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Jmjd2c maintains the ALDHbri+ cancer stemness with transcription factor SOX2 in lung squamous cell carcinoma. Jmjd2c通过转录因子SOX2维持肺鳞状细胞癌中ALDHbri+癌症干性。
IF 4.4 4区 医学 Q2 ONCOLOGY Pub Date : 2024-12-31 Epub Date: 2024-07-08 DOI: 10.1080/15384047.2024.2373447
Min Wang, Yuling Hu, Feng Cai, Lili Guo, Yimin Mao, Yingmin Zhang

Lung squamous cell carcinoma (LSCC) is a deadly cancer in the world. Histone demethylase Jmjd2c is a key epigenetic regulator in various tumors, while the molecular mechanism underlying Jmjd2c regulatory in LSCC is still unclear. We used the aldehyde dehydrogenasebright (ALDHbri+) subtype as a research model for cancer stem cells (CSCs) in LSCC and detected the sphere formation ability and the proportion of ALDHbri+ CSCs with Jmjd2c interference and caffeic acid (CA) treatment. Additionally, we carried out bioinformatic analysis on the expression file of Jmjd2c RNAi mice and performed western blotting, qRT-PCR, Co-IP and GST pull-down assays to confirm the bioinformatic findings. Moreover, we generated Jmjd2c-silenced and Jmjd2c-SOX2-silenced ALDHbri+ tumor-bearing BALB/c nude mice to detect the effects on tumor progression. The results showed that Jmjd2c downregulation inhibited the sphere formation and the proportion of ALDHbri+ CSCs. The SOX2 decreased expression significantly in Jmjd2c RNAi mice, and they were positively co-expressed according to the bioinformatic analysis. In addition, SOX2 expression decreased in Jmjd2c shRNA ALDHbri+ CSCs, Jmjd2c and SOX2 proteins interacted with each other. Furthermore, Jmjd2c interference revealed significant blocking effect, and Jmjd2c-SOX2 interference contributed even stronger inhibition on ALDHbri+ tumor progression. The Jmjd2c and SOX2 levels were closely related to the development and prognosis of LSCC patients. This study indicated that Jmjd2c played key roles on maintaining ALDHbri+ CSC activity in LSCC by interacting with transcription factor SOX2. Jmjd2c might be a novel molecule for therapeutic targets and biomarkers in the diagnosis and clinical treatment of lung cancer.

肺鳞状细胞癌(LSCC)是世界上一种致命的癌症。组蛋白去甲基化酶Jmjd2c是多种肿瘤的关键表观遗传调控因子,而Jmjd2c在LSCC中的调控分子机制尚不清楚。我们将醛脱氢酶布莱特(ALDHbri+)亚型作为LSCC中癌症干细胞(CSCs)的研究模型,并检测了Jmjd2c干扰和咖啡酸(CA)处理下的球形成能力和ALDHbri+ CSCs的比例。此外,我们还对Jmjd2c RNAi小鼠的表达文件进行了生物信息学分析,并进行了Western印迹、qRT-PCR、Co-IP和GST pull-down实验来证实生物信息学的研究结果。此外,我们还制作了Jmjd2c沉默和Jmjd2c-SOX2沉默的ALDHbri+肿瘤BALB/c裸鼠,以检测其对肿瘤进展的影响。结果显示,下调Jmjd2c可抑制球的形成和ALDHbri+ CSCs的比例。SOX2 在 Jmjd2c RNAi 小鼠中的表达明显下降,根据生物信息学分析,两者呈正性共表达。此外,SOX2在Jmjd2c shRNA ALDHbri+ CSCs中的表达也有所下降,Jmjd2c和SOX2蛋白之间存在相互作用。此外,Jmjd2c干扰具有显著的阻断作用,而Jmjd2c-SOX2干扰对ALDHbri+肿瘤进展的抑制作用更强。Jmjd2c和SOX2水平与LSCC患者的病情发展和预后密切相关。该研究表明,Jmjd2c通过与转录因子SOX2相互作用,在维持LSCC中ALDHbri+ CSC活性方面发挥了关键作用。Jmjd2c可能是肺癌诊断和临床治疗的治疗靶点和生物标志物。
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引用次数: 0
Agent-based modeling in cancer biomedicine: applications and tools for calibration and validation 癌症生物医学中基于代理的建模:校准和验证的应用与工具
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-28 DOI: 10.1080/15384047.2024.2344600
Nicolò Cogno, Cristian Axenie, Roman Bauer, Vasileios Vavourakis
Computational models are not just appealing because they can simulate and predict the development of biological phenomena across multiple spatial and temporal scales, but also because they can inte...
