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Gene transfer and genome editing for familial hypercholesterolemia. 家族性高胆固醇血症的基因转移和基因组编辑
Pub Date : 2023-04-03 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1140997
Cesare Canepari, Alessio Cantore

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by high circulating low-density lipoprotein (LDL) cholesterol. High circulating LDL cholesterol in FH is due to dysfunctional LDL receptors, and is mainly expressed by hepatocytes. Affected patients rapidly develop atherosclerosis, potentially leading to myocardial infarction and death within the third decade of life if left untreated. Here, we introduce the disease pathogenesis and available treatment options. We highlight different possible targets of therapeutic intervention. We then review different gene therapy strategies currently under development, which may become novel therapeutic options in the future, and discuss their advantages and disadvantages. Finally, we briefly outline the potential applications of some of these strategies for the more common acquired hypercholesterolemia disease.

家族性高胆固醇血症(FH)是一种常染色体显性遗传病,以高循环低密度脂蛋白(LDL)胆固醇为特征。FH中高循环LDL胆固醇是由于LDL受体功能失调,主要由肝细胞表达。受影响的患者迅速发展为动脉粥样硬化,如果不及时治疗,可能导致心肌梗死和在生命的第三个十年内死亡。在这里,我们介绍疾病的发病机制和现有的治疗方案。我们强调治疗干预的不同可能目标。然后,我们回顾了目前正在开发的不同基因治疗策略,这些策略可能在未来成为新的治疗选择,并讨论了它们的优缺点。最后,我们简要概述了这些策略在更常见的获得性高胆固醇血症疾病中的潜在应用。
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引用次数: 0
Gene therapy and genome editing for type I glycogen storage diseases. I型糖原储存病的基因治疗和基因组编辑
Pub Date : 2023-03-31 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1167091
Janice Y Chou, Brian C Mansfield

Type I glycogen storage diseases (GSD-I) consist of two major autosomal recessive disorders, GSD-Ia, caused by a reduction of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity and GSD-Ib, caused by a reduction in the glucose-6-phosphate transporter (G6PT or SLC37A4) activity. The G6Pase-α and G6PT are functionally co-dependent. Together, the G6Pase-α/G6PT complex catalyzes the translocation of G6P from the cytoplasm into the endoplasmic reticulum lumen and its subsequent hydrolysis to glucose that is released into the blood to maintain euglycemia. Consequently, all GSD-I patients share a metabolic phenotype that includes a loss of glucose homeostasis and long-term risks of hepatocellular adenoma/carcinoma and renal disease. A rigorous dietary therapy has enabled GSD-I patients to maintain a normalized metabolic phenotype, but adherence is challenging. Moreover, dietary therapies do not address the underlying pathological processes, and long-term complications still occur in metabolically compensated patients. Animal models of GSD-Ia and GSD-Ib have delineated the disease biology and pathophysiology, and guided development of effective gene therapy strategies for both disorders. Preclinical studies of GSD-I have established that recombinant adeno-associated virus vector-mediated gene therapy for GSD-Ia and GSD-Ib are safe, and efficacious. A phase III clinical trial of rAAV-mediated gene augmentation therapy for GSD-Ia (NCT05139316) is in progress as of 2023. A phase I clinical trial of mRNA augmentation for GSD-Ia was initiated in 2022 (NCT05095727). Alternative genetic technologies for GSD-I therapies, such as gene editing, are also being examined for their potential to improve further long-term outcomes.

