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Targeted gene delivery systems for T-cell engineering. 用于 T 细胞工程的靶向基因传递系统。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-05-16 DOI: 10.1007/s13402-024-00954-6
Fengling Wang, Yong Huang, JiaQian Li, Weilin Zhou, Wei Wang

T lymphocytes are indispensable for the host systems of defense against pathogens, tumors, and environmental threats. The therapeutic potential of harnessing the cytotoxic properties of T lymphocytes for antigen-specific cell elimination is both evident and efficacious. Genetically engineered T-cells, such as those employed in CAR-T and TCR-T cell therapies, have demonstrated significant clinical benefits in treating cancer and autoimmune disorders. However, the current landscape of T-cell genetic engineering is dominated by strategies that necessitate in vitro T-cell isolation and modification, which introduce complexity and prolong the development timeline of T-cell based immunotherapies. This review explores the complexities of gene delivery systems designed for T cells, covering both viral and nonviral vectors. Viral vectors are known for their high transduction efficiency, yet they face significant limitations, such as potential immunogenicity and the complexities involved in large-scale production. Nonviral vectors, conversely, offer a safer profile and the potential for scalable manufacturing, yet they often struggle with lower transduction efficiency. The pursuit of gene delivery systems that can achieve targeted gene transfer to T cell without the need for isolation represents a significant advancement in the field. This review assesses the design principles and current research progress of such systems, highlighting the potential for in vivo gene modification therapies that could revolutionize T-cell based treatments. By providing a comprehensive analysis of these systems, we aim to contribute valuable insights into the future development of T-cell immunotherapy.

T 淋巴细胞是宿主系统抵御病原体、肿瘤和环境威胁不可或缺的细胞。利用 T 淋巴细胞的细胞毒性特性消灭抗原特异性细胞的治疗潜力既明显又有效。基因工程 T 细胞,如 CAR-T 和 TCR-T 细胞疗法中使用的 T 细胞,已在治疗癌症和自身免疫性疾病方面取得了显著的临床疗效。然而,目前 T 细胞基因工程的主要策略是必须进行体外 T 细胞分离和修饰,这就增加了复杂性并延长了基于 T 细胞的免疫疗法的开发时间。本综述探讨了为 T 细胞设计的基因递送系统的复杂性,包括病毒载体和非病毒载体。病毒载体以转导效率高而著称,但也面临着很大的局限性,如潜在的免疫原性和大规模生产的复杂性。相反,非病毒载体具有更安全的特性和可规模化生产的潜力,但其转导效率往往较低。基因递送系统无需分离就能实现对 T 细胞的定向基因转移,是该领域的一大进步。这篇综述评估了这类系统的设计原理和目前的研究进展,强调了体内基因修饰疗法的潜力,这种疗法可能会彻底改变基于 T 细胞的治疗方法。通过对这些系统进行全面分析,我们希望为 T 细胞免疫疗法的未来发展提供有价值的见解。
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引用次数: 0
Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy. 揭示 Th 亚群:深入了解它们在免疫检查点抑制剂疗法中的作用。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-09-26 DOI: 10.1007/s13402-024-00992-0
Monika Ryba-Stanisławowska

T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.

T 辅助(Th)细胞亚群在调节肿瘤微环境中的免疫反应方面起着关键作用,影响着肿瘤的发展和抗肿瘤免疫。在这些亚群中,Th1 细胞通过产生 IFN-γ 促进细胞毒性反应,而 Th2 细胞和调节性 T 细胞(Tregs)则发挥免疫抑制作用,支持肿瘤生长。Th9和Th17细胞的作用与环境有关,在肿瘤免疫的促炎和调节过程中都有贡献。肿瘤微环境中的肿瘤抗原特异性 T 细胞由于 CTLA-4 和 PD-1 等抑制性受体的表达增加,往往表现出功能失调的表型,导致抗肿瘤活性降低。阻断这些抑制信号的单克隆抗体--统称为免疫检查点抑制剂(ICIs)--可以重新激活这些T细胞,增强它们靶向和消灭癌细胞的能力。最近的研究进展突显了 T 辅助细胞亚群在调节对 ICIs 的反应中的关键作用,它们之间的相互作用仍是当前研究的重点。据报道,ICIs 对 Th 细胞亚群既有积极影响,也有消极影响,有些影响取决于肿瘤微环境的类型。本综述总结了不同T辅助细胞亚群在肿瘤免疫中的关键作用及其与免疫检查点抑制剂疗法的复杂关系。
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引用次数: 0
Telomere transcripts act as tumor suppressor and are associated with favorable prognosis in colorectal cancer with low proliferating cell nuclear antigen expression. 端粒转录物是肿瘤抑制因子,与增殖细胞核抗原低表达的结直肠癌的良好预后有关。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-09-02 DOI: 10.1007/s13402-024-00986-y
Philip Kienzl, Abigail J Deloria, Monika Hunjadi, Juliane M Hadolt, Max-Felix Haering, Angrit Bothien, Doris Mejri, Medina Korkut-Demirbaş, Sandra Sampl, Gerhard Weber, Christine Pirker, Severin Laengle, Tamara Braunschmid, Eleni Dragona, Brigitte Marian, Sarantis Gagos, Lingeng Lu, Jeremy D Henson, Loretta M S Lau, Roger R Reddel, Wolfgang Mikulits, Stefan Stättner, Klaus Holzmann

