Translational Oncology最新文献

Clinical efficacies of different neoadjuvant therapies for non-small cell lung cancer 非小细胞肺癌不同新辅助疗法的临床疗效。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-17 DOI: 10.1016/j.tranon.2024.102195

Xin-chen Tan , Xin-yun Song , Meng-qi Jiang , Neng-yang Wang , Jun Liu , Wen Yu , Qin Zhang , Xu-wei Cai , Wen Feng , Xiao-long Fu

Neoadjuvant therapy followed by surgery is a common clinical strategy for operable non-small cell lung cancer (NSCLC), and the mainstream neoadjuvant therapies include chemoimmunotherapy, targeted therapy, and chemotherapy. However, there is a lack of studies to report the difference in benefits between these treatment modalities in the same institution. Therefore, this study aimed to depict the short-term efficacy of radiology and pathology achieved by different therapies and their impact on long-term survival as well as the underlying clinical significance. A total of 243 NSCLC patients who underwent different neoadjuvant therapies were eligible for inclusion. Demographic, radiological, and pathological features of patients were recorded. The event-free survival (EFS) outcome was analyzed using Kaplan-Meier analysis. The objective response rates (ORR) of primary tumor in the chemoimmunotherapy, targeted therapy, and chemotherapy cohorts were 48.95 %, 57.58 %, and 34.09 % respectively, major pathological response (MPR) rates were 58.74 %, 15.15 %, and 20.83 % (P<.0001), and pathological complete response (pCR) rates were 41.26 %, 0 %, and 11.11 % (P<.0001). For consistency between imaging and pathological evaluation, Cohen's Kappa were 0.275, 0.233, and 0.330. The EFS of MPR group was significantly longer than that of non-MPR group in the chemoimmunotherapy and chemotherapy cohorts (P=.0077**&.0343*, HR=0.3287&0.3715), but this improvement was not observed in the targeted therapy cohort. Neoadjuvant chemoimmunotherapy often underestimates pathological efficacy in imaging but shows consistent long-term outcomes. Neoadjuvant chemotherapy with moderate overall effectiveness has a significant correlation between short-term benefits and reduced recurrence. Neoadjuvant targeted therapy shows remarkable short-term imaging improvements but often fails to convert into sustained long-term survival.

新辅助治疗后再手术是可手术的非小细胞肺癌（NSCLC）的常见临床策略，主流的新辅助疗法包括化学免疫疗法、靶向疗法和化疗。然而，目前尚缺乏研究报告这些治疗方式在同一机构中的疗效差异。因此，本研究旨在描述不同疗法在放射学和病理学方面取得的短期疗效及其对长期生存的影响以及潜在的临床意义。共有243名接受了不同新辅助疗法的NSCLC患者符合纳入条件。研究人员记录了患者的人口学、放射学和病理学特征。采用Kaplan-Meier分析法对无事件生存期（EFS）结果进行了分析。化疗免疫疗法组、靶向疗法组和化疗组的原发肿瘤客观反应率（ORR）分别为48.95%、57.58%和34.09%，主要病理反应率（MPR）分别为58.74%、15.15%和20.83%（P＜0.05）。

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引用次数: 0

Integrated multi-omics demonstrates enhanced antitumor efficacy of donafenib combined with FADS2 inhibition in hepatocellular carcinoma 多组学综合研究表明，多纳非尼联合 FADS2 抑制剂可增强肝细胞癌的抗肿瘤疗效。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-17 DOI: 10.1016/j.tranon.2024.102142

Hui Li, Yafeng Dai, Di Wu, Song Gao, Jianhai Guo, Pengjun Zhang, Hui Chen, Fuxin Kou, Shaoxing Liu, Aiwei Feng, Baojiang Liu, Dongdong Hou, Xu Zhu

Pharmacotherapy is crucial for advanced hepatocellular carcinoma (HCC). The multi-kinase inhibitor donafenib offers superior survival benefits over sorafenib. Donafenib has first-line status, but there is limited research for combination therapies with this anticancer agent. This study aimed to delineate donafenib's antitumor effects, including transcriptomics and proteomics to characterize gene expression changes in donafenib-treated HCC cell lines. In vitro and in vivo tumorigenicity studies were conducted to evaluate the combined antitumor effects of donafenib. Proteomic and transcriptomic analyses identified that donafenib downregulated fatty acid desaturase 2 (FADS2) at the protein and mRNA levels. In vitro and in vivo assays revealed an inhibitory effect of FADS2 blockade on HCC cell malignancy. The combination of donafenib and the FADS2 inhibitor sc-26,196 produced synergistic antitumor action, enhancing therapeutic efficacy in HCC cell lines and xenografted tumors in nude mice. These findings highlight the potential of FADS2 as a biomarker for HCC and show a promising combinatorial therapy for its treatment. Thus, we provide a theoretical basis for translating laboratory research into clinical applications.

