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Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis. 瑞格列奈通过靶向 FOXO3/lumican/p53 轴抑制 HCC 的发展和恶化。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-07 DOI: 10.1007/s13402-024-00919-9
Yifei Tan, Yongjie Zhou, Wei Zhang, Zhenru Wu, Qing Xu, Qiong Wu, Jian Yang, Tao Lv, Lvnan Yan, Hong Luo, Yujun Shi, Jiayin Yang

Purpose: The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy.

Methods: Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl4).

Results: Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment.

Conclusion: Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis.

目的:近年来,N-连接的糖蛋白在各种恶性肿瘤的致癌过程中的作用受到关注,这促使我们探索导致 HCC 进展的异常表达的糖蛋白以及潜在的治疗策略:方法:应用质谱技术初步鉴定 HCC 中异常表达的糖蛋白,并通过免疫组织化学(IHC)染色对其进行进一步评估。通过集落形成、小鼠异种移植、RNA测序和Western印迹检测等方法,系统研究了所选糖蛋白在HCC发病中的作用及其内在机制。通过染色质免疫共沉淀(ChIP)和荧光素酶实验探讨了所选糖蛋白的潜在转录因子(TFs)。通过Western印迹和IHC评估了repaglinide(RPG)对lumican和下游效应物表达的调控,并通过体外和体内分析(包括使用西式饮食和四氯化碳(CCl4)建立的小鼠NASH-HCC模型)探讨了repaglinide对HCC恶性表型的影响:结果:Lumican 在血清和肿瘤组织中均有上调,其表达升高与 HCC 患者的预后不良有关。敲除 lumican 可显著降低 HCC 在体外和体内的生长。从机制上讲,lumican 通过抑制 p53/p21 信号通路促进了 HCC 恶性表型的形成。研究发现,叉头框O3(FOXO3)是lumican的TF,可转录增强lumican的表达。在不沉默 FOXO3 的情况下,RPG 阻断了 FOXO3 与 lumican 启动子区域的结合,从而抑制了 lumican/p53/p21 轴的激活。与对照组相比,接受RPG治疗的小鼠在发病24周后罹患的HCC数量更少、体积更小:我们的研究结果表明,RPG 可通过改变 FOXO3/lumican/p53 轴阻止 HCC 的发生和发展。
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引用次数: 0
IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/β-catenin signaling. IFIT1 通过 Wnt/β-catenin 信号调节胰腺癌细胞的增殖、迁移和侵袭。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-27 DOI: 10.1007/s13402-024-00925-x
Tian-Hao Li, Bang-Bo Zhao, Cheng Qin, Yuan-Yang Wang, Ze-Ru Li, Hong-Tao Cao, Xiao-Ying Yang, Xing-Tong Zhou, Wei-Bin Wang

Objectives: Previously, Interferon-induced Protein with Tetratricopeptide Repeats 1 (IFIT1) has been shown to promote cancer development. Here, we aimed to explore the role of IFIT1 in the development and progression of pancreatic cancer, including the underlying mechanisms.

Methods: We explored IFIT1 expression in pancreatic cancer samples using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Cell Counting Kit-8 (CCK8), colony formation, scratch wound-healing and Transwell assays were performed to assess the proliferation, migration and invasion abilities of pancreatic cancer cells. Gene Set Enrichment Analysis (GSEA) and Western blotting were performed to assess the regulatory effect of IFIT1 on the Wnt/β-catenin pathway.

Results: We found that upregulation of IFIT1 expression is common in pancreatic cancer and is negatively associated with overall patient survival. Knockdown of IFIT1 expression led to decreased proliferation, migration and invasion of pancreatic cancer cells. We also found that IFIT1 could regulate Wnt/β-catenin signaling, and that a Wnt/β-catenin agonist could reverse this effect. In addition, we found that IFIT1 can promote epithelial-mesenchymal transition (EMT) of pancreatic cancer cells.

Conclusions: Our data indicate that IFIT1 increases pancreatic cancer cell proliferation, migration and invasion by activating the Wnt/β-catenin pathway. In addition, we found that EMT could be regulated by IFIT1. IFIT1 may serve as a potential therapeutic target for pancreatic cancer.