I型糖原储存病(GSD-I)由两种主要的常染色体隐性遗传病组成,GSD-Ia是由葡萄糖-6-磷酸酶-α (G6Pase-α或G6PC)活性降低引起的,GSD-Ib是由葡萄糖-6-磷酸转运体(G6PT或SLC37A4)活性降低引起的。G6Pase-α和G6PT在功能上是相互依赖的。G6Pase-α/G6PT复合物共同催化G6P从细胞质转运到内质网管腔,并随后水解成葡萄糖释放到血液中以维持血糖。因此,所有gsd - 1患者都具有代谢表型,包括葡萄糖稳态丧失和肝细胞腺瘤/癌和肾脏疾病的长期风险。严格的饮食治疗使GSD-I患者保持正常的代谢表型,但坚持是具有挑战性的。此外,饮食疗法不能解决潜在的病理过程,长期并发症仍然发生在代谢代偿的患者中。GSD-Ia和GSD-Ib的动物模型描述了疾病生物学和病理生理学,并指导了针对这两种疾病的有效基因治疗策略的开发。GSD-I的临床前研究已经证实重组腺相关病毒载体介导的GSD-Ia和GSD-Ib基因治疗是安全有效的。截至2023年,raav介导的GSD-Ia (NCT05139316)基因增强治疗的III期临床试验正在进行中。GSD-Ia mRNA增强的I期临床试验于2022年启动(NCT05095727)。基因编辑等用于gsd - 1治疗的替代基因技术也正在研究其改善进一步长期结果的潜力。
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引用次数: 0
Human brain organoid code of conduct. 人脑类器官行为准则
Pub Date : 2023-03-23 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1143298
Meagan Hoppe, Ahmed Habib, Riya Desai, Lincoln Edwards, Chowdari Kodavali, Natalie Sandel Sherry Psy, Pascal O Zinn

Human brain organoids are models derived from human embryonic or induced pluripotent stem cells that mimic basic cerebral microanatomy and demonstrate simple functional neuronal networks. Brain organoids have been a rapidly expanding avenue for biomedical research in general and specifically: neural development, regeneration, and central nervous system pathophysiology. However, technology replicating functional aspects of the human brain, including electrically active neural networks, requires a responsible code of conduct. In this review, we focus the discussion on intrinsic and extrinsic ethical factors associated with organoids: intrinsic considerations arise with the growing complexity of human brain organoids, including human-animal chimerism, consciousness development, and questions of where these human-like beings fall in a moral hierarchy. Extrinsic considerations explore ethics on obtainment, manufacturing, and production of sophisticated human products. In summary, a thoughtful code of conduct using human brain organoids towards the advancement of science and medicine is crucial. This article shall facilitate a structured thought process approaching the moral landscape of organoid technology.

人脑类器官是源自人类胚胎或诱导多能干细胞的模型,模拟基本的大脑显微解剖,并展示简单的功能神经元网络。脑类器官一直是生物医学研究的一个快速扩展的途径,尤其是:神经发育、再生和中枢神经系统病理生理学。然而,复制人脑功能方面的技术,包括电活性神经网络,需要负责任的行为准则。在这篇综述中,我们重点讨论了与类器官相关的内在和外在伦理因素:随着人类大脑类器官的日益复杂,产生了内在的考虑因素,包括人与动物的嵌合、意识发展,以及这些类人在道德等级中的地位问题。外在的考虑探索了获得、制造和生产复杂人类产品的伦理。总之,利用人脑类器官促进科学和医学进步的深思熟虑的行为准则至关重要。这篇文章将促进一个结构化的思维过程,接近类器官技术的道德景观。
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引用次数: 0
The advent of a pan-collagenous CLOVIS POINT for pathotropic targeting and cancer gene therapy, a retrospective. 泛胶原CLOVIS POINT用于致病性靶向和癌症基因治疗的出现,回顾
Pub Date : 2023-02-28 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1125928
Erlinda M Gordon, Frederick L Hall