药物治疗对晚期肝细胞癌（HCC）至关重要。多激酶抑制剂多纳非尼的生存期优于索拉非尼。多纳非尼具有一线治疗的地位，但与这种抗癌药物联合治疗的研究却很有限。本研究旨在阐明多纳非尼的抗肿瘤作用，包括通过转录组学和蛋白质组学分析多纳非尼治疗的HCC细胞系的基因表达变化。研究还进行了体外和体内致瘤性研究，以评估多纳非尼的综合抗肿瘤作用。蛋白质组和转录组分析发现，多纳非尼在蛋白质和mRNA水平下调了脂肪酸去饱和酶2（FADS2）。体外和体内试验显示，FADS2阻断对HCC细胞恶性肿瘤有抑制作用。多奈非尼和 FADS2 抑制剂 sc-26,196 联合使用可产生协同抗肿瘤作用，提高对 HCC 细胞系和裸鼠异种移植肿瘤的疗效。这些发现凸显了 FADS2 作为 HCC 生物标记物的潜力，并展示了治疗 HCC 的组合疗法的前景。因此，我们为将实验室研究转化为临床应用提供了理论基础。

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引用次数: 0

KRas plays a negative role in regulating IDO1 expression KRas 在调节 IDO1 的表达方面起着负面作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-16 DOI: 10.1016/j.tranon.2024.102167

Xiandong Peng, Eunji Lee, Jialu liang, Tania Colon, Franklin Tran, Byeong H. Choi, Wei Dai

Ras proteins are integral to the mediation of signaling cascades to downstream effectors, regulating a multitude of cellular processes. Mutations within Ras and its associated signaling pathways are implicated in various human pathologies, including inflammatory disorders and malignancies. The immune checkpoint proteins, programmed cell death protein 1 (PD-1) and its ligands PD-L1, along with Indoleamine 2,3-dioxygenase-1 (IDO1), are pivotal in facilitating tumor immune escape. While the influence of oncogenic Ras on PD-L1 expression is extensively documented, the regulatory role of KRas in IDO1 expression remains inadequately understood. In the current study, we demonstrate that IDO1 and PD-L1 expressions are differentially regulated in KRas-mutant cancers. Treatment with the KRas^G12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRas^G12C-mutant H358 cell line. Notably, IDO1 expression was slightly diminished in KRas-mutant patients with lung and pancreatic ductal adenocarcinomas. Experimental data revealed that IFN-γ induces IDO1 expression; however, this induction is attenuated in the presence of constitutively active KRas. These findings suggest that KRas signaling negatively regulates IDO1 expression while enhancing PD-L1 expression. Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.

Ras 蛋白是向下游效应器传递信号级联的重要中介，可调节多种细胞过程。Ras 蛋白及其相关信号通路的突变与多种人类病症有关，包括炎症性疾病和恶性肿瘤。免疫检查点蛋白、程序性细胞死亡蛋白 1（PD-1）及其配体 PD-L1 以及吲哚胺 2,3-二氧合酶 1（IDO1）在促进肿瘤免疫逃逸方面起着关键作用。虽然致癌物质 Ras 对 PD-L1 表达的影响已被广泛记录，但 KRas 对 IDO1 表达的调控作用仍未得到充分了解。在本研究中，我们证明了 IDO1 和 PD-L1 的表达在 KRas 突变癌症中受到不同程度的调控。在KRasG12C突变的H358细胞系中，用KRasG12C特异性抑制剂ARS-1620治疗可显著增加IDO1的表达，而IDO1的表达与PD-L1的表达成反比。值得注意的是，在肺腺癌和胰腺导管腺癌的 KRas 突变患者中，IDO1 的表达略有减少。实验数据显示，IFN-γ能诱导IDO1的表达；但在KRas组成性活跃的情况下，这种诱导作用会减弱。这些发现表明，KRas 信号在增强 PD-L1 表达的同时负向调节 IDO1 的表达。此外，KRas抑制后对IDO1表达的诱导似乎独立于MAPK通路。我们的研究结果表明，同时靶向 KRas 和 IDO1 可以增强 KRas 突变癌症的疗效，克服免疫检查点阻断疗法的抗药性。