计算模型的吸引力不仅在于它们可以模拟和预测生物现象在多个空间和时间尺度上的发展,还在于它们可以将生物现象与时间、空间和空间尺度结合起来。
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引用次数: 0
MOICS, a novel classier deciphering immune heterogeneity and aid precise management of clear cell renal cell carcinoma at multiomics level. MOICS是一种新型分类器,可在多组学水平上破译免疫异质性,帮助对透明细胞肾细胞癌进行精确管理。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-24 DOI: 10.1080/15384047.2024.2345977
Ying Liu, Lin Qi, Bicheng Ye, Anbang Wang, Juan Lu, Le Qu, Peng Luo, Linhui Wang, Aimin Jiang
Recent studies have indicated that the tumor immune microenvironment plays a pivotal role in the initiation and progression of clear cell renal cell carcinoma (ccRCC). However, the characteristics and heterogeneity of tumor immunity in ccRCC, particularly at the multiomics level, remain poorly understood. We analyzed immune multiomics datasets to perform a consensus cluster analysis and validate the clustering results across multiple internal and external ccRCC datasets; and identified two distinctive immune phenotypes of ccRCC, which we named multiomics immune-based cancer subtype 1 (MOICS1) and subtype 2 (MOICS2). The former, MOICS1, is characterized by an immune-hot phenotype with poor clinical outcomes, marked by significant proliferation of CD4+ and CD8+ T cells, fibroblasts, and high levels of immune inhibitory signatures; the latter, MOICS2, exhibits an immune-cold phenotype with favorable clinical characteristics, characterized by robust immune activity and high infiltration of endothelial cells and immune stimulatory signatures. Besides, a significant negative correlation between immune infiltration and angiogenesis were identified. We further explored the mechanisms underlying these differences, revealing that negatively regulated endopeptidase activity, activated cornification, and neutrophil degranulation may promote an immune-deficient phenotype, whereas enhanced monocyte recruitment could ameliorate this deficiency. Additionally, significant differences were observed in the genomic landscapes between the subtypes: MOICS1 exhibited mutations in TTN, BAP1, SETD2, MTOR, MUC16, CSMD3, and AKAP9, while MOICS2 was characterized by notable alterations in the TGF-β pathway. Overall, our work demonstrates that multi-immune omics remodeling analysis enhances the understanding of the immune heterogeneity in ccRCC and supports precise patient management.
