-T细胞在消灭肿瘤细胞的同时也消灭了中性粒细胞，导致严重的粒细胞减少和随后的感染。考虑到CD15/CD16在中性粒细胞和AML细胞上的不同表达水平，我们设计了包含多种抑制元件的新型修饰CD15/CD16 - cll1 iCAR结构。通过广泛的结构优化筛选，我们已经成功鉴定出结合PD1和2B4阻断的CD16- cll1 iCAR-T细胞，以及单个VHH片段取代整个CD16 scFv识别域。这些修饰的细胞显示出增强的细胞毒性，同时减少中性粒细胞的消除。此外，它们的功能已通过体外和体内实验得到有效验证。总之，我们已经成功地设计了创新的CD16-CLL1 iCAR-T细胞，它保留了对肿瘤细胞的细胞毒性，同时防止了中性粒细胞的消除，从而显着降低了CAR-T治疗期间粒细胞减少的发生率。此外，我们未来的目标包括在临床试验中对这种突破性CAR-T疗法的有效性和安全性进行细致的验证，以及对其改善AML患者预后的潜力进行全面评估。

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引用次数: 0

EMC2 suppresses ferroptosis via regulating TFRC in nasopharyngeal carcinoma EMC2通过调节鼻咽癌TFRC抑制铁下垂。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102251

Xianghui Chen , Xiaoyan Wang , Yuxia Zou , Yan Wang , Tingting Duan , Zijie Zhou , Yi Huang , Qing Ye

Background

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with poorly understood underlying molecular mechanisms. Ferroptosis, a form of programmed cell death, is not fully elucidated in NPC.

Method

We conducted quantitative proteomics to detect dysregulated proteins in NPC tissues. The levels of endoplasmic reticulum membrane protein complex 2 (EMC2) in NPC tissue microarrays were evaluated by immunohistochemistry, and the prognostic value of EMC2 was analyzed in NPC patients. The role of EMC2 in ferroptosis and carcinogenesis was determined through in vitro and in vivo experiments. Quantitative proteomics, protease inhibition, ubiquitin detection, and rescue experiments were performed to explore the mechanism of EMC2-regulated ferroptosis.

Results

Significantly upregulated EMC2 was detected in NPC, and it was closely related to the characteristics of tumor progression. Elevated EMC2 was obviously correlated with poor survival in patients with NPC. EMC2 knockdown promoted ferroptosis, inhibiting cell viability, migration, and invasion, and enhancing the efficacy of cisplatin in NPC cells. Conversely, EMC2 overexpression contributed to ferroptosis repression, malignant progression, and reduced the efficacy of cisplatin. In addition, EMC2 knockdown suppressed xenograft tumor growth and enhanced ferroptosis in nude mice. Mechanistically, we identified transferrin receptor (TFRC) as a critical downstream protein. EMC2 interacted with TFRC and promoted its ubiquitin-proteasomal degradation. EMC2 regulated ferroptosis by mediating the level of TFRC.

Conclusions

EMC2 suppresses ferroptosis and promotes tumor progression, and the EMC2-TFRC axis is a novel ferroptosis regulatory pathway. EMC2 is a potentially biomarker and therapeutic target for NPC.

背景：鼻咽癌是一种上皮性恶性肿瘤，其分子机制尚不清楚。铁下垂是一种程序性细胞死亡形式，在鼻咽癌中尚未完全阐明。方法：采用定量蛋白质组学方法检测鼻咽癌组织中异常蛋白。应用免疫组织化学方法检测鼻咽癌组织微阵列中内质网膜蛋白复合物2 （EMC2）水平，并分析EMC2在鼻咽癌患者中的预后价值。通过体外和体内实验确定EMC2在铁下垂和癌变中的作用。通过定量蛋白质组学、蛋白酶抑制、泛素检测和救援实验探讨emc2调控铁凋亡的机制。结果：EMC2在鼻咽癌中表达显著上调，且与肿瘤进展特征密切相关。在鼻咽癌患者中，EMC2升高与较差的生存率明显相关。EMC2敲低可促进铁下垂，抑制细胞活力、迁移和侵袭，增强顺铂对鼻咽癌细胞的作用。相反，EMC2过表达有助于抑制铁下垂，恶性进展，并降低顺铂的疗效。此外，EMC2敲除抑制裸鼠异种移植物肿瘤生长并增强铁下垂。在机制上，我们发现转铁蛋白受体（TFRC）是一个关键的下游蛋白。EMC2与TFRC相互作用，促进其泛素-蛋白酶体降解。EMC2通过调节TFRC水平调控铁下垂。结论：EMC2抑制铁下垂并促进肿瘤进展，EMC2- tfrc轴是一种新的铁下垂调控通路。EMC2是鼻咽癌潜在的生物标志物和治疗靶点。