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引用次数: 0

Disruption of bioenergetics enhances the radio-sensitivity of patient-derived glioblastoma tumorspheres 破坏生物能增强源自患者的胶质母细胞瘤肿瘤球的放射敏感性

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-16 DOI: 10.1016/j.tranon.2024.102197

Seo Jin Kim , Junseong Park , Jin-kyoung Shim , Ran Joo Choi , Ju Hyung Moon , Eui Hyun Kim , Wan-Yee Teo , Jong Hee Chang , Seok-Gu Kang

Background

Despite available treatment approaches, including surgical resection along with chemotherapy and radiotherapy, glioblastoma (GBM), the most prevalent primary brain tumor, remains associated with a grim prognosis. Although radiotherapy is central to GBM treatment, its combination with bioenergetics regulators has not been validated in clinical practice. Here, we hypothesized that bioenergetics regulators can enhance the radio-sensitivity of GBM tumorspheres (TSs).

Methods

Gene expression profiles of GBM patient-derived TSs were obtained through microarray and RNA-seq. In vitro treatment efficacy was assessed using clonogenic assay, 3D invasion assay, neurosphere formation assay, and flow cytometry. Protein expression was measured via western blot, and γH2AX foci were detected via immunofluorescence. In vivo efficacy was confirmed in an orthotopic xenograft model.

Results

Based on radiation response-associated gene expression, GBM TSs were classified into high- or low-radioresistant groups. Among the five bioenergetics regulators, the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG notably enhanced the efficacy of ionizing radiation (IR) efficacy in vitro, reducing the survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. Combination with 2-DG further stimulated IR-induced DNA damage response and apoptosis in low-radioresistant GBM TSs. RNA-seq analysis revealed a downregulation of bioenergetics- and cell cycle-associated genes, whereas extracellular matrix- and cell adhesion-associated genes were enhanced by combined IR and 2-DG treatment. This therapeutic regimen extended survival and diminished tumor size in mouse xenograft models.

Conclusions

Our data suggest that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen.

背景：尽管现有的治疗方法包括手术切除、化疗和放疗，但胶质母细胞瘤（GBM）这种最常见的原发性脑肿瘤的预后仍然很差。尽管放疗是 GBM 治疗的核心，但其与生物能调节剂的结合尚未在临床实践中得到验证。在此，我们假设生物能调节剂能增强GBM瘤球（TSs）的放射敏感性：方法：通过芯片和 RNA-seq 获得 GBM 患者来源 TS 的基因表达谱。采用克隆形成试验、三维侵袭试验、神经球形成试验和流式细胞术评估体外治疗效果。蛋白表达通过 Western 印迹进行测量，γH2AX 病灶通过免疫荧光进行检测。结果：结果：根据辐射反应相关基因的表达，GBM TSs 被分为高耐受辐射组和低耐受辐射组。在五种生物能调节剂中，磷酸戊糖途径抑制剂 DHEA 和糖酵解抑制剂 2-DG 显著增强了电离辐射（IR）的体外疗效，降低了高耐受性和低耐受性 TS 的存活率、干性和侵袭性。与 2-DG 联用可进一步刺激红外诱导的 DNA 损伤反应和低耐受性 GBM TS 的细胞凋亡。RNA-seq分析显示生物能和细胞周期相关基因下调，而细胞外基质和细胞粘附相关基因在IR和2-DG联合治疗下增强。这种治疗方案延长了小鼠异种移植模型的生存期并缩小了肿瘤大小：我们的数据表明，与生物能调节剂 2-DG 联合使用可增强 GBM TSs 的放射敏感性，凸显了这种联合疗法的临床潜力。

