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Dual role of glycans and binding receptors in pathogenesis of enveloped viruses (by mainly focusing on two recent pandemics). 聚糖和结合受体在包膜病毒发病机制中的双重作用(主要关注最近的两次大流行)。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-05-10 DOI: 10.1017/erm.2023.12
Fatemeh Pourrajab, Mohamad Reza Zare-Khormizi

A period of about a decade has been estimated to pass for the emergence of a new infectious strain of a virus that may lead to the occurrence of a pandemic one. It is now suggested that the variants of the 1918 H1N1 and coronavirus disease-19 pandemics could have existed in humans after the initial cross-species introduction to humans and underwent multiple low-level seasonal epidemics before the occurrence of their outbreaks. They share similarities in the continuation, widespreadness due to high transmissibility, high fatality rate and clinical symptoms. They are assumed to share a similar principle of a zoonotic source and a cross-species pathway for transmission. They show some similarities in their pathogenesis with other enveloped viruses: Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), human immunodeficiency virus, Ebola, Lassa and measles viruses. The highly pathogenic nature of these viruses and their genetic variants may depend on their binding affinity for host cell receptors, whereby they efficiently circumvent or block host cell immune responses triggered by cytokines (interferon). High transmission rates and viral pathogenicity are attributed to glycan moieties that facilitate virus binding to host multiple receptors and cell entry, thereby helping viruses to evade immune recognition and response. Also, mucosa glycotopes are a matter of concern that play as primary sites for virus attachment and body entry. Finding general lectins or ligands that block the viral-host receptors interaction or identifying individual glycotopes is the therapeutic and prognosis topic that demands the main focus.

据估计,出现一种可能导致大流行的新的传染性病毒株的时间约为十年。现在认为,1918年H1N1和冠状病毒病-19大流行的变体可能在最初跨物种传入人类之后就存在于人类中,并在爆发之前经历了多次低水平的季节性流行。它们在延续性、高传播性、高致死率和临床症状方面具有相似之处。它们被认为具有人畜共患源和跨物种传播途径的类似原理。它们的发病机制与其他包膜病毒有一些相似之处:严重急性呼吸综合征冠状病毒-1 (SARS-CoV-1)、中东呼吸综合征冠状病毒(MERS-CoV)、人类免疫缺陷病毒、埃博拉病毒、拉沙病毒和麻疹病毒。这些病毒及其遗传变异的高致病性可能取决于它们与宿主细胞受体的结合亲和力,从而有效地规避或阻断由细胞因子(干扰素)触发的宿主细胞免疫反应。高传播率和病毒致病性归因于促进病毒与宿主多种受体结合和细胞进入的聚糖部分,从而帮助病毒逃避免疫识别和反应。此外,粘膜糖基是一个值得关注的问题,它是病毒附着和进入身体的主要位点。寻找阻断病毒-宿主受体相互作用的通用凝集素或配体或鉴定单个糖基是需要重点关注的治疗和预后主题。
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引用次数: 0
New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs. 胶质母细胞瘤DNA反应通路(DDR)的新视角,重点关注经典生物标志物和ncrna的新作用。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-05-08 DOI: 10.1017/erm.2023.10
Bianca Oana Pirlog, Silvina Ilut, Radu Pirlog, Paul Chiroi, Andreea Nutu, Delia Ioana Radutiu, George Daniel Cuc, Ioana Berindan-Neagoe, Seyed Fazel Nabavi, Rosanna Filosa, Seyed Mohammad Nabavi

Background: Glioblastoma (GBM) is the most frequent type of primary brain cancer, having a median survival of only 15 months. The current standard of care includes a combination of surgery, radiotherapy (RT) and chemotherapy with temozolomide, but with limited results. Moreover, multiple studies have shown that tumour relapse and resistance to classic therapeutic approaches are common events that occur in the majority of patients, and eventually leading to death. New approaches to better understand the intricated tumour biology involved in GBM are needed in order to develop personalised treatment approaches. Advances in cancer biology have widen our understanding over the GBM genome and allowing a better classification of these tumours based on their molecular profile.