The 'Clovis Point'-an enabling prehistoric gain-of-function in stone-age tool technologies which empowered the Paleoindian-Americans to hunt, to strike-deep, and to kill designated target megafauna more efficiently-was created biochemically by molecular-genetic bio-engineering. This Biomedical "Clovis Point" was crafted by adapting a broad-spectrum Pan-Collagen Binding Domain (Pan-Coll/CBD) found within the immature pre-pro-peptide segment of Von Willebrand Factor into a constructive series of advanced medical applications. Developed experimentally, preclinically, and clinically into a cutting-edge Biotechnology Platform, the Clovis Point is suitable for 1) solid-state binding of growth factors on collagenous scaffolds for improved orthopedic wound healing, 2) promoting regeneration of injured/diseased tissues; and 3) autologous stem cell capture, expansion, and gene-based therapies. Subsequent adaptations of the high-affinity Pan-Coll/CBD (exposed-collagen-seeking/surveillance function) for intravenous administration in humans, enabled the physiological delivery, aka Pathotropic Targeting to diseased tissues via the modified envelopes of gene vectors; enabling 4) precision tumor-targeting for cancer gene therapy and 5) adoptive/localized immunotherapies, demonstrating improved long-term survival value-thus pioneering a proximal and accessible cell cycle control point for cancer management-empowering modern medical oncologists to address persistent problems of chemotherapy resistance, recurrence, and occult progression of metastatic disease. Recent engineering adaptations have advanced the clinical utility to include the targeted delivery of small molecule APIs: including taxanes, mAbs, and RNA-based therapeutics.

“克洛维斯角”是通过分子遗传生物工程在生物化学上创造的,它使史前石器时代的工具技术得以发挥作用,使古印度裔美国人能够更有效地狩猎、深入打击和杀死指定的目标巨型动物。这种生物医学“Clovis Point”是通过将Von Willebrand因子的未成熟前肽段中发现的广谱泛胶原蛋白结合结构域(Pan-Coll/CBD)应用于一系列建设性的高级医学应用而制成的。Clovis Point经过实验、临床前和临床开发成为尖端的生物技术平台,适用于1)生长因子在胶原支架上的固态结合,以改善骨科伤口愈合,2)促进损伤/病变组织的再生;以及3)自体干细胞捕获、扩增和基于基因的治疗。随后,高亲和力Pan-Coll/CBD(暴露的胶原寻找/监测功能)适应于人类静脉给药,使得能够通过基因载体的修饰包膜向病变组织进行生理递送,也称为病理靶向;实现4)用于癌症基因治疗的精确肿瘤靶向和5)采用/局部免疫疗法,通过开创癌症管理的近端和可接近的细胞周期控制点,显示出改善的长期生存价值,使现代医学肿瘤学家能够解决化疗耐药性、复发、,转移性疾病的隐性进展。最近的工程改造提高了临床实用性,包括小分子API的靶向递送:包括紫杉烷、单克隆抗体和基于RNA的治疗方法。
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引用次数: 0
Using the Jurkat reporter T cell line for evaluating the functionality of novel chimeric antigen receptors. 利用Jurkat报告T细胞系评价新型嵌合抗原受体的功能
Pub Date : 2023-02-22 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1070384
Farhana Jahan, Jan Koski, Diana Schenkwein, Seppo Ylä-Herttuala, Helka Göös, Sini Huuskonen, Markku Varjosalo, Pilvi Maliniemi, Judith Leitner, Peter Steinberger, Hans-Jörg Bühring, Kim Vettenranta, Matti Korhonen