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引用次数: 0

Comparative transcriptomic analysis uncovers molecular heterogeneity in hepatobiliary cancers 比较转录组分析揭示了肝胆癌的分子异质性。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-14 DOI: 10.1016/j.tranon.2024.102192

Nabanita Roy , Ria Lodh , Susmita Mandal , Mohit Kumar Jolly , Anupam Sarma , Dhruba Kumar Bhattacharyya , Pankaj Barah

Hepatobiliary cancers (HBCs) pose a major global health challenge, with a lack of effective targeted biomarkers. Due to their complex anatomical locations, shared risk factors, and the limitations of targeted therapies, generalized treatment strategies are often used for gallbladder cancer (GBC), hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (ICC). This study aimed to identify specific transcriptomic signatures in GBC, HCC, and ICC. The transcriptomic data analysis revealed distinct expression profiles, highlighting complex molecular heterogeneity within these cancers, even within the same organ system. Functional annotation revealed distinct biological pathways associated with each type of HBCs. GBC was linked to cell cycle regulation, HCC was associated with immune system modulation, and ICC was involved in metabolic dysregulation, particularly lipid metabolism. Gene co-expression network (GCN) and protein-protein interaction (PPI) network analyses identified potential key genes, such as MAPK3 and ERBB2 in GBC, AC069287.1 and ACTN2 in HCC, and TRPC1 and BACE1 in ICC. The FOX family of transcription factors (TFs) was conserved across all three cancer types. To further explore the relationship between Epithelial-Mesenchymal Transition (EMT) and the identified hub genes and TFs, an EMT score analysis was conducted. This analysis revealed distinct phenotypic characteristics in each cancer type, with TFs identified in GBC and ICC showing a stronger correlation with EMT compared to those in HCC. External validation using The Cancer Genome Atlas (TCGA) databases confirmed the expression of candidate genes, underscoring their potential as therapeutic targets. These findings provide valuable insights into the molecular heterogeneity and complexity of HBCs, opening new avenues for personalized therapeutic interventions.

由于缺乏有效的靶向生物标志物，肝胆癌（HBC）对全球健康构成了重大挑战。由于胆囊癌（GBC）、肝细胞癌（HCC）和肝内胆管癌（ICC）的解剖位置复杂、具有共同的风险因素以及靶向治疗的局限性，因此通常采用通用的治疗策略。本研究旨在确定 GBC、HCC 和 ICC 的特定转录组特征。转录组数据分析揭示了不同的表达谱，凸显了这些癌症内部复杂的分子异质性，即使在同一器官系统中也是如此。功能注释揭示了与每种类型的 HBC 相关的不同生物通路。GBC与细胞周期调控有关，HCC与免疫系统调节有关，而ICC则涉及代谢失调，尤其是脂质代谢。基因共表达网络（GCN）和蛋白相互作用（PPI）网络分析发现了潜在的关键基因，如GBC中的MAPK3和ERBB2、HCC中的AC069287.1和ACTN2以及ICC中的TRPC1和BACE1。FOX转录因子家族在所有三种癌症类型中都是保守的。为了进一步探讨上皮-间质转化（EMT）与已确定的枢纽基因和转录因子之间的关系，我们进行了一项EMT评分分析。该分析揭示了每种癌症类型的不同表型特征，与HCC相比，在GBC和ICC中发现的TF与EMT的相关性更强。利用癌症基因组图谱（TCGA）数据库进行的外部验证证实了候选基因的表达，凸显了它们作为治疗靶点的潜力。这些发现为了解 HBCs 的分子异质性和复杂性提供了有价值的见解，为个性化治疗干预开辟了新途径。

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引用次数: 0

RPS21 Enhances hepatocellular carcinoma development through GPX4 stabilization RPS21 通过稳定 GPX4 促进肝细胞癌的发展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-14 DOI: 10.1016/j.tranon.2024.102189