Telomeric repeat-containing RNAs (TERRA) and telomerase RNA component (TERC) regulate telomerase activity (TA) and thereby contribute to telomere homeostasis by influencing telomere length (TL) and the cell immortality hallmark of cancer cells. Additionally, the non-canonical functions of telomerase reverse transcriptase (TERT) and TERRA appear to be involved in the epithelial-mesenchymal transition (EMT), which is important for cancer progression. However, the relationship between TERRA and patient prognosis has not been fully characterized. In this small-scale study, 68 patients with colorectal cancer (CRC) were evaluated for correlations between telomere biology, proliferation, and EMT gene transcripts and disease outcome. The proliferating cell nuclear antigen (PCNA) and the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) showed a positive correlation with TERRA, while TA and TERRA exhibited an inverse correlation. Consistent with previous findings, the present study revealed higher expression levels of TERT and TERC, and increased TA and TL in CRC tumor tissue compared to adjacent non-tumor tissue. In contrast, lower expression levels of TERRA were observed in tumor tissue. Patients with high TERRA expression and low PCNA levels exhibited favorable overall survival rates compared to individuals with the inverse pattern. Furthermore, TERRA suppressed CRC tumor growth in severe combined immunodeficiency disease (SCID) mice. In conclusion, our study extends previously published research on TERRA suggesting its potential therapeutic role in telomerase-positive CRC.

含端粒重复序列的RNA(TERRA)和端粒酶RNA成分(TERC)调节端粒酶活性(TA),从而通过影响端粒长度(TL)和癌细胞的细胞永生标志来促进端粒平衡。此外,端粒酶逆转录酶(TERT)和TERRA的非规范功能似乎参与了上皮-间充质转化(EMT),而EMT对癌症进展非常重要。然而,TERRA与患者预后之间的关系尚未完全定性。在这项小规模研究中,研究人员评估了68名结直肠癌(CRC)患者的端粒生物学、增殖和EMT基因转录物与疾病预后之间的相关性。增殖细胞核抗原(PCNA)和上皮剪接调节蛋白 1 和 2(ESRP1 和 ESRP2)与 TERRA 呈正相关,而 TA 与 TERRA 呈反相关。与之前的研究结果一致,本研究发现,与邻近的非肿瘤组织相比,CRC 肿瘤组织中 TERT 和 TERC 的表达水平较高,TA 和 TL 的表达水平也有所增加。相比之下,肿瘤组织中 TERRA 的表达水平较低。与反向模式的患者相比,TERRA表达量高而PCNA水平低的患者总体生存率较高。此外,TERRA 还能抑制重症联合免疫缺陷病(SCID)小鼠的 CRC 肿瘤生长。总之,我们的研究扩展了以前发表的有关 TERRA 的研究,表明它在端粒酶阳性的 CRC 中具有潜在的治疗作用。
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引用次数: 0
Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma. 嵌合抗原受体 T 细胞治疗复发/难治性 B 细胞非霍奇金淋巴瘤患者后维持程序性细胞死亡 1 抑制剂的疗效。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-04-02 DOI: 10.1007/s13402-024-00940-y
Xiangke Xin, Xiaojian Zhu, Yang Yang, Na Wang, Jue Wang, Jinhuan Xu, Jia Wei, Liang Huang, Miao Zheng, Yi Xiao, Chunrui Li, Yang Cao, Fankai Meng, Lijun Jiang, Yicheng Zhang

Introduction: Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options.

Methods: A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy.

Results: In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy.

Conclusion: PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.

