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ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma ATF3 诱导的 NF-κB 通路激活导致胰腺腺癌对 PARP 抑制剂产生获得性耐药性
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-15 DOI: 10.1007/s13402-023-00907-5
Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, Baiyong Shen

Purpose

Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy.

Methods

In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay).

Results

According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells.

Conclusion

Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer.

目的奥拉帕利是一种聚腺苷二磷酸核糖聚合酶(PARP)抑制剂,已被证明对BRCA1/2基因突变的胰腺癌患者有抗癌作用。方法在这项研究中,使用转座酶可及染色质测序法(ATAC-seq)和mRNA-seq评估了亲代胰腺癌细胞系和奥拉帕尼耐药胰腺癌细胞系的染色质可及性和差异表达转录本。结果根据通路富集分析,奥拉帕尼耐药细胞中的差异表达基因明显富集在 NF-κB 信号通路中。通过ATAC-seq,我们发现了奥拉帕尼耐药细胞中具有较高可及性的染色质区域,并预测了一系列重要的转录因子。其中,激活转录因子3(ATF3)明显高表达。结论体外和体内实验表明,ATF3可通过NF-κB信号通路增强奥拉帕尼耐药性,这表明ATF3可作为胰腺癌患者奥拉帕尼敏感性和预后指标。
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引用次数: 0
DNA repair in tumor radioresistance: insights from fruit flies genetics 肿瘤放射抗性中的 DNA 修复:果蝇遗传学的启示
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-14 DOI: 10.1007/s13402-023-00906-6
Antonella Porrazzo, Matteo Cassandri, Andrea D’Alessandro, Patrizia Morciano, Rossella Rota, Francesco Marampon, Giovanni Cenci

Background

Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy.

Conclusion

Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on Drosophila melanogaster we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.

背景放射治疗(RT)是一种关键的抗癌治疗方法,它涉及到使用电离辐射杀死肿瘤细胞。然而,由于周围正常组织的辐射暴露,这种疗法可能导致短期和长期的不良反应。放射治疗造成的DNA损伤类型决定了它的效果。高水平的基因毒性损伤可导致细胞周期阻滞、衰老和细胞死亡,但许多肿瘤可以通过激活保护机制来应对这种损伤。固有和获得性放射耐药是肿瘤复发的主要原因,了解这些机制对癌症治疗至关重要。辐射抗性背后的机制包括缺氧反应、细胞增殖、DNA修复、细胞凋亡抑制和自噬等过程。本文简要综述了遗传和表观遗传因素在DNA修复和DNA损伤反应调控中促进辐射抵抗的作用。此外,利用我们最近关于低剂量率(LDR)电离辐射对黑腹果蝇的影响的研究结果,我们讨论了这种模式生物如何有助于识别参与肿瘤对放射治疗耐药的保守因子。
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引用次数: 0
CSGALNACT2 restricts ovarian cancer migration and invasion by modulating MAPK/ERK pathway through DUSP1 CSGALNACT2 通过 DUSP1 调节 MAPK/ERK 通路,从而限制卵巢癌的迁移和侵袭
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-12 DOI: 10.1007/s13402-023-00903-9
Mingjun Ma, Chao Wang, Meixuan Wu, Sijia Gu, Jiani Yang, Yue Zhang, Shanshan Cheng, Shilin Xu, Minghai Zhang, Yongsong Wu, Yaqian Zhao, Xiu Tian, Dominic Chih-Cheng Voon, Chiaki Takahashi, Jindan Sheng, Yu Wang

Purpose

Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain.

Methods

The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2.

Results

We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy.

Conclusion

As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.