Siyuan Wu , Gaochao Wang , Likai Gu , Yinjie Zhang , Zhihuai Wang

The study highlights that RPS21, a gene encoding a component of the 40S ribosomal subunit, plays an oncogenic role in hepatocellular carcinoma (HCC) and may influence tumor aggressiveness by affecting antioxidant capacity. RPS21 was found to be upregulated in HCC through RNA-sequencing of clinical samples and analysis of the TCGA database. Kaplan-Meier survival analyses linked higher RPS21 expression to lower survival rates across multiple metrics (OS, PFS, RFS, DSS). Mutation analysis via the cBioPortal showed that primarily amplifications in RPS21 are associated with a poorer prognosis. Tissue microarrays confirmed higher RPS21 levels in tumor samples, which were associated with more advanced clinical stages and grades. Experimental interventions involving lentiviral knockdown or overexpression of RPS21 significantly altered HCC cell proliferation and migration. These findings were supported by mouse models, which showed impacts on tumor growth and metastasis. Further mechanistic studies indicated that RPS21 modulates the ubiquitination and stability of GPX4, a key player in ferroptosis and oxidative stress regulation in HCC cells. This comprehensive study, which merges bioinformatic analysis with laboratory research, positions RPS21 as a viable target for HCC therapy and opens new pathways for understanding and treating liver cancer.

该研究强调，RPS21是40S核糖体亚基的一个编码基因，它在肝细胞癌（HCC）中起着致癌作用，并可能通过影响抗氧化能力来影响肿瘤的侵袭性。通过对临床样本进行 RNA 测序和 TCGA 数据库分析，发现 RPS21 在 HCC 中上调。Kaplan-Meier生存分析将较高的RPS21表达与较低的多种指标（OS、PFS、RFS、DSS）生存率联系起来。通过 cBioPortal 进行的突变分析表明，RPS21 的主要扩增与较差的预后有关。组织微阵列证实，肿瘤样本中的RPS21水平较高，与较晚期的临床分期和分级有关。慢病毒敲除或过表达 RPS21 的实验干预能显著改变 HCC 细胞的增殖和迁移。这些发现得到了小鼠模型的支持，小鼠模型显示了对肿瘤生长和转移的影响。进一步的机理研究表明，RPS21 可调节 GPX4 的泛素化和稳定性，而 GPX4 是 HCC 细胞铁变态反应和氧化应激调节的关键角色。这项综合研究将生物信息学分析与实验室研究相结合，将 RPS21 定位为治疗 HCC 的可行靶点，为了解和治疗肝癌开辟了新途径。

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引用次数: 0

Methionine restriction promotes the polarization of macrophages towards M1 and the immunotherapy effect of PD-L1/PD-1 blockades by inhibiting the secretion of MIF by gastric carcinoma cells 通过抑制胃癌细胞分泌 MIF，限制蛋氨酸可促进巨噬细胞向 M1 分化，并促进 PD-L1/PD-1 阻断剂的免疫治疗效果。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-13 DOI: 10.1016/j.tranon.2024.102181

Lin Xin , Jiang Liu , Jun-Yan Lai , He-Song Xu , Luo-Jun Fan , Yong-Hui Zou , Qi Zhou , Zhen- Qi Yue , Jin-Heng Gan

Background

The limited curative effect of PD-L1/PD-1 blockades presents challenges to immunotherapy for advanced gastric cancer. We have found that methionine restriction (MR) enhances the drug resistance of gastric carcinoma cells. We aimed to explore whether MR can enhance the efficacy of PD-L1/PD-1 blockades in gastric cancer.

Methods

To conduct MR, gastric carcinoma cells were transfected with LV-METase in vitro, and 615 mice were injected with MFC cells with stable METase expression in vivo. Flow cytometry was conducted to measure the proportions of M1/M2 macrophages and CD8⁺ GZMB⁺/IFN-γ⁺ T cells. Additionally, the levels of M1/M2 macrophage markers and MIF were also detected.

Results

MR increased M1 and down-regulated M2 macrophages. MR suppressed MIF levels in gastric carcinoma cells, while the addition of anti-MIF neutralizing antibody inhibited the effect of MR on macrophage M1/M2 polarization. MR enhanced the increase of the proportion of CD8⁺ GZMB⁺ T cells and CD8⁺ IFN-γ⁺ T cells induced by PD-L1/PD-1 blockades. In vivo detection verified the efficacy of the combination of MR and PD-L1/PD-1 blockades on gastric cancer.

Conclusions

MR inhibits the secretion of MIF by gastric carcinoma cells, promotes macrophage M1 polarization, and enhances the therapeutic effect of PD-L1/PD-1 blockades in gastric cancer.