研究目的以前的研究表明,具有四肽重复序列的干扰素诱导蛋白1(IFIT1)可促进癌症的发展。在此,我们旨在探索 IFIT1 在胰腺癌发生和发展中的作用,包括其潜在机制:我们利用癌症基因组图谱(TCGA)和基因表达总库(GEO)数据集探讨了胰腺癌样本中 IFIT1 的表达。通过细胞计数试剂盒-8(CCK8)、集落形成、划痕伤口愈合和Transwell试验来评估胰腺癌细胞的增殖、迁移和侵袭能力。基因组富集分析(Gene Set Enrichment Analysis,GSEA)和Western印迹法评估了IFIT1对Wnt/β-catenin通路的调控作用:结果:我们发现IFIT1表达上调在胰腺癌中很常见,并且与患者的总生存率呈负相关。抑制 IFIT1 的表达可减少胰腺癌细胞的增殖、迁移和侵袭。我们还发现,IFIT1 可以调节 Wnt/β-catenin 信号转导,而 Wnt/β-catenin 激动剂可以逆转这种效应。此外,我们还发现IFIT1能促进胰腺癌细胞的上皮-间质转化(EMT):我们的数据表明,IFIT1 可通过激活 Wnt/β-catenin 通路增加胰腺癌细胞的增殖、迁移和侵袭。此外,我们还发现 IFIT1 可调控 EMT。IFIT1 可作为胰腺癌的潜在治疗靶点。
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引用次数: 0
Mapping the immune terrain in lung adenocarcinoma progression: Tfh-like cells in tertiary lymphoid structures. 绘制肺腺癌发展过程中的免疫地形图:三级淋巴结构中的Tfh样细胞
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-16 DOI: 10.1007/s13402-024-00936-8
Jialei Gong, Di Yu
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引用次数: 0
Copy number signatures and CCNE1 amplification reveal the involvement of replication stress in high-grade endometrial tumors oncogenesis. 拷贝数特征和 CCNE1 扩增揭示了复制压力在高级别子宫内膜肿瘤发生过程中的作用。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-04-02 DOI: 10.1007/s13402-024-00942-w
Regine Marlin, Jean-Samuel Loger, Clarisse Joachim, Coralie Ebring, Guillaume Robert-Siegwald, Sabrina Pennont, Mickaelle Rose, Kevin Raguette, Valerie Suez-Panama, Sylviane Ulric-Gervaise, Sylvie Lusbec, Odile Bera, Alexis Vallard, Aude Aline-Fardin, Emeline Colomba, Mehdi Jean-Laurent

Purpose: Managing high-grade endometrial cancer in Martinique poses significant challenges. The diversity of copy number alterations in high-grade endometrial tumors, often associated with a TP53 mutation, is a key factor complicating treatment. Due to the high incidence of high-grade tumors with poor prognosis, our study aimed to characterize the molecular signature of these tumors within a cohort of 25 high-grade endometrial cases.

Methods: We conducted a comprehensive pangenomic analysis to categorize the copy number alterations involved in these tumors. Whole-Exome Sequencing (WES) and Homologous Recombination (HR) analysis were performed. The alterations obtained from the WES were classified into various signatures using the Copy Number Signatures tool available in COSMIC.

Results: We identified several signatures that correlated with tumor stage and disctinct prognoses. These signatures all seem to be linked to replication stress, with CCNE1 amplification identified as the primary driver of oncogenesis in over 70% of tumors analyzed.

Conclusion: The identification of CCNE1 amplification, which is currently being explored as a therapeutic target in clinical trials, suggests new treatment strategies for high-grade endometrial cancer. This finding holds particular significance for Martinique, where access to care is challenging.