目的卵巢癌是女性癌症相关死亡的主要原因之一。CSGALNACT2 是一种重要的高尔基体转移酶,与多种人类疾病相关。方法 利用癌症基因组图谱和 GEPIA 数据库评估 CSGALNACT2 在卵巢癌患者中的表达。采用 RNA-seq、qRT-PCR 和 IHC 验证 CSGALNACT2 在卵巢癌组织中的表达。然后,通过体内和体外实验评估 CSGALNACT2 在卵巢癌进展中的作用。结果表明,在卵巢癌和卵巢癌转移组织中,CSGALNACT2的mRNA表达和蛋白水平均显著下调。CSGALNACT2在体外能明显抑制卵巢癌的迁移、侵袭和克隆性生长,在体内卵巢癌进展过程中会逐渐消失。通过RNA-seq、KEGG分析和Western印迹,CSGALNACT2通过DUSP1调节MAPK/ERK通路抑制卵巢癌的迁移和侵袭。此外,CSGALNACT2的表达与免疫细胞浸润相关,在不同免疫细胞富集或减少的卵巢癌中具有预后价值。结论 作为一种卵巢癌抑制基因,CSGALNACT2能抑制卵巢癌的发展,可作为卵巢癌患者的预后生物标志物。
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引用次数: 0
Publisher Correction to: RETRACTED ARTICLE: Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microRNA-34a ameliorate glioblastoma development via down-regulating MYCN. 过表达microRNA-34a的人骨髓间充质干细胞分泌外泌体通过下调MYCN改善胶质母细胞瘤的发展。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-01 DOI: 10.1007/s13402-023-00900-y
Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li
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引用次数: 0
Role of ELMO1 in inflammation and cancer—clinical implications ELMO1在炎症和癌症中的作用-临床意义
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-06-06 DOI: 10.1007/s13402-022-00680-x
Stefania Tocci, Stella-Rita C. Ibeawuchi, Soumita Das, I. Sayed
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引用次数: 5
GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer. GAS41通过haa - z介导GEM的增殖和化学耐药。2和Notch1在胰腺癌中的表达
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-06-01 Epub Date: 2022-05-03 DOI: 10.1007/s13402-022-00675-8
Shilong Han, Chuanwu Cao, Rui Liu, YiFeng Yuan, Long Pan, Minjie Xu, Chao Hu, Xiaojun Zhang, Maoquan Li, Xiaoping Zhang

Purpose: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.

Methods: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.

Results: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.

Conclusion: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

目的:GAS41是一种YEATS结构域蛋白,在非小细胞肺癌中与乙酰化组蛋白H3结合,促进H2A.Z的染色质沉积。GAS41 在胰腺癌中的作用尚不清楚。在此,我们旨在揭示这一作用:方法:使用 qRT-PCR、Western 印迹和免疫组化技术检测 GAS41 在胰腺癌组织和细胞系中的表达。方法:利用 qRTCR、Western 印迹和免疫组化技术检测了 GAS41 在胰腺癌组织和细胞系中的表达,并进行了 MTT、菌落形成、球形体形成和体内肿瘤发生试验,以评估胰腺癌细胞的增殖、肿瘤发生、干性和吉西他滨(GEM)耐药性。从机理上讲,我们采用了共免疫沉淀(co-immunoprecipitation,co-IP)和染色质免疫沉淀(chromatin immunoprecipitation,ChIP)实验来评估GAS41、H2A.Z.2和Notch1在胰腺癌中的作用:结果:我们发现 GAS41 在人类胰腺癌组织和细胞系中过表达,并且在获得 GEM 抗性后其表达增加。我们还发现 GAS41 在体外和体内上调 Notch 以及胰腺癌细胞的干性和 GEM 抗性。我们发现,GAS41与H2A.Z.2结合并激活Notch及其下游介质,从而调节干性和耐药性。研究发现,删除 GAS41 或 H2A.Z.2 可下调 Notch,并使胰腺癌细胞对 GEM 敏感:我们的数据表明,GAS41通过H2A.Z.2和Notch1介导了胰腺癌细胞的增殖和对GEM的耐药性。
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引用次数: 5
IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer. IRAK2-NF-κB信号传导促进癌症糖酵解依赖性肿瘤生长
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-06-01 Epub Date: 2022-04-29 DOI: 10.1007/s13402-022-00670-z
Jian Yang, De-Jun Liu, Jia-Hao Zheng, Rui-Zhe He, Da-Peng Xu, Min-Wei Yang, Hong-Fei Yao, Xue-Liang Fu, Jian-Yu Yang, Yan-Miao Huo, Ling-Ye Tao, Rong Hua, Yong-Wei Sun, Xian-Ming Kong, Shu-Heng Jiang, Wei Liu

Background: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism.

Methods: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms.

Results: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression.