最近的研究表明,肿瘤免疫微环境在透明细胞肾细胞癌(ccRCC)的发生和发展过程中起着关键作用。然而,人们对ccRCC中肿瘤免疫的特征和异质性,尤其是多组学水平的特征和异质性仍然知之甚少。我们分析了免疫多组学数据集,进行了共识聚类分析,并在多个内部和外部ccRCC数据集中验证了聚类结果;我们发现了ccRCC的两种独特免疫表型,并将其命名为基于多组学免疫的癌症亚型1(MOICS1)和亚型2(MOICS2)。前者(MOICS1)表现为免疫热表型,临床预后差,CD4+和CD8+ T细胞、成纤维细胞显著增殖,免疫抑制特征水平高;后者(MOICS2)表现为免疫冷表型,临床特征好,免疫活性强,内皮细胞浸润高,免疫刺激特征高。此外,我们还发现免疫浸润与血管生成之间存在明显的负相关。我们进一步探讨了造成这些差异的机制,发现负调控的内肽酶活性、活化的粟粒化和中性粒细胞脱颗粒可能会促进免疫缺陷表型的形成,而单核细胞招募的增强则可以改善这种缺陷。此外,亚型之间的基因组图谱也存在显著差异:MOICS1 表现出 TTN、BAP1、SETD2、MTOR、MUC16、CSMD3 和 AKAP9 的突变,而 MOICS2 则以 TGF-β 通路的显著改变为特征。总之,我们的工作表明,多免疫组学重塑分析可提高对ccRCC免疫异质性的认识,并支持精确的患者管理。
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引用次数: 0
Significant response to pembrolizumab plus lenvatinib in Epstein–Barr-virus-associated intrahepatic cholangiocarcinoma: a case report 彭博利珠单抗联合来伐替尼治疗 Epstein-Barr 病毒相关肝内胆管癌的显著疗效:病例报告
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-22 DOI: 10.1080/15384047.2024.2338644
Lisha Li, Dandan Yu, Jinru Yang, Fangyuan Zhang, Dejun Zhang, Zhenyu Lin, Meng-lan Zhai, Jing Wang, Tao Zhang, Lei Zhao
ABSTRACT Background The prognosis for advanced intrahepatic cholangiocarcinoma (iCCA) is poor, and there remains an urgent need to develop efficient systemic therapy. The efficacy of Pembrolizumab immunotherapy combined with lenvatinibin in iCCA is still unclear. The role of Epstein–Barr-virus (EBV) as a biomarker in iCCA for response to immunotherapy needs further exploration. Case presentation We report a case of a 60-year-old female with EBV-associated advanced iCCA (EBVaiCCA) who progressed after first-line therapy. She accomplished an available response to the combination therapy of pembrolizumab with lenvatinib, with overall survival of 20 months. Conclusions As far as we know, this is the first case report about the application of Pembrolizumab with lenvatinib for EBVaiCCA patients. This case indicates that the combination of immunotherapy and antiangiogenic therapy provides a glimmer of hope for advanced EBVaiCCA patients.
ABSTRACT 背景 晚期肝内胆管癌(iCCA)预后较差,目前仍急需开发高效的系统疗法。Pembrolizumab免疫疗法联合来伐替尼治疗iCCA的疗效尚不明确。EB病毒(Epstein-Barr-virus,EBV)作为生物标志物在iCCA中对免疫疗法反应的作用需要进一步探讨。病例介绍 我们报告了一例患有 EBV 相关晚期 iCCA(EBVaiCCA)的 60 岁女性患者,她在接受一线治疗后病情出现进展。她对 pembrolizumab 和来伐替尼的联合治疗产生了反应,总生存期为 20 个月。结论 据我们所知,这是第一例关于 EBVaiCCA 患者应用 Pembrolizumab 联合来伐替尼治疗的病例报告。该病例表明,免疫疗法和抗血管生成疗法的联合应用为晚期EBVaiCCA患者带来了一线希望。
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引用次数: 0
Understanding and overcoming resistance to immunotherapy in genitourinary cancers 了解并克服泌尿生殖系统癌症免疫疗法的抗药性
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-17 DOI: 10.1080/15384047.2024.2342599
Sean T Evans, Yash Jani, Caroline S Jansen, Ahmet Yildirim, Ecem Kalemoglu, Mehmet Asim Bilen
The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of ...
新型免疫疗法的引入极大地改变了泌尿生殖系统癌症(GU)的治疗格局,在某些情况下甚至成为治疗标准。其中一种...