导言:嵌合抗原受体(CAR)-T细胞在约30%至40%的复发/难治性(r/r)B细胞非霍奇金淋巴瘤(B-NHL)中获得了长期耐受性。CAR-T治疗后的维持治疗是必要的,而PD1抑制剂是重要的维持治疗选择之一:从2019年3月到2022年7月,共有173名r/r B-NHL患者在CD19/22 CAR-T疗法单独或与自体造血干细胞移植(ASCT)联合治疗后接受了PD1抑制剂维持治疗,他们接受了两项试验的资格评估。共有81名患者接受了PD1抑制剂维持治疗:在CD19/22 CAR-T疗法试验中,PD1抑制剂维持治疗组的客观反应率(ORR)(82.9% vs 60%;P = 0.04)和2年无进展生存期(PFS)(59.8% vs 21.3%;P = 0.001)均优于非维持治疗组。两组的估计两年总生存期(OS)相当(60.1% vs 45.1%;P = 0.112)。两组的CD19 CAR-T和CD22 CAR-T峰值扩增水平无差异。PD1抑制剂维持组CD19和CD22 CAR-T的持续时间长于非维持组。在CD19/22 CAR-T疗法联合ASCT试验中,非维持治疗组和PD1抑制剂维持治疗组的ORR(81.4% vs 84.8%;P = 0.67)、2年PFS(72.3% vs 74.9%;P = 0.73)和2年OS(84.1% vs 80.7%;P = 0.79)均无显著差异。CD19和CD22 CAR-T的峰值扩增水平和持续时间在两组之间没有统计学差异。在使用PD1抑制剂维持治疗期间,所有不良事件均可控。在多变量分析中,类型和R3m是影响CAR-T治疗后使用PD1抑制剂维持治疗的r/r B-NHL患者OS的独立预测因素:结论:CD19/22 CAR-T治疗后使用PD1抑制剂维持治疗可为r/r B-NHL患者带来更好的反应和生存率,但在CD19/22 CAR-T细胞治疗联合ASCT试验中则没有这种效果。
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引用次数: 0
Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma. 尼洛替尼与舒尼替尼联用可使MCL-1降解并激活自噬,从而克服肾细胞癌对舒尼替尼的耐药性。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-23 DOI: 10.1007/s13402-024-00927-9
Tingyu Liu, Xin Yue, Xue Chen, Ru Yan, Chong Wu, Yunzhi Li, Xianzhang Bu, Hui Han, Ran-Yi Liu

Purpose: Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application.

Methods: We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. RESULTS: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect.

Conclusion: Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.

目的:舒尼替尼是治疗转移性肾细胞癌(RCC)的推荐药物。然而,舒尼替尼的治疗潜力受到毒性和耐药性的影响。因此,我们试图探索一种组合策略,以提高低毒性剂量舒尼替尼的疗效,从而更好地应用于临床:方法:我们通过体外细胞活力评估,从包含 1374 种美国 FDA 批准药物的化合物库中筛选舒尼替尼的协同试剂。方法:我们通过体外细胞活力评估,从包含 1374 种 FDA 批准药物的化合物库中筛选出舒尼替尼协同试剂,并在体外和体内模型中证实了其协同抗增殖和促凋亡作用。通过磷酸化蛋白质组学、共免疫沉淀、免疫荧光和 Western-blot 检测等方法对其分子机制进行了研究。结果:通过四步筛选,尼罗替尼脱颖而出,成为与舒尼替尼联用的潜在协同杀手。随后的功能评估表明,尼洛替尼与舒尼替尼在体外和体内能协同抑制 RCC 细胞增殖并促进细胞凋亡。从机理上讲,尼洛替尼激活E3连接酶HUWE1,与舒尼替尼联用可使MCL-1通过蛋白酶体途径降解,导致Beclin-1从MCL-1/Beclin-1复合物中释放。随后,Beclin-1诱导完整的自噬通路以促进抗肿瘤效果:我们的研究结果揭示了尼洛替尼联合舒尼替尼克服RCC舒尼替尼耐药的新机制。因此,这种新型合理的联合治疗方案为转移性RCC提供了一种前景广阔的治疗途径,也为在临床上评估这种联合治疗方案提供了依据。
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引用次数: 0
STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma. STK3 激酶激活通过 FOXO1-TP53INP1/P21 通路抑制食管鳞状细胞癌的肿瘤增殖
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-04 DOI: 10.1007/s13402-024-00928-8
Ziying Zhao, Yuan Chu, Anqi Feng, Shihan Zhang, Hao Wu, Zhaoxing Li, Mingchuang Sun, Li Zhang, Tao Chen, Meidong Xu

Purpose: Esophageal squamous cell carcinoma (ESCC) is an aggressive disease with a poor prognosis, caused by the inactivation of critical cell growth regulators that lead to uncontrolled proliferation and increased malignancy. Although Serine/Threonine Kinase 3 (STK3), also known as Mammalian STE20-like protein kinase 2 (MST2), is a highly conserved kinase of the Hippo pathway, plays a critical role in immunomodulation, organ development, cellular differentiation, and cancer suppression, its phenotype and function in ESCC require further investigation. In this study, we report for the first time on the role of STK3 kinase and its activation condition in ESCC, as well as the mechanism and mediators of kinase activation.