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引用次数: 0

Design of a humanized CD40 agonist antibody with specific properties using AlphaFold2 and development of an anti-PD-L1/CD40 bispecific antibody for cancer immunotherapy 利用AlphaFold2设计具有特异性的人源化CD40激动剂抗体，并开发抗pd - l1 /CD40双特异性抗体用于癌症免疫治疗。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2025-02-01 DOI: 10.1016/j.tranon.2024.102247

Kun Du , He Huang

Bispecific antibodies (BsAbs) represent a promising strategy for cancer immunotherapy. Challenges in immunotherapy include inefficient early events in the immune response cycle, such as antigen presentation and T cell priming. Background stimulation of CD40 with agonistic antibodies is a promising strategy to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Assisted by Alphafold2(AlphaFold-Multimer), we developed a humanized CD40 agonistic antibody that exhibits activation only in the presence of cross-linking. It also demonstrates that the current AlphaFold2(AlphaFold2-Multimer) can predict antibody-antigen complexes. Due to the unique epitope, it demonstrates superior activation compared to APX005M (S267E). Building upon this, we created a novel bispecific antibody (anti-PD-L1/CD40 bispecific antibody, referred to as "BA4415") designed to activate CD40 signaling specifically in the context of PD-L1 while simultaneously blocking PD-1/PD-L1 signaling. Results from functional evaluations using effector cells revealed the superior biological activity of BA4415 compared to the combination of each monoclonal antibody. BA4415 demonstrated the ability to enhance T-cell cytokine release in vitro assays, exhibiting superior functional attributes compared to the anti-PD-L1 antibody. Furthermore, in humanized transgenic mice challenged with huPD-L1-expressing tumor cells, BA4415 induced superior anti-tumor activity. This novel anti-PD-L1/CD40 bispecific antibody holds potential for strong anti-tumor therapeutic efficacy by selectively restricting CD40 stimulation in tumors.

双特异性抗体（BsAbs）是一种很有前途的癌症免疫治疗策略。免疫治疗面临的挑战包括免疫反应周期中低效的早期事件，如抗原呈递和T细胞启动。利用激动抗体刺激CD40是提高免疫检查点抑制剂（ICIs）治疗效果的一种有希望的策略。在Alphafold2（AlphaFold-Multimer）的辅助下，我们开发了一种人源化CD40激动抗体，该抗体仅在交联存在时才表现出激活。这也证明了目前的AlphaFold2（AlphaFold2- multimer）可以预测抗体-抗原复合物。由于独特的表位，与APX005M （S267E）相比，它表现出更高的活化能力。在此基础上，我们创建了一种新的双特异性抗体（抗PD-L1/CD40双特异性抗体，称为“BA4415”），旨在在PD-L1的背景下特异性激活CD40信号，同时阻断PD-1/PD-L1信号传导。效应细胞功能评价结果显示，BA4415单克隆抗体的生物活性优于单克隆抗体组合。在体外测试中，BA4415显示出增强t细胞细胞因子释放的能力，与抗pd - l1抗体相比，显示出更优越的功能属性。此外，在用表达hupd - l1的肿瘤细胞攻击人源化转基因小鼠中，BA4415诱导了更强的抗肿瘤活性。这种新型抗pd - l1 /CD40双特异性抗体通过选择性地限制肿瘤中CD40的刺激，具有很强的抗肿瘤治疗功效。

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