Background: T cells that are genetically modified with chimeric antigen receptor (CAR) hold promise for immunotherapy of cancer. Currently, there are intense efforts to improve the safety and efficacy of CAR T cell therapies against liquid and solid tumors. Earlier we designed a novel CAR backbone (FiCAR) where the spacer is derived from immunoglobulin (Ig) -like domains of the signal-regulatory protein alpha (SIRPα). However, the analysis of novel CAR using primary T cells is slow and laborious. Methods: To explore the versatility of the CAR backbone, we designed a set of variant FiCARs with different spacer lengths and targeting antigens. To expedite the analysis of the novel CARs, we transduced the FiCAR genes using lentiviruses into Jurkat reporter T cells carrying fluorescent reporter genes. The expression of fluorescent markers in response to FiCAR engagement with targets was analyzed by flow cytometry, and cytotoxicity was evaluated using killing assays. Furthermore, the killing mechanisms that are employed by FiCAR-equipped Jurkat T cells were investigated by flow cytometry, and the intracellular pathways involved in signaling by FiCAR were analyzed by phosphoproteomic analysis using mass spectrometry. Results: Seven different CARs were designed and transduced into Jurkat reporter cells. We show that the SIRPα derived FiCARs can be detected by flow cytometry using the SE12B6A4 antibody recognizing SIRPα. Furthermore, FiCAR engagement leads to robust activation of NFκβ and NFAT signaling, as demonstrated by the expression of the fluorescent reporter genes. Interestingly, the Jurkat reporter system also revealed tonic signaling by a HER-2 targeting FiCAR. FiCAR-equipped Jurkat T cells were cytotoxic in cocultures with target cells and target cell engagement lead to an upregulation of CD107a on the Jurkat reporter T cell surface. Phosphoproteomic analyses confirmed signal transduction via the intracellular CD28/CD3ζ sequences upon the interaction of the FiCAR1 with its antigen. In addition, downstream signaling of CD3ζ/ZAP70- SLP-76-PLCγ, PI3K-AKT-NFκB pathways and activation of NFAT and AP-1 were observed. Conclusion: We conclude that the FiCAR backbone can be shortened and lengthened at will by engineering it with one to three SIRPα derived Ig-like domains, and the FiCARs are functional when equipped with different single chain variable fragment target binding domains. The Jurkat reporter system expedites the analysis of novel CARs as to their expression, signaling function, evaluation of tonic signaling issues and cytotoxic activity.

背景:经嵌合抗原受体(CAR)基因修饰的T细胞有望用于癌症的免疫治疗。目前,人们正在努力提高CAR - T细胞治疗液体和实体肿瘤的安全性和有效性。早些时候,我们设计了一种新的CAR骨架(FiCAR),其中间隔物来源于信号调节蛋白α (SIRPα)的免疫球蛋白(Ig)样结构域。然而,使用原代T细胞分析新型CAR是缓慢而费力的。方法:为了探索CAR骨架的多功能性,我们设计了一组具有不同间隔长度和靶向抗原的变体ficar。为了加快新car的分析,我们使用慢病毒将FiCAR基因转导到携带荧光报告基因的Jurkat报告T细胞中。通过流式细胞术分析荧光标记物在FiCAR与靶标结合时的表达,并通过杀伤试验评估细胞毒性。此外,通过流式细胞术研究了配备FiCAR的Jurkat T细胞的杀伤机制,并通过质谱分析磷酸化蛋白质组学分析了FiCAR参与的细胞内信号通路。结果:7种不同的car被设计并转导到Jurkat报告细胞中。我们发现,使用识别SIRPα的SE12B6A4抗体,流式细胞术可以检测到SIRPα衍生的ficar。此外,正如荧光报告基因的表达所证明的那样,FiCAR的参与导致NFκβ和NFAT信号的强烈激活。有趣的是,Jurkat报告系统也揭示了HER-2靶向FiCAR的滋补信号。配备ficar的Jurkat T细胞在与靶细胞共培养时具有细胞毒性,靶细胞参与导致Jurkat报告细胞表面CD107a的上调。磷酸化蛋白质组学分析证实了信号转导通过细胞内CD28/CD3ζ序列在FiCAR1与其抗原的相互作用。此外,我们还观察了CD3ζ/ZAP70- SLP-76-PLCγ、PI3K-AKT-NFκB通路的下游信号通路以及NFAT和AP-1的活化。结论:FiCAR骨架可以通过1 ~ 3个SIRPα衍生的Ig-like结构域进行随意的缩短和延长,并且当配备不同的单链可变片段靶结合结构域时,FiCAR骨架具有一定的功能。Jurkat报告系统加速了对新型car的表达、信号功能、补品信号问题和细胞毒性活性的分析。
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引用次数: 0
MCM10 expression is linked to cervical cancer aggressiveness. MCM10表达与宫颈癌症侵袭性相关
Pub Date : 2023-02-22 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1009903
Sumayyah M Q Ahmed, Suparna Laha, Ranajit Das, Mariam Anjum Ifthikar, Shankar Prasad Das