Methods: In this study, we investigated the expression and clinical significance of STK3 in ESCC. We first used bioinformatics databases and immunohistochemistry to analyze STK3 expression in the ESCC patient cohort and conducted survival analysis. In vivo, we conducted a tumorigenicity assay using nude mouse models to demonstrate the phenotypes of STK3 kinase. In vitro, we conducted Western blot analysis, qPCR analysis, CO-IP, and immunofluorescence (IF) staining analysis to detect molecule expression, interaction, and distribution. We measured proliferation, migration, and apoptosis abilities in ESCC cells in the experimental groups using CCK-8 and transwell assays, flow cytometry, and EdU staining. We used RNA-seq to identify genes that were differentially expressed in ESCC cells with silenced STK3 or FOXO1. We demonstrated the regulatory relationship of the TP53INP1/P21 gene medicated by the STK3-FOXO1 axis using Western blotting and ChIP in vitro.

Results: We demonstrate high STK3 expression in ESCC tissue and cell lines compared to esophageal epithelium. Cellular ROS induces STK3 autophosphorylation in ESCC cells, resulting in upregulated p-STK3/4. STK3 activation inhibits ESCC cell proliferation and migration by triggering apoptosis and suppressing the cell cycle. STK3 kinase activation phosphorylates FOXO1Ser212, promoting nuclear translocation, enhancing transcriptional activity, and upregulating TP53INP1 and P21. We also investigated TP53INP1 and P21's phenotypic effects in ESCC, finding that their knockdown significantly increases tumor proliferation, highlighting their crucial role in ESCC tumorigenesis.

Conclusion: STK3 kinase has a high expression level in ESCC and can be activated by cellular ROS, inhibiting cell proliferation and migration. Additionally, STK3 activation-mediated FOXO1 regulates ESCC cell apoptosis and cell cycle arrest by targeting TP53INP1/P21. Our research underscores the anti-tumor function of STK3 in ESCC and elucidates the mechanism underlying its anti-tumor effect on ESCC.

目的:食管鳞状细胞癌(ESCC)是一种预后不良的侵袭性疾病,其病因是关键细胞生长调节因子失活,导致增殖失控和恶性程度增加。虽然丝氨酸/苏氨酸激酶 3(STK3),又称哺乳动物 STE20 样蛋白激酶 2(MST2),是一种高度保守的 Hippo 通路激酶,在免疫调节、器官发育、细胞分化和癌症抑制中发挥着关键作用,但它在 ESCC 中的表型和功能还需要进一步研究。本研究首次报道了STK3激酶在ESCC中的作用及其激活条件,以及激酶激活的机制和介质:本研究探讨了 STK3 在 ESCC 中的表达及其临床意义。我们首先利用生物信息学数据库和免疫组化技术分析了 STK3 在 ESCC 患者队列中的表达情况,并进行了生存分析。在体内,我们利用裸鼠模型进行了致瘤性试验,以证明 STK3 激酶的表型。在体外,我们进行了 Western 印迹分析、qPCR 分析、CO-IP 和免疫荧光(IF)染色分析,以检测分子的表达、相互作用和分布。我们使用 CCK-8 和 transwell 试验、流式细胞仪和 EdU 染色法检测了实验组 ESCC 细胞的增殖、迁移和凋亡能力。我们使用 RNA-seq 鉴定了 STK3 或 FOXO1 沉默的 ESCC 细胞中差异表达的基因。我们利用 Western 印迹技术和体外 ChIP 技术证明了 STK3-FOXO1 轴对 TP53INP1/P21 基因的调控关系:结果:与食管上皮细胞相比,我们发现 STK3 在 ESCC 组织和细胞系中高表达。细胞ROS诱导ESCC细胞中STK3自身磷酸化,导致p-STK3/4上调。STK3 激活可通过触发细胞凋亡和抑制细胞周期来抑制 ESCC 细胞的增殖和迁移。STK3 激酶活化可使 FOXO1Ser212 磷酸化,促进核转位,增强转录活性,上调 TP53INP1 和 P21。我们还研究了TP53INP1和P21在ESCC中的表型效应,发现敲除它们会显著增加肿瘤的增殖,突出了它们在ESCC肿瘤发生中的关键作用:结论:STK3激酶在ESCC中表达水平较高,可被细胞ROS激活,抑制细胞增殖和迁移。此外,STK3 激活介导的 FOXO1 通过靶向 TP53INP1/P21 调节 ESCC 细胞凋亡和细胞周期停滞。我们的研究强调了 STK3 在 ESCC 中的抗肿瘤功能,并阐明了其对 ESCC 抗肿瘤作用的机制。
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引用次数: 0
DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer. DNA 低甲基化模式及其对结直肠癌肿瘤微环境的影响。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-23 DOI: 10.1007/s13402-024-00933-x
He Huang, Qian Li, Xusheng Tu, Dongyue Yu, Yundong Zhou, Lifei Ma, Kongyuan Wei, Yuzhen Gao, Guodong Zhao, Ruiqin Han, Fangdie Ye, Chunlian Ke

Background: Recent research underscores the pivotal role of immune checkpoints as biomarkers in colorectal cancer (CRC) therapy, highlighting the dynamics of resistance and response to immune checkpoint inhibitors. The impact of epigenetic alterations in CRC, particularly in relation to immune therapy resistance, is not fully understood.