目的:在马提尼克岛治疗高级别子宫内膜癌是一项重大挑战。高级别子宫内膜肿瘤拷贝数改变的多样性(通常与 TP53 突变有关)是导致治疗复杂化的一个关键因素。由于预后不良的高级别肿瘤发病率较高,我们的研究旨在对25例高级别子宫内膜癌病例进行分子特征描述:我们进行了全面的泛基因组学分析,对这些肿瘤中涉及的拷贝数改变进行了分类。我们进行了全外显子组测序(WES)和同源重组(HR)分析。利用 COSMIC 中的拷贝数特征工具将从 WES 中获得的改变归类为各种特征:结果:我们发现了几个与肿瘤分期和不同预后相关的特征。这些特征似乎都与复制压力有关,在超过70%的肿瘤分析中,CCNE1扩增被确定为肿瘤发生的主要驱动因素:结论:CCNE1扩增目前正在临床试验中作为治疗靶点进行探索,它的发现为高分化子宫内膜癌提供了新的治疗策略。这一发现对于医疗条件艰苦的马提尼克岛具有特别重要的意义。
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引用次数: 0
A novel risk score system based on immune subtypes for identifying optimal mRNA vaccination population in hepatocellular carcinoma. 基于免疫亚型的新型风险评分系统,用于确定肝细胞癌的最佳 mRNA 疫苗接种人群。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-05 DOI: 10.1007/s13402-024-00921-1
Hongkai Zhuang, Chenwei Tang, Han Lin, Zedan Zhang, Xinming Chen, Wentao Wang, Qingbin Wang, Wenliang Tan, Lei Yang, Zhiqin Xie, Bingkun Wang, Bo Chen, Changzhen Shang, Yajin Chen

Purpose: Although mRNA vaccines have shown certain clinical benefits in multiple malignancies, their therapeutic efficacies against hepatocellular carcinoma (HCC) remains uncertain. This study focused on establishing a novel risk score system based on immune subtypes so as to identify optimal HCC mRNA vaccination population.

Methods: GEPIA, cBioPortal and TIMER databases were utilized to identify candidate genes for mRNA vaccination in HCC. Subsequently, immune subtypes were constructed based on the candidate genes. According to the differential expressed genes among various immune subtypes, a risk score system was established using machine learning algorithm. Besides, multi-color immunofluorescence of tumor tissues from 72 HCC patients were applied to validate the feasibility and efficiency of the risk score system.

Results: Twelve overexpressed and mutated genes associated with poor survival and APCs infiltration were identified as potential candidate targets for mRNA vaccination. Three immune subtypes (e.g. IS1, IS2 and IS3) with distinct clinicopathological and molecular profiles were constructed according to the 12 candidate genes. Based on the immune subtype, a risk score system was developed, and according to the risk score from low to high, HCC patients were classified into four subgroups on average (e.g. RS1, RS2, RS3 and RS4). RS4 mainly overlapped with IS3, RS1 with IS2, and RS2+RS3 with IS1. ROC analysis also suggested the significant capacity of the risk score to distinguish between the three immune subtypes. Higher risk score exhibited robustly predictive ability for worse survival, which was further independently proved by multi-color immunofluorescence of HCC samples. Notably, RS4 tumors exhibited an increased immunosuppressive phenotype, higher expression of the twelve potential candidate targets and increased genome altered fraction, and therefore might benefit more from vaccination.

Conclusions: This novel risk score system based on immune subtypes enabled the identification of RS4 tumor that, due to its highly immunosuppressive microenvironment, may benefit from HCC mRNA vaccination.