Conclusions: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

背景:代谢重编程已成为癌症的核心标志,而癌症代谢长期以来一直等同于有氧糖酵解。此外,缺氧和低血管肿瘤微环境(TME)是胰腺导管腺癌(PDAC)的主要特征,其中糖酵解是肿瘤细胞生存和增殖的必要条件。在此,我们探讨了白介素1受体相关激酶2(IRAK2)对PDAC生物学行为的影响,并研究了其潜在机制:方法:在GEO、TCGA和Ren Ji数据集中确定了IRAK2的表达模式和临床相关性。方法:在GEO、TCGA和Ren Ji数据集中确定了IRAK2的表达模式和临床相关性,采用功能缺失和功能增益研究来探讨IRAK2在体外和体内的细胞功能。应用基因组富集分析、海马代谢分析、免疫组化和Western印迹等方法揭示了潜在的分子机制:结果:我们发现 IRAK2 在 PDAC 患者样本中高表达,且与预后不良有关。通过异常沃伯格效应,IRAK2 基因敲除导致 PDAC 细胞增殖明显受阻。外源 IRAK2 过表达则得到了相反的结果。从机理上讲,我们发现IRAK2对维持核因子κB(NF-κB)家族等转录因子的活化至关重要,而这些转录因子已被越来越多地认为是癌症发生和发展的许多步骤中的关键因素。用NF-κB抑制剂马斯林酸(MA)治疗PDAC细胞,可明显减轻IRAK2过表达导致的异常肿瘤行为:我们的数据揭示了 IRAK2 在 PDAC 代谢重编程中的作用。结论:我们的数据揭示了IRAK2在PDAC代谢重编程中的作用,此外,我们还获得了免疫相关通路如何影响PDAC进展的新见解,并表明靶向IRAK2可作为治疗PDAC的一种新方法。
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引用次数: 10
Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma. 胰腺癌中解除调控的长非编码RNA的注释和功能表征
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-06-01 Epub Date: 2022-05-14 DOI: 10.1007/s13402-022-00678-5
Vinicius Ferreira da Paixão, Omar Julio Sosa, Diogo Vieira da Silva Pellegrina, Bianca Dazzani, Thalita Bueno Corrêa, Ester Risério Bertoldi, Luís Bruno da Cruz E Alves-de-Moraes, Diogo de Oliveira Pessoa, Victoria de Paiva Oliveira, Ricardo Alberto Chiong Zevallos, Lilian Cristina Russo, Fabio Luis Forti, João Eduardo Ferreira, Helano Carioca Freitas, José Jukemura, Marcel Cerqueira César Machado, Maria Dirlei Begnami, João Carlos Setubal, Daniela Sanchez Bassères, Eduardo Moraes Reis

Purpose: Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored.

Methods: We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways.

Results: We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation.

Conclusions: Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.

目的:胰腺导管腺癌(PDAC)的转录组分析有助于确定维持恶性表型的基因表达变化。然而,大多数研究只检查了肿瘤组织,并侧重于蛋白编码基因,对长非编码 RNA(lncRNA)基本上没有进行探索:我们从患者匹配的肿瘤组织和非恶性胰腺组织中获得了总RNA-Seq数据,并利用计算管道调查了已知的和新的lncRNAs。通过基因共表达网络和功能富集分析,将失调的lncRNA归入生物过程和分子通路:结果:我们检测到了9,032个GENCODE lncRNAs以及523个未标注的lncRNAs,其中包括与患者预后显著相关的转录本。siRNA 介导的这些 lncRNAs(LINC01559、LINC01133、CCAT1、LINC00920 和 UCA1)亚群的敲除减少了细胞的增殖、迁移和侵袭。基因共表达网络分析显示,PDAC调控的lncRNA与多种生物过程有关,如细胞粘附、蛋白质糖基化和DNA修复。此外,研究还表明,UCA1基因敲除会特异性地降低参与DNA修复的共表达基因,并对电离辐射损伤后的DNA修复产生负面影响:我们的研究扩大了PDAC中被调控的lncRNA的范围,从而揭示了用于患者风险分层的新型候选生物标志物。它还为功能测定提供了一个路线图,旨在描述lncRNAs在胰腺癌中的新型作用机制,从而为治疗开发进行探索。
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引用次数: 2
Roles for macrophage-polarizing interleukins in cancer immunity and immunotherapy 巨噬细胞极化白介素在癌症免疫和免疫治疗中的作用
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-05-19 DOI: 10.1007/s13402-022-00667-8
K. Mortezaee, Jamal Majidpoor
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引用次数: 23
Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer 在er阴性乳腺癌中,NOTCH1、NOTCH4、HLA-DMA和HLA-DRA的表达与T细胞排斥、免疫检查点阻断疗效和复发风险协同相关
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-05-11 DOI: 10.1007/s13402-022-00677-6
Dingxie Liu, P. Hofman
{"title":"Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer","authors":"Dingxie Liu, P. Hofman","doi":"10.1007/s13402-022-00677-6","DOIUrl":"https://doi.org/10.1007/s13402-022-00677-6","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2022-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45890012","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: 3
期刊
Cellular Oncology
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