Methods: We integrated a comprehensive dataset encompassing TCGA-COAD, TCGA-READ, and multiple GEO series (GSE14333, GSE37892, GSE41258), along with key epigenetic datasets (TCGA-COAD, TCGA-READ, GSE77718). Hierarchical clustering, based on Euclidean distance and Ward's method, was applied to 330 primary tumor samples to identify distinct clusters. The immune microenvironment was assessed using MCPcounter. Machine learning algorithms were employed to predict DNA methylation patterns and their functional enrichment, in addition to transcriptome expression analysis. Genomic mutation profiles and treatment response assessments were also conducted.

Results: Our analysis delineated a specific tumor cluster with CpG Island (CGI) methylation, termed the Demethylated Phenotype (DMP). DMP was associated with metabolic pathways such as oxidative phosphorylation, implicating increased ATP production efficiency in mitochondria, which contributes to tumor aggressiveness. Furthermore, DMP showed activation of the Myc target pathway, known for tumor immune suppression, and exhibited downregulation in key immune-related pathways, suggesting a tumor microenvironment characterized by diminished immunity and increased fibroblast infiltration. Six potential therapeutic agents-lapatinib, RDEA119, WH.4.023, MG.132, PD.0325901, and AZ628-were identified as effective for the DMP subtype.

Conclusion: This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies.

背景:最近的研究强调了免疫检查点作为生物标志物在结直肠癌(CRC)治疗中的关键作用,突出了免疫检查点抑制剂的耐药性和反应的动态变化。目前还不完全清楚表观遗传学改变对 CRC 的影响,尤其是与免疫治疗耐药性的关系:我们整合了一个全面的数据集,包括TCGA-COAD、TCGA-READ和多个GEO系列(GSE14333、GSE37892、GSE41258),以及关键的表观遗传数据集(TCGA-COAD、TCGA-READ、GSE77718)。根据欧氏距离和沃德方法对 330 个原发性肿瘤样本进行了分层聚类,以确定不同的群组。免疫微环境使用 MCPcounter 进行评估。除了转录组表达分析外,还采用了机器学习算法来预测DNA甲基化模式及其功能富集。此外还进行了基因组突变分析和治疗反应评估:我们的分析划定了一个具有 CpG 岛(CGI)甲基化的特定肿瘤集群,称为去甲基化表型(DMP)。DMP与氧化磷酸化等代谢途径有关,表明线粒体产生ATP的效率增加,这有助于提高肿瘤的侵袭性。此外,DMP还显示出Myc靶点通路的激活(众所周知,Myc靶点通路可抑制肿瘤免疫)和关键免疫相关通路的下调,这表明肿瘤微环境的特点是免疫力下降和成纤维细胞浸润增加。六种潜在的治疗药物--拉帕替尼、RDEA119、WH.4.023、MG.132、PD.0325901和AZ628--被确定对DMP亚型有效:本研究揭示了一种与免疫检查点抑制剂耐药性相关的新型 CRC 表观遗传表型,提出了表观遗传学分类作为识别 CRC 免疫疗法理想候选者的一种手段,从而向个性化医疗迈出了重要一步。我们的研究结果还突显了针对 DMP 亚型的潜在治疗药物,为量身定制 CRC 治疗策略提供了新途径。
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引用次数: 0
Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights. 解密脂肪酸生物合成驱动的胰腺导管腺癌分子亚型,洞察预后。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-16 DOI: 10.1007/s13402-024-00953-7
Junyi Xu, Mingzhu Liu, Jing Xue, Ping Lu

Purpose: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis.

Methods: Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays.

Results: Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression.

Conclusion: In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.