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引用次数: 0
NRSN2 promotes the malignant behavior of HPV-transfected laryngeal carcinoma cells through AMPK/ULK1 pathway mediated autophagy activation NRSN2通过AMPK/ULK1通路介导的自噬激活促进HPV转染喉癌细胞的恶性行为
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-03 DOI: 10.1080/15384047.2024.2334463
Fan Guo, Wulin Wen, Zhipeng Mi, Chao Long, Qiangyou Shi, Meihua Yang, Jia Zhao, Ruixia Ma
Neurensin-2 (NRSN2) performs a pro-carcinogenic function in multiple cancers. However, the function of NRSN2 in HPV-infected laryngeal carcinoma (LC) remains unclear. HPV transfection was performed...
Neurensin-2(NRSN2)在多种癌症中具有促癌功能。然而,NRSN2在HPV感染的喉癌(LC)中的功能仍不清楚。HPV转染...
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引用次数: 0
A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance 癌症中的检查点阻断剂耐药性:潜在机制和克服耐药性的现有策略
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-02-02 DOI: 10.1080/15384047.2024.2308097
Ginette S. Santiago-Sánchez, Kellsye P. Fabian, James W. Hodge
The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high prop...
免疫检查点的发现和免疫检查点抑制剂(ICI)的开发为晚期癌症患者带来了持久的治疗效果。然而,目前仍有很高的比例...
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引用次数: 0
CDK2 inhibition disorders centrosome stoichiometry and alters cellular outcomes in aneuploid cancer cells. CDK2抑制紊乱中心体化学计量并改变非整倍体癌细胞的细胞结局。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-31 Epub Date: 2023-11-30 DOI: 10.1080/15384047.2023.2279241
Zibo Chen, Xi Liu, Masanori Kawakami, Xiuxia Liu, Allison Baker, Aayush Bhatawadekar, Liliya Tyutyunyk-Massey, Kedar Narayan, Ethan Dmitrovsky

Cyclin-dependent Kinase 2 (CDK2) inhibition prevents supernumerary centrosome clustering. This causes multipolarity, anaphase catastrophe and apoptotic death of aneuploid cancers. This study elucidated how CDK2 antagonism affected centrosome stoichiometry. Focused ion beam scanning electron microscopy (FIB-SEM) and immunofluorescent imaging were used. Studies interrogated multipolar mitosis after pharmacologic or genetic repression of CDK2. CDK2/9 antagonism with CYC065 (Fadraciclib)-treatment disordered centrosome stoichiometry in aneuploid cancer cells, preventing centrosome clustering. This caused ring-like chromosomes or multipolar cancer cells to form before onset of cell death. Intriguingly, CDK2 inhibition caused a statistically significant increase in single centrioles rather than intact centrosomes with two centrioles in cancer cells having chromosome rings or multipolarity. Statistically significant alterations in centrosome stoichiometry were undetected in other mitotic cancer cells. To confirm this pharmacodynamic effect, CDK2 but not CDK9 siRNA-mediated knockdown augmented cancer cells with chromosome ring or multipolarity formation. Notably, engineered gain of CDK2, but not CDK9 expression, reversed emergence of cancer cells with chromosome rings or multipolarity, despite CYC065-treatment. In marked contrast, CDK2 inhibition of primary human alveolar epithelial cells did not confer statistically significant increases of cells with ring-like chromosomes or multipolarity. Hence, CDK2 antagonism caused differential effects in malignant versus normal alveolar epithelial cells. Translational relevance was confirmed by CYC065-treatment of syngeneic lung cancers in mice. Mitotic figures in tumors exhibited chromosome rings or multipolarity. Thus, CDK2 inhibition preferentially disorders centrosome stoichiometry in cancer cells. Engaging this disruption is a strategy to explore against aneuploid cancers in future clinical trials.