Methods: A new targeted therapeutic approach that is currently investigated in multiple clinical trials in GBM is represented by molecules that target various defects in the DNA damage repair (DDR) pathway, a mechanism activated by endogenous and exogenous factors that induce alteration of DNA, and is involved for the development of chemotherapy and RT resistance. This intricate pathway is regulated by p53, two important kinases ATR and ATM and non-coding RNAs including microRNAs, long-non-coding RNAs and circular RNAs that regulate the expression of all the proteins involved in the pathway.

Results: Currently, the most studied DDR inhibitors are represented by PARP inhibitors (PARPi) with important results in ovarian and breast cancer. PARPi are a class of tumour agnostic drugs that showed their efficacy also in other localisations such as colon and prostate tumours that have a molecular signature associated with genomic instability. These inhibitors induce the accumulation of intracellular DNA damage, cell cycle arrest, mitotic catastrophe and apoptosis.

Conclusions: This study aims to provide an integrated image of the DDR pathway in glioblastoma under physiological and treatment pressure with a focus of the regulatory roles of ncRNAs. The DDR inhibitors are emerging as an important new therapeutic approach for tumours with genomic instability and alterations in DDR pathways. The first clinical trials with PARPi in GBM are currently ongoing and will be presented in the article. Moreover, we consider that by incorporating the regulatory network in the DDR pathway in GBM we can fill the missing gaps that limited previous attempts to effectively target it in brain tumours. An overview of the importance of ncRNAs in GBM and DDR physiology and how they are interconnected is presented.

背景:胶质母细胞瘤(GBM)是最常见的原发性脑癌类型,中位生存期仅为15个月。目前的治疗标准包括手术、放疗(RT)和替莫唑胺化疗的联合治疗,但效果有限。此外,多项研究表明,肿瘤复发和对经典治疗方法的耐药性是大多数患者发生的常见事件,并最终导致死亡。为了开发个性化的治疗方法,需要新的方法来更好地了解涉及GBM的复杂肿瘤生物学。癌症生物学的进步扩大了我们对GBM基因组的了解,并允许基于分子谱对这些肿瘤进行更好的分类。方法:目前在多个临床试验中研究的一种新的靶向治疗GBM的方法是以靶向DNA损伤修复(DDR)途径中各种缺陷的分子为代表的,这是一种由内源性和外源性因素激活,诱导DNA改变的机制,参与化疗和RT耐药的发展。这一复杂的通路受p53、两种重要的激酶ATR和ATM以及非编码rna(包括microrna、长链非编码rna和环状rna)调控,这些非编码rna调节通路中所有蛋白质的表达。结果:目前研究最多的DDR抑制剂以PARP抑制剂(PARPi)为代表,在卵巢癌和乳腺癌中有重要作用。PARPi是一类肿瘤不确定药物,在其他部位,如结肠和前列腺肿瘤中也显示出其疗效,这些肿瘤具有与基因组不稳定性相关的分子特征。这些抑制剂诱导细胞内DNA损伤积累、细胞周期阻滞、有丝分裂突变和细胞凋亡。结论:本研究旨在提供胶质母细胞瘤在生理和治疗压力下的DDR通路的综合图像,重点关注ncrna的调控作用。DDR抑制剂正在成为治疗具有基因组不稳定性和DDR通路改变的肿瘤的重要新方法。PARPi在GBM中的首次临床试验目前正在进行中,并将在文章中介绍。此外,我们认为通过整合GBM中DDR通路的调控网络,我们可以填补先前限制其有效靶向脑肿瘤的缺失空白。概述了ncrna在GBM和DDR生理学中的重要性以及它们如何相互连接。
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引用次数: 2
Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics. 蒂莫西综合征心律失常的最新进展:遗传学、机制和治疗。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-05-03 DOI: 10.1017/erm.2023.11
Congshan Jiang, Yanmin Zhang

Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene CACNA1C encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of CACNA1C gene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation-transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.