目的:尽管 mRNA 疫苗在多种恶性肿瘤中显示出一定的临床疗效,但其对肝细胞癌(HCC)的疗效仍不确定。本研究的重点是建立基于免疫亚型的新型风险评分系统,以确定最佳的 HCC mRNA 疫苗接种人群:方法:利用 GEPIA、cBioPortal 和 TIMER 数据库确定 HCC mRNA 疫苗接种的候选基因。随后,根据候选基因构建了免疫亚型。根据不同免疫亚型的差异表达基因,利用机器学习算法建立了风险评分系统。此外,还对 72 例 HCC 患者的肿瘤组织进行了多色免疫荧光检测,以验证风险评分系统的可行性和有效性:结果:12个与生存率低和APCs浸润相关的过表达和突变基因被确定为mRNA疫苗接种的潜在候选靶点。根据这 12 个候选基因,构建了三种具有不同临床病理和分子特征的免疫亚型(如 IS1、IS2 和 IS3)。根据免疫亚型建立了风险评分系统,按照风险评分从低到高将 HCC 患者平均分为四个亚组(如 RS1、RS2、RS3 和 RS4)。RS4 主要与 IS3 重叠,RS1 与 IS2 重叠,RS2+RS3 与 IS1 重叠。ROC 分析还表明,风险评分在区分三种免疫亚型方面具有显著的能力。风险评分越高,预测生存率越低的能力越强,HCC样本的多色免疫荧光进一步证明了这一点。值得注意的是,RS4肿瘤表现出更高的免疫抑制表型、更高的12个潜在候选靶点表达量和更高的基因组改变部分,因此可能从疫苗接种中获益更多:结论:这种基于免疫亚型的新型风险评分系统能够识别 RS4 肿瘤,由于其具有高度免疫抑制的微环境,RS4 肿瘤可能会从 HCC mRNA 疫苗接种中获益。
{"title":"A novel risk score system based on immune subtypes for identifying optimal mRNA vaccination population in hepatocellular carcinoma.","authors":"Hongkai Zhuang, Chenwei Tang, Han Lin, Zedan Zhang, Xinming Chen, Wentao Wang, Qingbin Wang, Wenliang Tan, Lei Yang, Zhiqin Xie, Bingkun Wang, Bo Chen, Changzhen Shang, Yajin Chen","doi":"10.1007/s13402-024-00921-1","DOIUrl":"10.1007/s13402-024-00921-1","url":null,"abstract":"<p><strong>Purpose: </strong>Although mRNA vaccines have shown certain clinical benefits in multiple malignancies, their therapeutic efficacies against hepatocellular carcinoma (HCC) remains uncertain. This study focused on establishing a novel risk score system based on immune subtypes so as to identify optimal HCC mRNA vaccination population.</p><p><strong>Methods: </strong>GEPIA, cBioPortal and TIMER databases were utilized to identify candidate genes for mRNA vaccination in HCC. Subsequently, immune subtypes were constructed based on the candidate genes. According to the differential expressed genes among various immune subtypes, a risk score system was established using machine learning algorithm. Besides, multi-color immunofluorescence of tumor tissues from 72 HCC patients were applied to validate the feasibility and efficiency of the risk score system.</p><p><strong>Results: </strong>Twelve overexpressed and mutated genes associated with poor survival and APCs infiltration were identified as potential candidate targets for mRNA vaccination. Three immune subtypes (e.g. IS1, IS2 and IS3) with distinct clinicopathological and molecular profiles were constructed according to the 12 candidate genes. Based on the immune subtype, a risk score system was developed, and according to the risk score from low to high, HCC patients were classified into four subgroups on average (e.g. RS1, RS2, RS3 and RS4). RS4 mainly overlapped with IS3, RS1 with IS2, and RS2+RS3 with IS1. ROC analysis also suggested the significant capacity of the risk score to distinguish between the three immune subtypes. Higher risk score exhibited robustly predictive ability for worse survival, which was further independently proved by multi-color immunofluorescence of HCC samples. Notably, RS4 tumors exhibited an increased immunosuppressive phenotype, higher expression of the twelve potential candidate targets and increased genome altered fraction, and therefore might benefit more from vaccination.</p><p><strong>Conclusions: </strong>This novel risk score system based on immune subtypes enabled the identification of RS4 tumor that, due to its highly immunosuppressive microenvironment, may benefit from HCC mRNA vaccination.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling. 微生物代谢物三甲胺-N-氧化物通过抑制类雌激素 X 受体信号传导诱发肠癌。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-05 DOI: 10.1007/s13402-024-00920-2
Wanru Zhang, Xiali Qin, Kexin Zhang, Jiahui Ma, Mengfan Li, Ge Jin, Xiang Liu, Sinan Wang, Bangmao Wang, Jing Wu, Tianyu Liu, Weilong Zhong, Hailong Cao

Purpose: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression.

Methods: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC.

Results: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/β-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/β-catenin pathway activation.

Conclusion: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.