细胞周期蛋白依赖性激酶2 (CDK2)抑制防止多余中心体聚集。这导致非整倍体癌症的多极性、后期突变和凋亡死亡。本研究阐明了CDK2拮抗剂如何影响中心体的化学计量。采用聚焦离子束扫描电镜(FIB-SEM)和免疫荧光成像技术。研究询问多极有丝分裂后药物或遗传抑制CDK2。CYC065 (Fadraciclib)拮抗CDK2/9治疗非整倍体癌细胞中心体化学计量紊乱,防止中心体聚集。这导致环状染色体或多极癌细胞在细胞死亡之前形成。有趣的是,在具有染色体环或多极的癌细胞中,CDK2抑制导致单个中心粒而不是具有两个中心粒的完整中心体的统计学显著增加。在其他有丝分裂癌细胞中未发现有统计学意义的中心体化学计量变化。为了证实这种药效学效应,CDK2而不是CDK9 sirna介导的敲低增强了具有染色体环或多极形成的癌细胞。值得注意的是,尽管cyc065治疗,CDK2的工程增益,而不是CDK9的表达,逆转了具有染色体环或多极的癌细胞的出现。与之形成鲜明对比的是,CDK2抑制原代人肺泡上皮细胞并没有使环状染色体或多极细胞数量显著增加。因此,CDK2拮抗剂在恶性肺泡上皮细胞和正常肺泡上皮细胞中引起不同的作用。cyc065治疗小鼠同基因肺癌证实了翻译相关性。肿瘤有丝分裂象表现为染色体环或多极。因此,CDK2抑制优先扰乱了癌细胞中中心体的化学计量。参与这种破坏是在未来的临床试验中探索对抗非整倍体癌症的策略。
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引用次数: 0
Serum ferritin level is an effective prognostic factor for lung cancer immunotherapy. 血清铁蛋白水平是肺癌免疫治疗的有效预后因素。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-31 Epub Date: 2023-11-30 DOI: 10.1080/15384047.2023.2285367
Fei Wang, Guodong Deng, Ning Liang, Pingping Hu, Kuo Liu, Tong Liu, Yang Li, Meng Yuan, Li Liu, Jian Xie, Lili Qiao, Fengjun Liu, Jiandong Zhang

Immunotherapy of lung cancer has achieved promising clinical results. However, it is urgent to develop predictive biomarkers for effective immunotherapy. While ferroptosis plays a critical role in immunotherapy efficacy, ferritin is an important regulatory factor. We, therefore, hypothesize that basal serum ferritin levels before immunotherapy and their corresponding changes during immunotherapy can be useful predictors of immunotherapy response in patients with lung cancer. We measured serum ferritin levels in 107 patients with lung cancer before and during immune checkpoint blockade treatments and studied the correlation between ferritin levels, response rate, and survival. Moreover, the correlation between basal ferritin and PD-L1 expression, tumor stages and pathological types was also analyzed. Patients with lower basal serum ferritin levels before immunotherapy had longer progression-free survival (PFS) (median 7 vs 4 months, P = .023) and higher disease control rate (DCR) (X2 = 4.837, P = .028), those with downregulated serum ferritin levels during immunotherapy correlated with longer PFS (median 9.5 vs 4 months, P < .001) and higher DCR (X2 = 6.475, P = .011). However, the "integrated factor", which was calculated as the combination of lower basal serum ferritin levels before immunotherapy and downregulated serum ferritin levels during immunotherapy, correlated with prolonged PFS (P < .001). Multivariate analyses revealed that the basal serum ferritin levels before immunotherapy and the corresponding changes during immunotherapy were both strong independent prognostic factors (hazard ratio (HR) = 1.60, P = .041; HR = 2.65, P = .001). These findings suggest that serum ferritin levels can be used as a prognostic biomarker for lung cancer in predicting immunotherapy efficacy.