目的:胰腺导管腺癌(PDAC)具有高度异质性和侵袭性,是一项重大挑战。认识到划分分子亚型的紧迫性,我们的研究聚焦于 PDAC 脂质代谢重塑这一新兴领域,尤其是探索与脂肪酸生物合成相关的预后潜力和分子分类:方法:采用基因组变异分析(GSVA)和单样本基因组富集分析(ssGSEA)评估 PDAC 的脂质代谢失调。利用单变量Cox分析和LASSO模块建立了预后风险评分特征。通过基因本体(GO)和京都基因组百科全书(KEGG)富集分析以及加权基因共表达网络分析(WGCNA),探讨了不同风险组的基因表达差异。通过体外实验验证了7-hub基因特征面板中的关键基因--乙酰辅酶长链家族成员5(ACSL5)的生物学功能:我们的研究发现了一个与脂肪酸生物合成相关基因(FRGs)相关的7-hub基因特征,为预后预测提供了一个强有力的工具。高FRGs得分组预后较差,免疫细胞浸润减少,肿瘤突变负荷较高。有趣的是,根据癌症药物敏感性基因组学(GDSC)数据库,这组患者对各种化合物的反应性更强。值得注意的是,ACSL5在PDAC中上调,对肿瘤进展至关重要:总之,我们的研究定义了两种基于脂肪酸生物合成的新型 PDAC 亚型,它们具有不同的转录特征。这些亚型不仅可作为预后指标,还为了解其转移倾向和治疗潜力提供了有价值的见解。
{"title":"Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights.","authors":"Junyi Xu, Mingzhu Liu, Jing Xue, Ping Lu","doi":"10.1007/s13402-024-00953-7","DOIUrl":"10.1007/s13402-024-00953-7","url":null,"abstract":"<p><strong>Purpose: </strong>Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis.</p><p><strong>Methods: </strong>Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays.</p><p><strong>Results: </strong>Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression.</p><p><strong>Conclusion: </strong>In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.</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":"140944880","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
3D bioprinted tumor model: a prompt and convenient platform for overcoming immunotherapy resistance by recapitulating the tumor microenvironment. 三维生物打印肿瘤模型:通过再现肿瘤微环境克服免疫疗法耐药性的便捷平台。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-23 DOI: 10.1007/s13402-024-00935-9
Zhanyi Zhang, Xuebo Chen, Sujie Gao, Xuedong Fang, Shengnan Ren

Background: Cancer immunotherapy is receiving worldwide attention for its induction of an anti-tumor response. However, it has had limited efficacy in some patients who acquired resistance. The dynamic and sophisticated complexity of the tumor microenvironment (TME) is the leading contributor to this clinical dilemma. Through recapitulating the physiological features of the TME, 3D bioprinting is a promising research tool for cancer immunotherapy, which preserves in vivo malignant aggressiveness, heterogeneity, and the cell-cell/matrix interactions. It has been reported that application of 3D bioprinting holds potential to address the challenges of immunotherapy resistance and facilitate personalized medication.

Conclusions and perspectives: In this review, we briefly summarize the contributions of cellular and noncellular components of the TME in the development of immunotherapy resistance, and introduce recent advances in 3D bioprinted tumor models that served as platforms to study the interactions between tumor cells and the TME. By constructing multicellular 3D bioprinted tumor models, cellular and noncellular crosstalk is reproduced between tumor cells, immune cells, fibroblasts, adipocytes, and the extracellular matrix (ECM) within the TME. In the future, by quickly preparing 3D bioprinted tumor models with patient-derived components, information on tumor immunotherapy resistance can be obtained timely for clinical reference. The combined application with tumoroid or other 3D culture technologies will also help to better simulate the complexity and dynamics of tumor microenvironment in vitro. We aim to provide new perspectives for overcoming cancer immunotherapy resistance and inspire multidisciplinary research to improve the clinical application of 3D bioprinting technology.