目的:微生物菌群失调被认为是结直肠癌(CRC)的特征之一。三甲胺-N-氧化物(TMAO)作为一种依赖于肠道微生物群的代谢物,最近被认为与 CRC 的发生有关。然而,TMAO 与肠癌发生有关的证据在很大程度上仍未得到探讨。在此,我们旨在研究 TMAO 在 CRC 进展中的关键作用:方法:用 TMAO 或无菌 PBS 处理 Apcmin/+ 小鼠 14 周。方法:用 TMAO 或无菌 PBS 处理 Apcmin/+ 小鼠 14 周,分离肠组织以评估 TMAO 对肠腺瘤恶性转化的影响。通过 16S rRNA 测序分析检测小鼠粪便中的肠道微生物群。使用 HCT-116 细胞进一步证明了 TMAO 对 CRC 进展的影响:结果:服用 TMAO 会增加肿瘤细胞和干细胞增殖,减少细胞凋亡,并伴有 DNA 损伤和肠道屏障受损。肠道微生物群分析表明,TMAO诱导肠道微生物群落结构发生变化,表现为微生物群多样性和有益菌减少。从机理上讲,TMAO与类雌激素X受体(FXR)结合,从而抑制了FXR-成纤维细胞生长因子15(FGF15)轴,激活了Wnt/β-catenin信号通路,而FXR激动剂GW4064则可以抑制TMAO诱导的Wnt/β-catenin通路激活:结论:微生物代谢物TMAO可通过抑制FXR-FGF15通路促进肠癌的发生。
{"title":"Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.","authors":"Wanru Zhang, Xiali Qin, Kexin Zhang, Jiahui Ma, Mengfan Li, Ge Jin, Xiang Liu, Sinan Wang, Bangmao Wang, Jing Wu, Tianyu Liu, Weilong Zhong, Hailong Cao","doi":"10.1007/s13402-024-00920-2","DOIUrl":"10.1007/s13402-024-00920-2","url":null,"abstract":"<p><strong>Purpose: </strong>Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression.</p><p><strong>Methods: </strong>Apc<sup>min/+</sup> mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC.</p><p><strong>Results: </strong>TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/β-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/β-catenin pathway activation.</p><p><strong>Conclusion: </strong>The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The predictive significance of chromobox family members in prostate cancer in humans. 染色盒家族成员对人类前列腺癌的预测意义。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-01 DOI: 10.1007/s13402-024-00929-7
Xiaoting Xu, Cong Lai, Jiawen Luo, Juanyi Shi, Kaixuan Guo, Jintao Hu, Yelisudan Mulati, Yunfei Xiao, Degeng Kong, Cheng Liu, Jingang Huang, Kewei Xu

Purpose: The Chromobox (CBX) family proteins are crucial elements of the epigenetic regulatory machinery and play a significant role in the development and advancement of cancer. Nevertheless, there is limited understanding regarding the role of CBXs in development or progression of prostate cancer (PCa). Our objective is to develop a unique prognostic model associated with CBXs to improve the accuracy of predicting outcomes of patients with PCa.

Methods: Data from TCGA and GEO databases were analyzed to assess differential expression, prognostic value, gene pathway enrichment, and immune cell infiltration. COX regression analysis was utilized to identify the independent prognostic factors that impact disease-free survival (DFS). The expression of CBX2 and FOXP3+ cells infiltration was verified by immunohistochemical staining of clinical tissue sections. In vitro proliferation, migration and invasion assay were conducted to examine the function of CBX2. RNA-seq was employed to examine the CBX2 related pathway enrichment.

Results: CBX2, CBX3, CBX4, and CBX8 were upregulated, while CBX6 and CBX7 were downregulated in PCa tissues. CBXs expression varied by stage and grade. Elevated expression of CBX1, CBX2, CBX3, CBX4 and CBX8 is correlated with poor outcome. CBX2 expression, T stage, and Gleason score were independent prognostic factors. The expression level of CBX2 in PCa tissues was significantly higher than that in adjacent normal tissues. More Treg infiltration was observed in the group with high CBX2 expression. CBX2 expression affected PCa cell growth, migration, and invasion.

Conclusions: CBX2 is involved in the development and advancement of PCa, suggesting its potential as a reliable prognostic indicator for PCa patients.