背景：PD-L1/PD-1阻断剂的疗效有限，这给晚期胃癌的免疫疗法带来了挑战。我们发现蛋氨酸限制（MR）会增强胃癌细胞的耐药性。我们的目的是探讨 MR 能否增强 PD-L1/PD-1 阻断剂在胃癌中的疗效：为了进行MR研究，我们在体外用LV-METase转染了胃癌细胞，并在体内给615只小鼠注射了稳定表达METase的MFC细胞。流式细胞术测量了 M1/M2 巨噬细胞和 CD8+ GZMB+/IFN-γ+ T 细胞的比例。此外，还检测了 M1/M2 巨噬细胞标记物和 MIF 的水平：结果：MR增加了M1巨噬细胞，下调了M2巨噬细胞。MR抑制了胃癌细胞中的MIF水平，而加入抗MIF中和抗体则抑制了MR对巨噬细胞M1/M2极化的影响。MR增强了PD-L1/PD-1阻断剂诱导的CD8+ GZMB+ T细胞和CD8+ IFN-γ+ T细胞比例的增加。体内检测验证了MR和PD-L1/PD-1阻断剂联合使用对胃癌的疗效：结论：MR能抑制胃癌细胞分泌MIF，促进巨噬细胞M1极化，增强PD-L1/PD-1阻断剂对胃癌的治疗效果。

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引用次数: 0

Combining methylated RNF180 and SFRP2 plasma biomarkers for noninvasive diagnosis of gastric cancer 结合甲基化 RNF180 和 SFRP2 血浆生物标记物进行胃癌无创诊断

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-13 DOI: 10.1016/j.tranon.2024.102190

Zhihao Dai , Jin Jiang , Qianping Chen , Minghua Bai , Quanquan Sun , Yanru Feng , Dong Liu , Dong Wang , Tong Zhang , Liang Han , Litheng Ng , Jun Zheng , Hao Zou , Wei Mao , Ji Zhu

Introduction

Gastric cancer (GC) is a common malignant tumor, and early diagnosis significantly improves patient survival rates. This study aimed to investigate the diagnostic value of ring finger protein 180 (RNF180) and secreted frizzled protein 2 (SFRP2) in GC.

Materials & Methods

A total of 165 healthy individuals, 34 patients with precancerous gastric lesions, and 104 patients with confirmed GC were divided into training and validation sets; methylated RNF180 and SFRP2 were detected in circulating DNA from blood samples. Six models, including those based on logistic regression, Naive Bayes, K-nearest neighbor algorithm, glmnet, neural network, and random forest (RF) were built and validated. Area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value were determined.

Results

In the training set, the RF model with RNF180 and SFRP2 (R + S) had an AUC of 0.839 (95 % CI: 0.727–0.951), sensitivity of 60.3 %, and specificity of 85.5 % for diagnosing GC. The RF model with R + S+ Tumor markers had an AUC of 0.849 (95 % CI: 0.717–0.981), sensitivity of 62.8 %, and specificity of 87.1 %. In the validation set, the RF model with R + S had an AUC of 0.844 (95 % CI: 0.774–0.923), sensitivity of 87.8 %, and specificity of 69.2 %. The RF model with R + S + Tumor markers had an AUC of 0.858 (95 % CI: 0.781–0.939), sensitivity of 85.4 %, and specificity of 76.9 %.

Conclusion

Our results suggest that RNF180 and SFRP2 could serve as diagnostic biomarkers for GC when using the RF model.

简介胃癌（GC）是一种常见的恶性肿瘤，早期诊断可显著提高患者的生存率。本研究旨在探讨环指蛋白180（RNF180）和分泌型脆裂蛋白2（SFRP2）在胃癌中的诊断价值：将165名健康人、34名胃癌前病变患者和104名确诊GC患者分为训练集和验证集；在血液样本的循环DNA中检测甲基化的RNF180和SFRP2。建立并验证了六个模型，包括基于逻辑回归、Naive Bayes、K-近邻算法、glmnet、神经网络和随机森林（RF）的模型。确定了曲线下面积（AUC）、灵敏度、特异性、阳性预测值和阴性预测值：在训练集中，含有 RNF180 和 SFRP2（R + S）的 RF 模型诊断 GC 的 AUC 为 0.839（95 % CI：0.727-0.951），灵敏度为 60.3%，特异度为 85.5%。带有 R + S+ 肿瘤标记物的 RF 模型的 AUC 为 0.849（95 % CI：0.717-0.981），灵敏度为 62.8 %，特异性为 87.1 %。在验证集中，带有 R + S 的 RF 模型的 AUC 为 0.844（95 % CI：0.774-0.923），灵敏度为 87.8 %，特异度为 69.2 %。R+S+肿瘤标记物的RF模型的AUC为0.858（95% CI：0.781-0.939），灵敏度为85.4%，特异度为76.9%：我们的研究结果表明，在使用RF模型时，RNF180和SFRP2可作为GC的诊断生物标志物。