Cervical cancer screening is a challenge mainly in developing countries. In developed countries, both incidence and mortality rates have been decreasing due to well organized screening programs. One of the potential biomarkers being exploited are the minichromosome maintenance proteins (MCMs), which show both specificity and sensitivity. MCM2-7 are involved in DNA replication initiation and elongation, and the MCM subunits are highly expressed in malignant tissues. Unlike other MCMs, MCM10, which is not part of the core helicase complex, is a critical determinant of origin activation and its levels are limiting in cancer cells. In this study, we performed bioinformatic analysis on the expression profile of all DNA replication associated MCM proteins in cervical cancer. MCM10 showed a relatively higher expression profile compared to the other MCMs. The mRNA expression levels of the MCMs were significantly increased in tumour tissues compared to normal, and MCM10 showed a fold change of 3.4. In order to understand if MCM10 is associated with the aggressiveness of cervical cancer, we looked into the mRNA expression pattern of MCM10 in three cervical cancer cell lines and one normal cervical cell line. MCM10 expression was significantly higher in the case of the more aggressive cancer cell line HeLa compared to controls. MCM10, therefore, can serve as a prominent biomarker for cancer progression and thus aid in early detection to control the spread of cancer cells. Our results show that MCM10 expression levels in cervical cancer cell lines are associated with cancer aggressiveness, demonstrating its clinical significance.

子宫颈癌症筛查主要在发展中国家是一项挑战。在发达国家,由于组织良好的筛查计划,发病率和死亡率都在下降。正在开发的潜在生物标志物之一是微染色体维持蛋白(MCMs),它显示出特异性和敏感性。MCM2-7参与DNA复制的起始和延伸,并且MCM亚基在恶性组织中高度表达。与其他MCM不同,MCM10不是核心解旋酶复合物的一部分,是起源激活的关键决定因素,其水平在癌症细胞中受到限制。在本研究中,我们对癌症中所有DNA复制相关的MCM蛋白的表达谱进行了生物信息学分析。与其它MCM相比,MCM10显示出相对较高的表达谱。与正常人相比,肿瘤组织中MCMs的mRNA表达水平显著增加,MCM10显示3.4倍的变化。为了了解MCM10是否与癌症的侵袭性有关,我们研究了三种癌症宫颈细胞系和一种正常宫颈细胞系中MCM10的mRNA表达模式。与对照相比,在更具侵袭性的癌症细胞系HeLa的情况下,MCM10的表达显著更高。因此,MCM10可以作为癌症进展的显著生物标志物,从而有助于早期检测以控制癌症细胞的扩散。我们的研究结果表明,MCM10在宫颈癌症细胞系中的表达水平与癌症侵袭性有关,表明其临床意义。
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引用次数: 0
Cancer immunotherapies: A hope for the uncurable? 癌症免疫疗法:治愈的希望?
Pub Date : 2023-02-17 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1140977
Firas Hamdan, Vincenzo Cerullo

The use of cancer immunotherapies is not novel but has been used over the decades in the clinic. Only recently have we found the true potential of stimulating an anti-tumor response after the breakthrough of checkpoint inhibitors. Cancer immunotherapies have become the first line treatment for many malignancies at various stages. Nevertheless, the clinical results in terms of overall survival and progression free survival were not as anticipated. Majority of cancer patients do not respond to immunotherapies and the reasons differ. Hence, further improvements for cancer immunotherapies are crucially needed. In the review, we will discuss various forms of cancer immunotherapies that are being tested or already in the clinic. Moreover, we also highlight future directions to improve such therapies.