目的:Chromobox(CBX)家族蛋白是表观遗传调控机制的关键元素,在癌症的发生和发展中发挥着重要作用。然而,人们对 CBX 在前列腺癌(PCa)的发生和发展中的作用了解有限。我们的目标是建立一个与 CBXs 相关的独特预后模型,以提高预测 PCa 患者预后的准确性:方法:分析来自 TCGA 和 GEO 数据库的数据,以评估差异表达、预后价值、基因通路富集和免疫细胞浸润。利用 COX 回归分析确定影响无病生存期(DFS)的独立预后因素。临床组织切片的免疫组化染色验证了 CBX2 的表达和 FOXP3+ 细胞的浸润。体外增殖、迁移和侵袭试验检验了 CBX2 的功能。采用RNA-seq技术检测CBX2相关通路的富集情况:结果:在PCa组织中,CBX2、CBX3、CBX4和CBX8上调,而CBX6和CBX7下调。CBXs的表达因分期和分级而异。CBX1、CBX2、CBX3、CBX4和CBX8的表达升高与预后不良有关。CBX2的表达、T期和Gleason评分是独立的预后因素。CBX2 在 PCa 组织中的表达水平明显高于邻近的正常组织。在CBX2高表达组中观察到更多的Treg浸润。CBX2的表达影响了PCa细胞的生长、迁移和侵袭:CBX2参与了PCa的发生和发展,表明它有可能成为PCa患者的可靠预后指标。
{"title":"The predictive significance of chromobox family members in prostate cancer in humans.","authors":"Xiaoting Xu, Cong Lai, Jiawen Luo, Juanyi Shi, Kaixuan Guo, Jintao Hu, Yelisudan Mulati, Yunfei Xiao, Degeng Kong, Cheng Liu, Jingang Huang, Kewei Xu","doi":"10.1007/s13402-024-00929-7","DOIUrl":"10.1007/s13402-024-00929-7","url":null,"abstract":"<p><strong>Purpose: </strong>The Chromobox (CBX) family proteins are crucial elements of the epigenetic regulatory machinery and play a significant role in the development and advancement of cancer. Nevertheless, there is limited understanding regarding the role of CBXs in development or progression of prostate cancer (PCa). Our objective is to develop a unique prognostic model associated with CBXs to improve the accuracy of predicting outcomes of patients with PCa.</p><p><strong>Methods: </strong>Data from TCGA and GEO databases were analyzed to assess differential expression, prognostic value, gene pathway enrichment, and immune cell infiltration. COX regression analysis was utilized to identify the independent prognostic factors that impact disease-free survival (DFS). The expression of CBX2 and FOXP3<sup>+</sup> cells infiltration was verified by immunohistochemical staining of clinical tissue sections. In vitro proliferation, migration and invasion assay were conducted to examine the function of CBX2. RNA-seq was employed to examine the CBX2 related pathway enrichment.</p><p><strong>Results: </strong>CBX2, CBX3, CBX4, and CBX8 were upregulated, while CBX6 and CBX7 were downregulated in PCa tissues. CBXs expression varied by stage and grade. Elevated expression of CBX1, CBX2, CBX3, CBX4 and CBX8 is correlated with poor outcome. CBX2 expression, T stage, and Gleason score were independent prognostic factors. The expression level of CBX2 in PCa tissues was significantly higher than that in adjacent normal tissues. More Treg infiltration was observed in the group with high CBX2 expression. CBX2 expression affected PCa cell growth, migration, and invasion.</p><p><strong>Conclusions: </strong>CBX2 is involved in the development and advancement of PCa, suggesting its potential as a reliable prognostic indicator for PCa patients.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comprehensive multiomics analysis of the signatures of gastric mucosal bacteria and plasma metabolites across different stomach microhabitats in the development of gastric cancer. 对胃癌发生过程中不同胃微生境下胃黏膜细菌和血浆代谢物特征的多组学综合分析
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-07-04 DOI: 10.1007/s13402-024-00965-3
Bingsen Wang, Jiahui Luan, Weidong Zhao, Junbao Yu, Anqing Li, Xinxin Li, Xiaoqin Zhong, Hongyun Cao, Ruicai Wang, Bo Liu, Shiyong Lu, Mei Shi

Purpose: As an important component of the microenvironment, the gastric microbiota and its metabolites are associated with tumour occurrence, progression, and metastasis. However, the relationship between the gastric microbiota and the development of gastric cancer is unclear. The present study investigated the role of the gastric mucosa microbiome and metabolites as aetiological factors in gastric carcinogenesis.

Methods: Gastric biopsies from different stomach microhabitats (n = 70) were subjected to 16S rRNA gene sequencing, and blood samples (n = 95) were subjected to untargeted metabolome (gas chromatography‒mass spectrometry, GC‒MS) analyses. The datasets were analysed using various bioinformatics approaches.