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引用次数: 0

Identification of cancer-associated fibrolast subtypes and distinctive role of MFAP5 in CT-detected extramural venous invasion in gastric cancer 确定癌症相关纤维细胞亚型以及 MFAP5 在 CT 检测到的胃癌壁外静脉侵犯中的独特作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-12 DOI: 10.1016/j.tranon.2024.102188

Bo Gao , Xinyi Gou , Caizhen Feng , Yinli Zhang , Huining Gu , Fan Chai , Yi Wang , Yingjiang Ye , Nan Hong , Guohua Hu , Boshi Sun , Jin Cheng , Hao Yang

Extramural venous invasion (EMVI) detected by computed tomography has been identified as an independent risk factor for distant metastasis in patients with advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) are critical for remodeling the tumor microenvironment in GCs. Here, we report that MFAP5+ CAFs promote the formation of EMVI imaging in GC. We detected gene expression in pathological samples from 13 advanced GC patients with EMVI. Radiogenomics results showed the degree of CAFs infiltration was directly proportional to the EMVI score and EMT pathway in GC patients. Single-cell sequencing data analysis results showed that MFAP5+CAFs subtypes in GC were negatively correlated with patient prognosis and were enriched in tumor lactylation modification and EMT pathways. Immunohistochemistry results showed that the expression of MFAP5, L-lactyl and EMT markers in GC tissues was proportional to the EMVI score. CAF from gastric cancer tissue was extracted using collagenase method and co-cultured with GC cell line in vitro. After lentivirus knockdown of MFAP5 in CAFs, the levels of L-lactoyl and histone lactylation modifications were significantly reduced, and the sphere-forming and vascularization abilities of CAFs were significantly inhibited. Cell function experiments showed that MFAP5+ CAFs can affect the EMT, metastasis and invasion capabilities of GC cells. In vivo experimental results of the nude mouse in situ EMVI model suggest that MFAP5+ CAF may promote the formation of EMVI imaging features in GC by regulating lactylation modification. This innovative work may provide important new references for the diagnosis and treatment of GC.

通过计算机断层扫描检测到的壁外静脉侵犯（EMVI）已被确定为晚期胃癌（GC）患者发生远处转移的独立危险因素。癌症相关成纤维细胞（CAFs）对于重塑胃癌的肿瘤微环境至关重要。在此，我们报告了 MFAP5+ CAFs 可促进 GC 中 EMVI 成像的形成。我们检测了 13 例晚期 GC 患者病理样本中 EMVI 的基因表达。放射基因组学结果显示，CAFs的浸润程度与GC患者的EMVI评分和EMT途径成正比。单细胞测序数据分析结果显示，GC中的MFAP5+CAFs亚型与患者预后呈负相关，并富集于肿瘤乳化修饰和EMT通路。免疫组化结果显示，胃癌组织中MFAP5、L-乳酸和EMT标记物的表达与EMVI评分成正比。用胶原酶法提取胃癌组织中的CAF，并在体外与GC细胞系共同培养。慢病毒敲除CAF中的MFAP5后，L-乳酰基和组蛋白乳酰化修饰水平明显降低，CAF的球形成能力和血管化能力明显受到抑制。细胞功能实验表明，MFAP5+ CAFs能影响GC细胞的EMT、转移和侵袭能力。裸鼠原位EMVI模型的体内实验结果表明，MFAP5+ CAF可通过调控乳化修饰促进GC形成EMVI成像特征。这项创新性工作可为 GC 的诊断和治疗提供新的重要参考。