蒂莫西综合征(Timothy syndrome, TS)是一种极其罕见的疾病,其特征是多系统功能障碍,尤其是纠正后QT间期延长和手/脚并指同步出现,影响生命早期,伴有破坏性心律失常。本文首先对心脏l型电压门控钙通道(LTCC)的致病基因CACNA1C的各种突变,以及TS的遗传病因和命名进行了综述。其次,讨论了编码Cav1.2蛋白的CACNA1C基因的表达谱和功能,以及其在TS中导致多器官疾病表型特别是心律失常的功能获得性突变。更重要的是,我们关注TS中心律失常的分子机制改变,并讨论TS中LTCC功能障碍如何导致细胞内钙过量的无序钙处理及其引发的兴奋-转录偶联失调。此外,目前治疗TS心脏表型包括LTCC阻滞剂,β -肾上腺素能阻滞剂,钠通道阻滞剂,多通道抑制剂和起搏器进行了总结。最后,使用患者特异性诱导多能干细胞的研究策略被推荐为未来发展治疗方法的有希望的方向之一。本文综述了TS破坏性心律失常的遗传学和分子机制的研究进展和未来研究方向,并为制定治疗措施提供了新的见解。
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引用次数: 0
Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia. 靶向n -钙粘蛋白(CDH2)与急性白血病恶性骨髓微环境的关系。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-05-03 DOI: 10.1017/erm.2023.13
Jessica Parker, Sean Hockney, Orest W Blaschuk, Deepali Pal

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.

本文综述了急性儿科白血病的研究现状、白血病骨髓(BM)微环境以及最近发现的靶向白血病-生态位相互作用的治疗机会。肿瘤微环境在赋予白血病细胞治疗耐药性方面起着不可或缺的作用,这是阻碍这种疾病管理的关键临床挑战。在这里,我们关注细胞粘附分子n -钙粘蛋白(CDH2)在恶性脑转移微环境中的作用以及可能作为治疗靶点的相关信号通路。此外,我们讨论了微环境驱动的治疗耐药和复发,并阐述了cdh2介导的癌细胞对化疗的保护作用。最后,我们回顾了直接针对骨髓细胞和白血病细胞之间cdh2介导的粘附相互作用的新兴治疗方法。
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引用次数: 3
25 years of ERMM. 25年的ERMM。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-04-18 DOI: 10.1017/erm.2023.8
Nicola Curtin
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引用次数: 0
Fusobacterium nucleatum: a novel immune modulator in breast cancer? 核梭杆菌:乳腺癌中一种新的免疫调节剂?
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-04-03 DOI: 10.1017/erm.2023.9
Alexa Little, Mark Tangney, Michael M Tunney, Niamh E Buckley

Breast cancer was the most commonly diagnosed cancer worldwide in 2020. Greater understanding of the factors which promote tumour progression, metastatic development and therapeutic resistance is needed. In recent years, a distinct microbiome has been detected in the breast, a site previously thought to be sterile. Here, we review the clinical and molecular relevance of the oral anaerobic bacterium Fusobacterium nucleatum in breast cancer. F. nucleatum is enriched in breast tumour tissue compared with matched healthy tissue and has been shown to promote mammary tumour growth and metastatic progression in mouse models. Current literature suggests that F. nucleatum modulates immune escape and inflammation within the tissue microenvironment, two well-defined hallmarks of cancer. Furthermore, the microbiome, and F. nucleatum specifically, has been shown to affect patient response to therapy including immune checkpoint inhibitors. These findings highlight areas of future research needed to better understand the influence of F. nucleatum in the development and treatment of breast cancer.

2020年,乳腺癌是全球最常见的癌症。需要更好地了解促进肿瘤进展、转移发展和治疗耐药的因素。近年来,在乳房中发现了一种独特的微生物群,而乳房以前被认为是无菌的。在这里,我们回顾口腔厌氧杆菌核梭杆菌在乳腺癌中的临床和分子相关性。与匹配的健康组织相比,核核梭菌在乳腺肿瘤组织中富集,并在小鼠模型中显示可促进乳腺肿瘤生长和转移进展。目前的文献表明,核梭菌调节免疫逃逸和组织微环境中的炎症,这是癌症的两个明确的标志。此外,微生物组,特别是具核梭菌,已被证明会影响患者对包括免疫检查点抑制剂在内的治疗的反应。这些发现突出了未来的研究领域,需要更好地了解具核梭菌在乳腺癌发展和治疗中的影响。
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引用次数: 3
Autophagic mechanisms in longevity intervention: role of natural active compounds. 自噬机制在长寿干预:天然活性化合物的作用。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-30 DOI: 10.1017/erm.2023.5
Kevser Taban Akça, İlknur Çınar Ayan, Sümeyra Çetinkaya, Ece Miser Salihoğlu, İpek Süntar