Results: The microbiota diversity and community composition markedly changed during gastric carcinogenesis. High Helicobacter. pylori colonization modified the overall diversity and composition of the microbiota associated with gastritis and cancer in the stomach. Most importantly, analysis of the functional features of the microbiota revealed that nitrate reductase genes were significantly enriched in the tumoral microbiota, while urease-producing genes were significantly enriched in the microbiota of H. pylori-positive patients. A panel of 81 metabolites was constructed to discriminate gastric cancer patients from gastritis patients, and a panel of 15 metabolites was constructed to discriminate H. pylori-positive patients from H. pylori-negative patients. receiver operator characteristic (ROC) curve analysis identified a series of gastric microbes and plasma metabolites as potential biomarkers of gastric cancer.

Conclusion: The present study identified a series of signatures that may play important roles in gastric carcinogenesis and have the potential to be used as biomarkers for diagnosis and for the surveillance of gastric cancer patients with minimal invasiveness.

目的:作为微环境的重要组成部分,胃微生物群及其代谢产物与肿瘤的发生、发展和转移有关。然而,胃微生物群与胃癌发病之间的关系尚不清楚。本研究探讨了胃黏膜微生物组和代谢物在胃癌发生中作为致病因素的作用:方法:对来自不同胃微生境的胃活检样本(n = 70)进行 16S rRNA 基因测序,并对血液样本(n = 95)进行非靶向代谢组(气相色谱-质谱法,GC-MS)分析。采用各种生物信息学方法对数据集进行了分析:结果:在胃癌发生过程中,微生物群的多样性和群落组成发生了明显变化。幽门螺杆菌的高定植率改变了与胃炎和胃癌相关的微生物群的整体多样性和组成。最重要的是,对微生物群功能特征的分析表明,硝酸还原酶基因在肿瘤微生物群中显著富集,而尿素酶产生基因在幽门螺杆菌阳性患者的微生物群中显著富集。由81种代谢物组成的小组被用来区分胃癌患者和胃炎患者,由15种代谢物组成的小组被用来区分幽门螺杆菌阳性患者和幽门螺杆菌阴性患者。接收操作者特征(ROC)曲线分析确定了一系列胃微生物和血浆代谢物是胃癌的潜在生物标志物:本研究发现了一系列可能在胃癌发生过程中发挥重要作用的特征,这些特征有可能被用作诊断和监测微创胃癌患者的生物标志物。
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引用次数: 0
TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer. TIPRL1及其atm依赖性磷酸化促进头颈癌放疗抵抗。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-01 Epub Date: 2023-11-16 DOI: 10.1007/s13402-023-00895-6
Célie Cokelaere, Rüveyda Dok, Emanuela E Cortesi, Peihua Zhao, Anna Sablina, Sandra Nuyts, Rita Derua, Veerle Janssens

Purpose: TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 - all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC).

Methods: TIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells.

Results: TIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A non-phospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation.

Conclusions: Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.

