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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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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 Q1 BIOCHEMISTRY & 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
Efficacy of immune checkpoint inhibitor monotherapy or combined with other small molecule-targeted agents in ovarian cancer. 免疫检查点抑制剂单药或联合其他小分子靶向药物治疗卵巢癌的疗效。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-01-24 DOI: 10.1017/erm.2023.3
Munawaer Muaibati, Abasi Abuduyilimu, Tao Zhang, Yun Dai, Ruyuan Li, Fanwei Huang, Kexin Li, Qing Tong, Xiaoyuan Huang, Liang Zhuang

Ovarian cancer is the most lethal female reproductive system tumour. Despite the great advances in surgery and systemic chemotherapy over the past two decades, almost all patients in stages III and IV relapse and develop resistance to chemotherapy after first-line treatment. Ovarian cancer has an extraordinarily complex immunosuppressive tumour microenvironment in which immune checkpoints negatively regulate T cells activation and weaken antitumour immune responses by delivering immunosuppressive signals. Therefore, inhibition of immune checkpoints can break down the state of immunosuppression. Indeed, Immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic landscape of many solid tumours. However, ICIs have yielded modest benefits in ovarian cancer. Therefore, a more comprehensive understanding of the mechanistic basis of the immune checkpoints is needed to improve the efficacy of ICIs in ovarian cancer. In this review, we systematically introduce the mechanisms and expression of immune checkpoints in ovarian cancer. Moreover, this review summarises recent updates regarding ICI monotherapy or combined with other small-molecule-targeted agents in ovarian cancer.

卵巢癌是最致命的女性生殖系统肿瘤。尽管在过去的二十年中手术和全身化疗取得了巨大的进步,但几乎所有的III期和IV期患者在一线治疗后都会复发并对化疗产生耐药性。卵巢癌具有非常复杂的免疫抑制肿瘤微环境,其中免疫检查点通过传递免疫抑制信号负调控T细胞激活并削弱抗肿瘤免疫应答。因此,免疫检查点的抑制可以打破免疫抑制状态。事实上,免疫检查点抑制剂(ICIs)已经彻底改变了许多实体肿瘤的治疗前景。然而,ICIs对卵巢癌的疗效并不明显。因此,需要更全面地了解免疫检查点的机制基础,以提高ICIs在卵巢癌中的疗效。在本文中,我们系统地介绍了免疫检查点在卵巢癌中的作用机制和表达。此外,本综述总结了ICI单药治疗或与其他小分子靶向药物联合治疗卵巢癌的最新进展。
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引用次数: 0
Autophagy of naïve CD4+ T cells in aging - the role of body adiposity and physical fitness. naïve CD4+ T细胞的自噬在衰老中的作用——身体肥胖和身体健康。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-01-19 DOI: 10.1017/erm.2023.2
Camila S Padilha, Mehdi Kushkestani, Liliana P Baptista, Karsten Krüger, Fábio Santos Lira

Life expectancy has increased exponentially in the last century accompanied by disability, poor quality of life, and all-cause mortality in older age due to the high prevalence of obesity and physical inactivity in older people. Biologically, the aging process reduces the cell's metabolic and functional efficiency, and disrupts the cell's anabolic and catabolic homeostasis, predisposing older people to many dysfunctional conditions such as cardiovascular disease, neurodegenerative disorders, cancer, and diabetes. In the immune system, aging also alters cells' metabolic and functional efficiency, a process known as 'immunosenescence', where cells become more broadly inflammatory and their functionality is altered. Notably, autophagy, the conserved and important cellular process that maintains the cell's efficiency and functional homeostasis may protect the immune system from age-associated dysfunctional changes by regulating cell death in activated CD4+ T cells. This regulatory process increases the delivery of the dysfunctional cytoplasmic material to lysosomal degradation while increasing cytokine production, proliferation, and differentiation of CD4+ T cell-mediated immune responses. Poor proliferation and diminished responsiveness to cytokines appear to be ubiquitous features of aged T cells and may explain the delayed peak in T cell expansion and cytotoxic activity commonly observed in the 'immunosenescence' phenotype in the elderly. On the other hand, physical exercise stimulates the expression of crucial nutrient sensors and inhibits the mechanistic target of the rapamycin (mTOR) signaling cascade which increases autophagic activity in cells. Therefore, in this perspective review, we will first contextualize the overall view of the autophagy process and then, we will discuss how body adiposity and physical fitness may counteract autophagy in naïve CD4+ T cells in aging.

在上个世纪,预期寿命呈指数级增长,伴随而来的是残疾、生活质量差以及由于老年人肥胖和缺乏身体活动的高发而导致的老年全因死亡率。从生物学上讲,衰老过程降低了细胞的代谢和功能效率,破坏了细胞的合成代谢和分解代谢稳态,使老年人容易患上许多功能失调的疾病,如心血管疾病、神经退行性疾病、癌症和糖尿病。在免疫系统中,衰老也会改变细胞的代谢和功能效率,这一过程被称为“免疫衰老”,细胞变得更容易发炎,它们的功能也会改变。值得注意的是,自噬是一个保守而重要的细胞过程,维持细胞的效率和功能稳态,可能通过调节活化CD4+ T细胞的细胞死亡来保护免疫系统免受与年龄相关的功能失调变化。这一调节过程增加了功能失调的细胞质物质向溶酶体降解的传递,同时增加了细胞因子的产生、增殖和CD4+ T细胞介导的免疫反应的分化。增殖不良和对细胞因子的反应减弱似乎是老年T细胞的普遍特征,这可能解释了在老年人的“免疫衰老”表型中常见的T细胞扩增和细胞毒性活性峰值延迟。另一方面,体育锻炼刺激关键营养传感器的表达,抑制雷帕霉素(mTOR)信号级联的机制目标,从而增加细胞的自噬活性。因此,在这篇前瞻性综述中,我们将首先对自噬过程的整体观点进行背景介绍,然后讨论身体肥胖和身体健康如何在衰老过程中抵消naïve CD4+ T细胞的自噬。
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引用次数: 0
Lactate, histone lactylation and cancer hallmarks. 乳酸、组蛋白乳酸化和癌症标志。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-01-09 DOI: 10.1017/erm.2022.42
Xinyu Lv, Yingying Lv, Xiaofeng Dai

Histone lactylation, an indicator of lactate level and glycolysis, has intrinsic connections with cell metabolism that represents a novel epigenetic code affecting the fate of cells including carcinogenesis. Through delineating the relationship between histone lactylation and cancer hallmarks, we propose histone lactylation as a novel epigenetic code priming cells toward the malignant state, and advocate the importance of identifying novel therapeutic strategies or dual-targeting modalities against lactylation toward effective cancer control. This review underpins important yet less-studied area in histone lactylation, and sheds insights on its clinical impact as well as possible therapeutic tools targeting lactylation.

组蛋白乳酸化是乳酸水平和糖酵解的一个指标,它与细胞代谢有着内在的联系,代表了一种影响细胞命运的新型表观遗传密码,包括癌变。通过描述组蛋白乳酸化与癌症特征之间的关系,我们提出组蛋白乳酸化是一种新的表观遗传密码,将细胞引向恶性状态,并主张确定新的治疗策略或针对乳酸化的双靶向模式对有效控制癌症的重要性。这篇综述支持了组蛋白乳酸化的重要但研究较少的领域,并揭示了其临床影响以及针对乳酸化的可能的治疗工具。
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引用次数: 9
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Expert Reviews in Molecular Medicine
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