The term 'autophagy' literally translates to 'self-eating' and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they might be connected to both aging and the onset and progression of disease. Additionally, we go over the most recent preclinical data supporting the use of autophagy modulators as age-related illnesses including cancer, cardiovascular and neurodegenerative diseases, and metabolic dysfunction. It is crucial to discover important targets in the autophagy pathway in order to create innovative therapies that effectively target autophagy. Natural products have pharmacological properties that can be therapeutically advantageous for the treatment of several diseases and they also serve as valuable sources of inspiration for the development of possible new small-molecule drugs. Indeed, recent scientific studies have shown that several natural products including alkaloids, terpenoids, steroids, and phenolics, have the ability to alter a number of important autophagic signalling pathways and exert therapeutic effects, thus, a wide range of potential targets in various stages of autophagy have been discovered. In this review, we summarised the naturally occurring active compounds that may control the autophagic signalling pathways.

“自噬”一词的字面意思是“自我吞噬”,自噬的改变已被确定为多种物种随着衰老而发生的几种分子变化之一。自噬与衰老之间有着复杂而多方面的关系,由于我们对自噬对组织稳态的各种底物的理解有所突破,这一关系最近才得以揭示。一些研究揭示了自噬与年龄相关疾病之间的关系。本综述着眼于自噬的几个新方面,并推测它们可能与衰老和疾病的发生和进展有关。此外,我们回顾了最新的临床前数据,这些数据支持自噬调节剂用于与年龄相关的疾病,包括癌症、心血管和神经退行性疾病以及代谢功能障碍。为了创造有效靶向自噬的创新疗法,发现自噬途径中的重要靶点至关重要。天然产物具有的药理学特性可以在治疗几种疾病方面具有优势,它们也可以作为开发可能的新型小分子药物的宝贵灵感来源。事实上,最近的科学研究表明,包括生物碱、萜类、类固醇和酚类物质在内的几种天然产物能够改变一些重要的自噬信号通路并发挥治疗作用,因此,在自噬的各个阶段已经发现了广泛的潜在靶点。在这篇综述中,我们总结了可能控制自噬信号通路的天然活性化合物。
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引用次数: 0
MicroRNAs in cancer metastasis: biological and therapeutic implications. microrna在癌症转移中的生物学和治疗意义。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-17 DOI: 10.1017/erm.2023.7
Marie Sell, Charmaine A Ramlogan-Steel, Jason C Steel, Bijay P Dhungel

Cancer metastasis is the primary cause of cancer-related deaths. The seeding of primary tumours at a secondary site is a highly inefficient process requiring substantial alterations in the genetic architecture of cancer cells. These alterations include significant changes in global gene expression patterns. MicroRNAs are small, non-protein coding RNAs which play a central role in regulating gene expression. Here, we focus on microRNA determinants of cancer metastasis and examine microRNA dysregulation in metastatic cancer cells. We dissect the metastatic process in a step-wise manner and summarise the involvement of microRNAs at each step. We also discuss the advantages and limitations of different microRNA-based strategies that have been used to target metastasis in pre-clinical models. Finally, we highlight current clinical trials that use microRNA-based therapies to target advanced or metastatic tumours.

癌症转移是癌症相关死亡的主要原因。在继发部位播种原发肿瘤是一个非常低效的过程,需要对癌细胞的遗传结构进行实质性的改变。这些改变包括全球基因表达模式的显著变化。MicroRNAs是一种小的非蛋白质编码rna,在调节基因表达中起着核心作用。在这里,我们专注于癌症转移的microRNA决定因素,并研究转移性癌细胞中的microRNA失调。我们以循序渐进的方式剖析了转移过程,并总结了microrna在每个步骤中的作用。我们还讨论了在临床前模型中用于靶向转移的不同基于microrna的策略的优点和局限性。最后,我们重点介绍了目前使用基于microrna的疗法靶向晚期或转移性肿瘤的临床试验。
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引用次数: 3
Telomerase inhibition in malignant gliomas: a systematic review. 端粒酶抑制在恶性胶质瘤中的作用:一项系统综述。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-15 DOI: 10.1017/erm.2023.6
Quintino Giorgio D'Alessandris, Marco Battistelli, Giovanni Pennisi, Martina Offi, Maurizio Martini, Tonia Cenci, Maria Laura Falchetti, Liverana Lauretti, Alessandro Olivi, Roberto Pallini, Nicola Montano

Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18 months. Thus, new therapeutic strategies are urgently needed. However, the identification of cancer-specific targets is particularly challenging in GBM, due to the high heterogeneity of this tumour in terms of histopathological, molecular, genetic and epigenetic features. Telomerase reactivation is a hallmark of malignant glioma. An activating mutation of the hTERT gene, encoding for the active subunit of telomerase, is one of the molecular criteria to establish a diagnosis of GBM, IDH-wildtype, in the 2021 WHO classification of central nervous system tumours. Telomerase inhibition therefore represents, at least theoretically, a promising strategy for GBM therapy: pharmacological compounds, as well as direct gene expression modulation therapies, have been successfully employed in in vitro and in vivo settings. Unfortunately, the clinical applications of telomerase inhibition in GBM are currently scarce. The aim of the present systematic review is to provide an up-to-date report on the studies investigating telomerase inhibition as a therapeutic strategy for malignant glioma in order to foster the future translational and clinical research on this topic.

胶质母细胞瘤(GBM)是最常见的成人恶性脑肿瘤,尽管治疗方法不同,但中位总生存期仍在14至18个月之间。因此,迫切需要新的治疗策略。然而,由于这种肿瘤在组织病理、分子、遗传和表观遗传特征方面的高度异质性,在GBM中确定癌症特异性靶点尤其具有挑战性。端粒酶再激活是恶性胶质瘤的标志。编码端粒酶活性亚基的hTERT基因的激活突变是2021年世卫组织中枢神经系统肿瘤分类中确定GBM (IDH-wildtype)诊断的分子标准之一。因此,端粒酶抑制至少在理论上代表了一种有希望的GBM治疗策略:药物化合物以及直接基因表达调节疗法已经成功地应用于体外和体内环境。不幸的是,端粒酶抑制在GBM中的临床应用目前很少。本系统综述的目的是提供端粒酶抑制作为恶性胶质瘤治疗策略的最新研究报告,以促进该主题的未来转化和临床研究。
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引用次数: 1
Identity matters: cancer stem cells and tumour plasticity in head and neck squamous cell carcinoma. 身份问题:头颈部鳞状细胞癌的癌症干细胞和肿瘤可塑性。
IF 6.2 2区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-02-06 DOI: 10.1017/erm.2023.4
Abdelhakim Salem, Tuula Salo

Head and neck squamous cell carcinoma (HNSCC) represents frequent yet aggressive tumours that encompass complex ecosystems of stromal and neoplastic components including a dynamic population of cancer stem cells (CSCs). Recently, research in the field of CSCs has gained increased momentum owing in part to their role in tumourigenicity, metastasis, therapy resistance and relapse. We provide herein a comprehensive assessment of the latest progress in comprehending CSC plasticity, including newly discovered influencing factors and their possible application in HNSCC. We further discuss the dynamic interplay of CSCs within tumour microenvironment considering our evolving appreciation of the contribution of oral microbiota and the pressing need for relevant models depicting their features. In sum, CSCs and tumour plasticity represent an exciting and expanding battleground with great implications for cancer therapy that are only beginning to be appreciated in head and neck oncology.

头颈部鳞状细胞癌(HNSCC)是一种常见但具有侵袭性的肿瘤,它包含复杂的间质和肿瘤成分生态系统,包括癌症干细胞(CSCs)的动态种群。近年来,由于CSCs在致瘤性、转移、治疗抵抗和复发中的作用,CSCs领域的研究得到了越来越多的关注。本文综合评述了近年来有关CSC塑性研究的最新进展,包括新发现的影响因素及其在HNSCC中的应用前景。考虑到我们对口腔微生物群贡献的不断发展的认识以及对描述其特征的相关模型的迫切需要,我们进一步讨论了肿瘤微环境中csc的动态相互作用。总之,CSCs和肿瘤可塑性代表了一个令人兴奋和不断扩大的战场,对癌症治疗具有重大意义,而这在头颈部肿瘤治疗中才刚刚开始受到重视。
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引用次数: 2
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Expert Reviews in Molecular Medicine
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