癌症免疫疗法的应用并不新颖,但在临床上已经使用了几十年。直到最近,我们才发现在检查点抑制剂取得突破后刺激抗肿瘤反应的真正潜力。癌症免疫疗法已成为许多不同阶段恶性肿瘤的一线治疗方法。然而,总体生存率和无进展生存率方面的临床结果并不像预期的那样。大多数癌症患者对免疫疗法没有反应,原因各不相同。因此,癌症免疫疗法的进一步改进是至关重要的。在这篇综述中,我们将讨论正在测试或已经在临床上的各种形式的癌症免疫疗法。此外,我们还强调了改进此类疗法的未来方向。
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引用次数: 0
The Fault in Our Astrocytes - cause or casualties of proteinopathies of ALS/FTD and other neurodegenerative diseases? 星形胶质细胞的缺陷——ALS/FTD和其他神经退行性疾病蛋白病变的病因或损伤?
Pub Date : 2023-02-16 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1075805
Lynette M Bustos, Rita Sattler

Many neurodegenerative diseases fall under the class of diseases known as proteinopathies, whereby the structure and localization of specific proteins become abnormal. These aberrant proteins often aggregate within cells which disrupts vital homeostatic and physiological cellular functions, ultimately contributing to cell death. Although neurodegenerative disease research is typically neurocentric, there is evidence supporting the role of non-neuronal cells in the pathogenesis of these diseases. Specifically, the role of astrocytes in neurodegenerative diseases has been an ever-growing area of research. Astrocytes are one of the most abundant cell types in the central nervous system (CNS) and provide an array of essential homeostatic functions that are disrupted in neurodegenerative diseases. Astrocytes can exhibit a reactive phenotype that is characterized by molecular changes, as well as changes in morphology and function. In neurodegenerative diseases, there is potential for reactive astrocytes to assume a loss-of-function phenotype in homeostatic operations such as synapse maintenance, neuronal metabolic support, and facilitating cell-cell communication between glia and neurons. They are also able to concurrently exhibit gain-of-function phenotypes that can be destructive to neural networks and the astrocytes themselves. Additionally, astrocytes have been shown to internalize disease related proteins and reflect similar or exacerbated pathology that has been observed in neurons. Here, we review several major neurodegenerative disease-specific proteinopathies and what is known about their presence in astrocytes and the potential consequences regarding cell and non-cell autonomous neurodegeneration.

许多神经退行性疾病属于被称为蛋白质病的一类疾病,即特定蛋白质的结构和定位变得异常。这些异常蛋白经常聚集在细胞内,破坏重要的体内平衡和生理细胞功能,最终导致细胞死亡。虽然神经退行性疾病的研究通常以神经为中心,但有证据支持非神经元细胞在这些疾病的发病机制中的作用。具体来说,星形胶质细胞在神经退行性疾病中的作用一直是一个不断发展的研究领域。星形胶质细胞是中枢神经系统(CNS)中最丰富的细胞类型之一,并提供一系列在神经退行性疾病中被破坏的基本稳态功能。星形胶质细胞可以表现出反应性表型,其特征是分子变化,以及形态和功能的变化。在神经退行性疾病中,反应性星形胶质细胞有可能在突触维持、神经元代谢支持和促进胶质细胞和神经元之间的细胞间通讯等稳态操作中呈现功能丧失表型。它们也能够同时表现出对神经网络和星形胶质细胞本身具有破坏性的功能获得表型。此外,星形胶质细胞已被证明内化疾病相关蛋白,并反映在神经元中观察到的类似或加剧的病理。在这里,我们回顾了几种主要的神经退行性疾病特异性蛋白质病变,以及它们在星形胶质细胞中的存在以及与细胞和非细胞自主神经变性有关的潜在后果。
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引用次数: 0
Definition of a microbial signature as a predictor of endoscopic post-surgical recurrence in patients with Crohn's disease. 微生物特征作为克罗恩病患者术后内镜复发预测指标的定义
Pub Date : 2023-02-03 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1046414
Lia Oliver, Blau Camps, David Julià-Bergkvist, Joan Amoedo, Sara Ramió-Pujol, Marta Malagón, Anna Bahí, Paola Torres, Eugeni Domènech, Jordi Guardiola, Mariona Serra-Pagès, Jesus Garcia-Gil, Xavier Aldeguer