背景:癌症免疫疗法因其诱导抗肿瘤反应而受到全世界的关注。然而,这种疗法对一些产生抗药性的患者疗效有限。肿瘤微环境(TME)的动态性和复杂性是造成这种临床困境的主要原因。通过再现肿瘤微环境的生理特点,三维生物打印保留了体内恶性肿瘤的侵袭性、异质性以及细胞-细胞/基质之间的相互作用,是一种很有前景的癌症免疫疗法研究工具。据报道,应用三维生物打印技术有可能解决免疫治疗耐药性的挑战,并促进个性化用药:在这篇综述中,我们简要总结了TME的细胞和非细胞成分在免疫治疗耐药性发展中的贡献,并介绍了三维生物打印肿瘤模型作为研究肿瘤细胞与TME之间相互作用的平台的最新进展。通过构建多细胞三维生物打印肿瘤模型,再现了肿瘤细胞、免疫细胞、成纤维细胞、脂肪细胞和细胞外基质(ECM)之间的细胞和非细胞相互作用。未来,通过快速制备具有患者来源成分的三维生物打印肿瘤模型,可以及时获得肿瘤免疫治疗耐药性的信息,供临床参考。与类肿瘤或其他三维培养技术的结合应用也将有助于更好地模拟肿瘤微环境在体外的复杂性和动态变化。我们旨在为克服肿瘤免疫治疗耐药性提供新的视角,并启发多学科研究,提高三维生物打印技术的临床应用水平。
{"title":"3D bioprinted tumor model: a prompt and convenient platform for overcoming immunotherapy resistance by recapitulating the tumor microenvironment.","authors":"Zhanyi Zhang, Xuebo Chen, Sujie Gao, Xuedong Fang, Shengnan Ren","doi":"10.1007/s13402-024-00935-9","DOIUrl":"10.1007/s13402-024-00935-9","url":null,"abstract":"<p><strong>Background: </strong>Cancer immunotherapy is receiving worldwide attention for its induction of an anti-tumor response. However, it has had limited efficacy in some patients who acquired resistance. The dynamic and sophisticated complexity of the tumor microenvironment (TME) is the leading contributor to this clinical dilemma. Through recapitulating the physiological features of the TME, 3D bioprinting is a promising research tool for cancer immunotherapy, which preserves in vivo malignant aggressiveness, heterogeneity, and the cell-cell/matrix interactions. It has been reported that application of 3D bioprinting holds potential to address the challenges of immunotherapy resistance and facilitate personalized medication.</p><p><strong>Conclusions and perspectives: </strong>In this review, we briefly summarize the contributions of cellular and noncellular components of the TME in the development of immunotherapy resistance, and introduce recent advances in 3D bioprinted tumor models that served as platforms to study the interactions between tumor cells and the TME. By constructing multicellular 3D bioprinted tumor models, cellular and noncellular crosstalk is reproduced between tumor cells, immune cells, fibroblasts, adipocytes, and the extracellular matrix (ECM) within the TME. In the future, by quickly preparing 3D bioprinted tumor models with patient-derived components, information on tumor immunotherapy resistance can be obtained timely for clinical reference. The combined application with tumoroid or other 3D culture technologies will also help to better simulate the complexity and dynamics of tumor microenvironment in vitro. We aim to provide new perspectives for overcoming cancer immunotherapy resistance and inspire multidisciplinary research to improve the clinical application of 3D bioprinting technology.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DNA-methylome-derived epigenetic fingerprint as an immunophenotype indicator of durable clinical immunotherapeutic benefits in head and neck squamous cell carcinoma. DNA-甲基组衍生的表观遗传学指纹是头颈部鳞状细胞癌临床免疫治疗持久疗效的免疫表型指标。
IF 4.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-05 DOI: 10.1007/s13402-024-00917-x
Rui Li, Xin Wen, Ru-Xue Lv, Xian-Yue Ren, Bing-Lin Cheng, Yi-Kai Wang, Ru-Zhen Chen, Wen Hu, Xin-Ran Tang

Background: Cancer immunotherapy provides durable response and improves survival in a subset of head and neck squamous cell carcinoma (HNSC) patients, which may due to discriminative tumor microenvironment (TME). Epigenetic regulations play critical roles in HNSC tumorigenesis, progression, and activation of functional immune cells. This study aims to identify an epigenetic signature as an immunophenotype indicator of durable clinical immunotherapeutic benefits in HNSC patients.

Methods: Unsupervised consensus clustering approach was applied to distinguish immunophenotypes based on five immune signatures in The Cancer Genome Atlas (TCGA) HNSC cohort. Two immunophenotypes (immune 'Hot' and immune 'Cold') that had different TME features, diverse prognosis, and distinct DNA methylation patterns were recognized. Immunophenotype-related methylated signatures (IPMS) were identified by the least absolute shrinkage and selector operation algorithm. Additionally, the IPMS score by deconvolution algorithm was constructed as an immunophenotype classifier to predict clinical outcomes and immunotherapeutic response.

Results: The 'Hot' HNSC immunophenotype had higher immunoactivity and better overall survival (p = 0.00055) compared to the 'Cold' tumors. The immunophenotypes had distinct DNA methylation patterns, which was closely associated with HNSC tumorigenesis and functional immune cell infiltration. 311 immunophenotype-related methylated CpG sites (IRMCs) was identified from TCGA-HNSC dataset. IPMS score model achieved a strong clinical predictive performance for classifying immunophenotypes. The area under the curve value (AUC) of the IPMS score model reached 85.9% and 89.8% in TCGA train and test datasets, respectively, and robustness was verified in five HNSC validation datasets. It was also validated as an immunophenotype classifier for predicting durable clinical benefits (DCB) in lung cancer patients who received anti-PD-1/PD-L1 immunotherapy (p = 0.017) and TCGA-SKCM patients who received distinct immunotherapy (p = 0.033).

Conclusions: This study systematically analyzed DNA methylation patterns in distinct immunophenotypes to identify IPMS with clinical prognostic potential for personalized epigenetic anticancer approaches in HNSC patients. The IPMS score model may serve as a reliable epigenome prognostic tool for clinical immunophenotyping to guide immunotherapeutic strategies in HNSC.