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引用次数: 0

Machine learning-derived natural killer cell signature predicts prognosis and therapeutic response in clear cell renal cell carcinoma 机器学习衍生的自然杀伤细胞特征可预测透明细胞肾细胞癌的预后和治疗反应。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-12 DOI: 10.1016/j.tranon.2024.102180

Jinchen Luo , Mingjie Lin , Minyu Chen , Jinwei Chen , Xinwei Zhou , Kezhi Liu , Yanping Liang , Jiajie Chen , Hui Liang , Zhu Wang , Qiong Deng , Jieyan Wang , Meiyu Jin , Junhang Luo , Wei Chen , Junjie Cen

Background

Natural killer cells, interconnected with patient prognosis and treatment response, play a pivotal role in the tumor immune microenvironment and may serve as potential novel predictive biomarkers for renal cell carcinoma.

Methods

Clear cell renal cell carcinoma transcriptome data and the corresponding clinical data were obtained from the Cancer Genome Atlas (TCGA) database. Single-cell sequencing data were sourced from the Gene Expression Omnibus (GEO) database. A risk model was established by integrating ten different machine learning algorithms, which resulted in 101 combined models. The model with the highest average C-index was selected for further analysis, and was assessed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan–Meier survival analysis. The differences in immune infiltration fractions, clinicopathological features, and response to various targeted therapies and immunotherapy between high- and low-risk groups were investigated. Furthermore, qRT-PCR, IHC, colony formation test, CCK8 assay and flow cytometry were conducted to explore the expression pattern and function of ARHGAP9 in our own patient samples and renal cancer cell lines.

Results

Totally, 156 NK cell-related genes and 5189 prognosis-related genes were identified, and 36 genes of their intersection demonstrated prognostic value. A risk model with 18 genes was established by Coxboost plus plsRcox, which can accurately predict the prognosis of ccRCC patients. Significant correlations were determined between risk score and tumor malignancy and immune cell infiltration. Meanwhile, a combination of tumor mutation burden plus risk score could have higher accuracy of predicting clinical outcomes. Moreover, high-risk group patients were more likely to be responsive to targeted therapy but show no response to immunotherapy.

Conclusions

Intricate signaling interactions between NK cells and various cellular subgroups were depicted and the developmental trajectory of NK cells was elucidated. A NK cells-related risk model was established, which can provide reliable prognostic information and identified patients with more probability of benefiting from therapy.

背景：自然杀伤细胞与患者预后和治疗反应相互关联，在肿瘤免疫微环境中发挥着关键作用，可作为肾细胞癌潜在的新型预测生物标志物：透明细胞肾细胞癌转录组数据和相应的临床数据来自癌症基因组图谱（TCGA）数据库。单细胞测序数据来自基因表达总库（GEO）数据库。通过整合十种不同的机器学习算法建立了一个风险模型，最终形成了 101 个组合模型。选取平均 C 指数最高的模型进行进一步分析，并使用提名图、时间依赖性接收器操作特征（ROC）和 Kaplan-Meier 生存分析进行评估。研究还探讨了高风险组和低风险组在免疫浸润比例、临床病理特征以及对各种靶向疗法和免疫疗法的反应方面的差异。此外，还采用 qRT-PCR、IHC、集落形成试验、CCK8 检测和流式细胞术等方法，探讨 ARHGAP9 在患者样本和肾癌细胞系中的表达模式和功能：结果：共鉴定出 156 个 NK 细胞相关基因和 5189 个预后相关基因，其中 36 个基因的交叉点具有预后价值。通过 Coxboost 加 plsRcox 建立了包含 18 个基因的风险模型，该模型可准确预测 ccRCC 患者的预后。风险评分与肿瘤恶性程度和免疫细胞浸润之间存在显著相关性。同时，肿瘤突变负荷加风险评分的组合能更准确地预测临床预后。此外，高风险组患者更有可能对靶向治疗有反应，但对免疫治疗无反应：结论：该研究描绘了NK细胞与各种细胞亚群之间错综复杂的信号相互作用，并阐明了NK细胞的发育轨迹。建立了一个与 NK 细胞相关的风险模型，该模型可提供可靠的预后信息，并识别出更有可能从治疗中获益的患者。

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引用次数: 0