Background and aims: Although there are several effective drugs for the treatment of Crohn's disease (CD), almost 70% of patients will require surgical resection during their lifetime. This procedure is not always curative, as endoscopic recurrence occurs in 65%-90% of patients in the first year after surgery. The aetiology of the recurrence is unknown; however, several studies have shown how the resident microbiota is modified after surgery. The aim of this study was to evaluate samples from patients with Crohn's disease before and after an intestinal resection to determine whether there were differences in the abundance of different microbial markers, which may predict endoscopic recurrence at baseline. Methods: In this observational study, a stool sample was obtained from 25 patients with Crohn's disease before undergoing surgery, recruited at three Catalan hospitals. From each sample, DNA was purified and the relative abundance of nine microbial markers was quantified using qPCR. Results: An algorithm composed of four microbial markers (E. coli, F. prausnitzii phylogroup I, Bacteroidetes, and Eubacteria) showed a sensitivity and specificity of 90.91% and 85.71%, respectively, and a positive and negative predictive value of 83.33% and 92.31%, respectively. Conclusion: A microbial signature to determine patients who will have post-surgical recurrence was identified. This tool might be very useful in daily clinical practice, allowing the scheduling of personalized therapy and enabling preventive treatment only in patients who really require it.

背景和目的:尽管有几种有效的药物可以治疗克罗恩病(CD),但近70%的患者在一生中需要手术切除。这种手术并不总是可以治愈的,因为65%–90%的患者在手术后的第一年会出现内镜复发。复发的病因尚不清楚;然而,几项研究表明,手术后常驻微生物群是如何改变的。本研究的目的是评估克罗恩病患者在肠道切除前后的样本,以确定不同微生物标志物的丰度是否存在差异,这可能预测基线时的内镜复发。方法:在这项观察性研究中,从加泰罗尼亚三家医院招募的25名克罗恩病患者在接受手术前采集粪便样本。从每个样品中纯化DNA,并使用qPCR定量九种微生物标记的相对丰度。结果:由四种微生物标记物(大肠杆菌、普氏菌门群I、拟杆菌门和真细菌)组成的算法的敏感性和特异性分别为90.91%和85.71%,阳性和阴性预测值分别为83.33%和92.31%。结论:确定了一种确定术后复发患者的微生物特征。该工具在日常临床实践中可能非常有用,可以安排个性化治疗,并仅对真正需要的患者进行预防性治疗。
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引用次数: 0
Why should we care about astrocytes in a motor neuron disease? 为什么我们要关心运动神经元疾病中的星形胶质细胞?
Pub Date : 2023-01-23 eCollection Date: 2023-01-01 DOI: 10.3389/fmmed.2023.1047540
Katarina Stoklund Dittlau, Ludo Van Den Bosch

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.

肌萎缩侧索硬化症(Amyotrophic lateral sclerosis, ALS)是成人最常见的运动神经元疾病,可引起运动神经元进行性变性,导致肌肉萎缩、呼吸衰竭,最终导致患者死亡。ALS的发病机制是复杂的,广泛的努力集中在揭示潜在的分子机制,重点是死亡的运动神经元。然而,最近关注的焦点转向支持胶质细胞群体已经揭示了在ALS中的巨大贡献和影响,这强调了更详细地探索这一领域的必要性。特别是对星形胶质细胞的研究,神经元的稳态支持细胞,已经揭示了ALS中显著的星形胶质细胞功能障碍,因此可能为新的和有希望的治疗切入点提供靶点。在这篇综述中,我们概述了星形胶质细胞的一般功能,并总结了目前关于星形胶质细胞在ALS中的作用的文献,并对其潜在的分子机制进行了分类。我们讨论了目前在星形胶质细胞靶向治疗方面的努力,并强调了现有模型的潜力和缺点。
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引用次数: 0
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Frontiers in molecular medicine
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