肺癌的免疫治疗取得了良好的临床效果。然而,迫切需要开发有效免疫治疗的预测性生物标志物。铁下垂在免疫治疗疗效中起关键作用,而铁蛋白是一个重要的调节因子。因此,我们假设免疫治疗前的基础血清铁蛋白水平及其在免疫治疗期间的相应变化可以作为肺癌患者免疫治疗反应的有用预测指标。我们测量了107例肺癌患者在免疫检查点阻断治疗前和治疗期间的血清铁蛋白水平,并研究了铁蛋白水平、反应率和生存率之间的相关性。分析基础铁蛋白与PD-L1表达、肿瘤分期及病理类型的相关性。免疫治疗前血清铁蛋白基础水平较低的患者无进展生存期(PFS)较长(中位7 vs 4个月,P = 0.023),疾病控制率(DCR)较高(X2 = 4.837, P = 0.028),免疫治疗期间血清铁蛋白水平下调的患者PFS较长(中位9.5 vs 4个月,P = 6.475, P = 0.011)。然而,“综合因子”,即免疫治疗前较低的基础血清铁蛋白水平和免疫治疗期间下调的血清铁蛋白水平的组合,与PFS延长相关(P P = 0.041;Hr = 2.65, p = .001)。这些发现提示血清铁蛋白水平可作为预测肺癌免疫治疗疗效的预后生物标志物。
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引用次数: 0
Aldolase A promotes cervical cancer cell radioresistance by regulating the glycolysis and DNA damage after irradiation. 醛缩酶A通过调节辐照后糖酵解和DNA损伤促进宫颈癌细胞的辐射抵抗。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-31 Epub Date: 2023-11-27 DOI: 10.1080/15384047.2023.2287128
Junying Zhou, Ningjing Lei, Bo Qin, Mengyu Chen, Shuai Gong, Hao Sun, Luojie Qiu, Fengling Wu, Ruixia Guo, Qian Ma, Yong Li, Lei Chang

Radioresistance is the major obstacle that affects the efficacy of radiotherapy which is an important treatment for cervical cancer. By analyzing the databases, we found that aldolase A (ALDOA), which is a key enzyme in metabolic reprogramming, has a higher expression in cervical cancer patients and is associated with poor prognosis. We detected the expression of ALDOA in the constructed cervical cancer radioresistance (RR) cells by repetitive irradiation and found that it was upregulated compared to the control cells. Functional assays were conducted and the results showed that the knockdown of ALDOA in cervical cancer RR cells inhibited the proliferation, migration, and clonogenic abilities by regulating the cell glycolysis. In addition, downregulation of ALDOA enhanced radiation-induced apoptosis and DNA damage by causing G2/M phase arrest and further promoted radiosensitivity of cervical cancer cells. The functions of ALDOA in regulating tumor radiosensitivity were also verified by the mouse tumor transplantation model in vivo. Therefore, our study provides new insights into the functions of ALDOA in regulating the efficacy of radiotherapy and indicates that ALDOA might be a promising target for enhancing radiosensitivity in treating cervical cancer patients.

放疗是宫颈癌的一种重要治疗方法,放射耐药是影响放疗效果的主要障碍。通过对数据库的分析,我们发现醛缩酶A (ALDOA)是代谢重编程的关键酶,在宫颈癌患者中表达较高,且与预后不良相关。通过重复照射,我们检测了构建的宫颈癌放射抵抗(RR)细胞中ALDOA的表达,发现与对照细胞相比,它的表达上调。功能实验结果表明,敲低ALDOA可通过调节细胞糖酵解抑制宫颈癌RR细胞的增殖、迁移和克隆生成能力。此外,下调ALDOA通过引起G2/M期阻滞,增强辐射诱导的宫颈癌细胞凋亡和DNA损伤,进一步提高宫颈癌细胞的放射敏感性。体内小鼠肿瘤移植模型也验证了ALDOA调节肿瘤放射敏感性的功能。因此,我们的研究为ALDOA调节放疗疗效的功能提供了新的见解,并提示ALDOA可能是宫颈癌患者提高放射敏感性的一个有希望的靶点。
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引用次数: 0
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Cancer Biology & Therapy
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