目的:TIPRL1(雷帕霉素信号通路调控因子样1的靶标)是已知的蛋白磷酸酶PP2A、PP4和PP6的相互作用因子和抑制剂,这些蛋白磷酸酶都是DNA损伤反应(DDR)的多效调节剂。在这里,我们研究了TIPRL1在头颈部鳞状细胞癌(HNSCC)放疗(RT)反应中的作用。方法:将HNSCC样品中的TIPRL1 mRNA (cBioportal)和蛋白表达(免疫组化)与临床患者数据相关联。通过CRISPR/Cas9编辑生成tiprl1缺失的HNSCC细胞,并评估RT后对集落生长、微核形成(显微镜)、细胞周期(流式细胞术)、DDR信号(免疫印迹)和蛋白质组学(质谱)的影响。质谱法用于辐照细胞中TIPRL1磷酸化和相互作用分析。结果:与非肿瘤组织相比,TIPRL1在肿瘤组织中的表达增加,肿瘤组织中TIPRL1的高表达与较低的局部区域控制率和rt治疗患者的生存率降低相关。HNSCC细胞中TIPRL1缺失导致RT敏感性增加,细胞周期停滞更快但延长,微核形成增加,蛋白质组范围内DDR改变。辐照后,ATM使TIPRL1的Ser265位点磷酸化。非磷酸化Ser265Ala突变体不能挽救tiprl1缺失细胞增加的放射敏感性表型。虽然证实与pp2a样磷酸酶结合,但dna依赖性蛋白激酶(DNA-PKcs), RAD51重组酶和核小体组蛋白被确定为新的TIPRL1相互作用物。组蛋白结合虽然受到RT的刺激,但却受到TIPRL1 Ser265磷酸化的不利影响。结论:我们的研究结果强调了TIPRL1及其atm依赖性磷酸化通过调节DDR在RT耐药中的临床相关作用,强调了其作为新的HNSCC预测标志物和治疗靶点的潜力。
{"title":"TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.","authors":"Célie Cokelaere, Rüveyda Dok, Emanuela E Cortesi, Peihua Zhao, Anna Sablina, Sandra Nuyts, Rita Derua, Veerle Janssens","doi":"10.1007/s13402-023-00895-6","DOIUrl":"10.1007/s13402-023-00895-6","url":null,"abstract":"<p><strong>Purpose: </strong>TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 - all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC).</p><p><strong>Methods: </strong>TIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells.</p><p><strong>Results: </strong>TIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A non-phospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation.</p><p><strong>Conclusions: </strong>Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy. 病理反应和肿瘤基质免疫原性特征可预测非小细胞肺癌新辅助化疗后的长期生存率。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-02-06 DOI: 10.1007/s13402-023-00914-6
Shuaibo Wang, Xujie Sun, Jiyan Dong, Li Liu, Hao Zhao, Renda Li, Zhenlin Yang, Na Cheng, Yalong Wang, Li Fu, Hang Yi, Zhuoheng Lv, Huandong Huo, Donghui Jin, Yousheng Mao, Lin Yang

Purpose: Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined.

Methods: We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS.

Results: Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS.

Conclusion: NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.

目的:主要病理反应(MPR)已成为非小细胞肺癌(NSCLC)新辅助治疗后总生存期(OS)的替代终点,然而,新辅助治疗后的预后组织学特征和最佳N描述指标尚未明确:我们回顾性分析了2010年1月至2020年12月期间接受新辅助化疗(NAC)后手术的368例NSCLC患者的数据。我们全面审查了原发肿瘤、淋巴结(LN)和肿瘤基质内炎症成分中残留的存活肿瘤的百分比。主要终点是OS:在368名入组患者中,12.0%(44/368)的原发肿瘤实现了MPR,这与显著改善的OS(HR,0.36 0.17-0.77,P = 0.008)和DFS(HR = 0.59,0.36-0.92,P = 0.038)相关。在未发生 MPR 的患者中,我们发现原发性肿瘤中存在一种免疫激活表型,其特征是肿瘤浸润淋巴细胞或多核巨细胞的强烈浸润,这种表型与发生 MPR 的患者的 OS 和 DFS 相似。由 MPR 和免疫激活表型组成的新辅助病理分级(NPG)确定了 30.7% (113/368)的患者可从 NAC 中获得显著的 OS(HR 0.28,0.17-0.46,p < 0.001)和 DFS(HR 0.44,0.31-0.61,p < 0.001)获益。此外,在多变量分析中,与ypTNM阶段相比,NPG与LN阳性站数(nS)的组合在检查OS时具有更高的C指数(0.711 vs. 0.663,p < 0.001):结论:NPG与nS整合可提供一种简单、实用且稳健的方法,在临床实践中评估新辅助化疗时可对患者进行更好的分层。
{"title":"Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.","authors":"Shuaibo Wang, Xujie Sun, Jiyan Dong, Li Liu, Hao Zhao, Renda Li, Zhenlin Yang, Na Cheng, Yalong Wang, Li Fu, Hang Yi, Zhuoheng Lv, Huandong Huo, Donghui Jin, Yousheng Mao, Lin Yang","doi":"10.1007/s13402-023-00914-6","DOIUrl":"10.1007/s13402-023-00914-6","url":null,"abstract":"<p><strong>Purpose: </strong>Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined.</p><p><strong>Methods: </strong>We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS.</p><p><strong>Results: </strong>Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS.</p><p><strong>Conclusion: </strong>NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cellular Oncology
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