背景:癌症免疫疗法为部分头颈部鳞状细胞癌(HNSC)患者提供了持久的应答并提高了生存率,这可能是由于肿瘤微环境(TME)的鉴别作用。表观遗传调控在头颈部鳞状细胞癌的肿瘤发生、进展和功能性免疫细胞的激活过程中发挥着关键作用。本研究旨在确定表观遗传特征,作为HNSC患者获得持久临床免疫治疗效果的免疫表型指标:方法:采用无监督共识聚类方法,根据癌症基因组图谱(TCGA)HNSC队列中的五个免疫特征区分免疫表型。研究发现,两种免疫表型(免疫 "热 "型和免疫 "冷 "型)具有不同的TME特征、不同的预后和不同的DNA甲基化模式。免疫表型相关甲基化特征(IPMS)是通过最小绝对缩减和选择器操作算法确定的。此外,通过解卷积算法得出的IPMS得分被构建为免疫表型分类器,用于预测临床结果和免疫治疗反应:结果:与 "冷 "肿瘤相比,"热 "HNSC免疫表型具有更高的免疫活性和更好的总生存率(p = 0.00055)。免疫表型具有不同的DNA甲基化模式,这与HNSC肿瘤发生和功能性免疫细胞浸润密切相关。从 TCGA-HNSC 数据集中发现了 311 个免疫表型相关的甲基化 CpG 位点(IRMCs)。IPMS 评分模型对免疫表型的分类具有很强的临床预测性能。在 TCGA 训练数据集和测试数据集中,IPMS 评分模型的曲线下面积值(AUC)分别达到了 85.9% 和 89.8%,其稳健性在五个 HNSC 验证数据集中得到了验证。该模型还被验证为一种免疫表型分类器,可预测接受抗PD-1/PD-L1免疫疗法的肺癌患者的持久临床获益(DCB)(p = 0.017)和接受不同免疫疗法的TCGA-SKCM患者的持久临床获益(p = 0.033):本研究系统分析了不同免疫分型中的DNA甲基化模式,以确定具有临床预后潜力的IPMS,为HNSC患者的个性化表观遗传抗癌方法提供依据。IPMS评分模型可作为临床免疫分型的可靠表观基因组预后工具,指导HNSC的免疫治疗策略。
{"title":"DNA-methylome-derived epigenetic fingerprint as an immunophenotype indicator of durable clinical immunotherapeutic benefits in head and neck squamous cell carcinoma.","authors":"Rui Li, Xin Wen, Ru-Xue Lv, Xian-Yue Ren, Bing-Lin Cheng, Yi-Kai Wang, Ru-Zhen Chen, Wen Hu, Xin-Ran Tang","doi":"10.1007/s13402-024-00917-x","DOIUrl":"10.1007/s13402-024-00917-x","url":null,"abstract":"<p><strong>Background: </strong>Cancer immunotherapy provides durable response and improves survival in a subset of head and neck squamous cell carcinoma (HNSC) patients, which may due to discriminative tumor microenvironment (TME). Epigenetic regulations play critical roles in HNSC tumorigenesis, progression, and activation of functional immune cells. This study aims to identify an epigenetic signature as an immunophenotype indicator of durable clinical immunotherapeutic benefits in HNSC patients.</p><p><strong>Methods: </strong>Unsupervised consensus clustering approach was applied to distinguish immunophenotypes based on five immune signatures in The Cancer Genome Atlas (TCGA) HNSC cohort. Two immunophenotypes (immune 'Hot' and immune 'Cold') that had different TME features, diverse prognosis, and distinct DNA methylation patterns were recognized. Immunophenotype-related methylated signatures (IPMS) were identified by the least absolute shrinkage and selector operation algorithm. Additionally, the IPMS score by deconvolution algorithm was constructed as an immunophenotype classifier to predict clinical outcomes and immunotherapeutic response.</p><p><strong>Results: </strong>The 'Hot' HNSC immunophenotype had higher immunoactivity and better overall survival (p = 0.00055) compared to the 'Cold' tumors. The immunophenotypes had distinct DNA methylation patterns, which was closely associated with HNSC tumorigenesis and functional immune cell infiltration. 311 immunophenotype-related methylated CpG sites (IRMCs) was identified from TCGA-HNSC dataset. IPMS score model achieved a strong clinical predictive performance for classifying immunophenotypes. The area under the curve value (AUC) of the IPMS score model reached 85.9% and 89.8% in TCGA train and test datasets, respectively, and robustness was verified in five HNSC validation datasets. It was also validated as an immunophenotype classifier for predicting durable clinical benefits (DCB) in lung cancer patients who received anti-PD-1/PD-L1 immunotherapy (p = 0.017) and TCGA-SKCM patients who received distinct immunotherapy (p = 0.033).</p><p><strong>Conclusions: </strong>This study systematically analyzed DNA methylation patterns in distinct immunophenotypes to identify IPMS with clinical prognostic potential for personalized epigenetic anticancer approaches in HNSC patients. The IPMS score model may serve as a reliable epigenome prognostic tool for clinical immunophenotyping to guide immunotherapeutic strategies in HNSC.</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":"139693348","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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