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Challenges and Opportunities in the Clinical Translation of High-Resolution Spatial Transcriptomics. 高分辨率空间转录组学临床转化的挑战与机遇。
IF 28.4 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-30 DOI: 10.1146/annurev-pathmechdis-111523-023417
Tancredi Massimo Pentimalli, Nikos Karaiskos, Nikolaus Rajewsky

Pathology has always been fueled by technological advances. Histology powered the study of tissue architecture at single-cell resolution and remains a cornerstone of clinical pathology today. In the last decade, next-generation sequencing has become informative for the targeted treatment of many diseases, demonstrating the importance of genome-scale molecular information for personalized medicine. Today, revolutionary developments in spatial transcriptomics technologies digitalize gene expression at subcellular resolution in intact tissue sections, enabling the computational analysis of cell types, cellular phenotypes, and cell-cell communication in routinely collected and archival clinical samples. Here we review how such molecular microscopes work, highlight their potential to identify disease mechanisms and guide personalized therapies, and provide guidance for clinical study design. Finally, we discuss remaining challenges to the swift translation of high-resolution spatial transcriptomics technologies and how integration of multimodal readouts and deep learning approaches is bringing us closer to a holistic understanding of tissue biology and pathology.

病理学的发展始终离不开技术的进步。组织学推动了单细胞分辨率的组织结构研究,至今仍是临床病理学的基石。在过去十年中,新一代测序技术为许多疾病的靶向治疗提供了信息,证明了基因组规模的分子信息对个性化医疗的重要性。如今,空间转录组学技术的革命性发展将完整组织切片中亚细胞分辨率的基因表达数字化,从而能够对常规收集和存档临床样本中的细胞类型、细胞表型和细胞间通讯进行计算分析。在此,我们回顾了此类分子显微镜的工作原理,强调了它们在确定疾病机制和指导个性化疗法方面的潜力,并为临床研究设计提供了指导。最后,我们将讨论在快速转化高分辨率空间转录组学技术方面仍然存在的挑战,以及多模态读数和深度学习方法的整合如何使我们更接近于全面了解组织生物学和病理学。
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引用次数: 0
RNA Damage Responses in Cellular Homeostasis, Genome Stability, and Disease. 细胞稳态、基因组稳定性和疾病中的 RNA 损伤反应
IF 28.4 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-30 DOI: 10.1146/annurev-pathmechdis-111523-023516
Hani S Zaher, Nima Mosammaparast

All cells are exposed to chemicals that can damage their nucleic acids. Cells must protect these polymers because they code for key factors or complexes essential for life. Much of the work on nucleic acid damage has naturally focused on DNA, partly due to the connection between mutagenesis and human disease, especially cancer. Recent work has shed light on the importance of RNA damage, which triggers a host of conserved RNA quality control mechanisms. Because many RNA species are transient, and because of their ability to be retranscribed, RNA damage has largely been ignored. Yet, because of the connection between damaged RNA and DNA during transcription, and the association between essential complexes that process or decode RNAs, notably spliceosomes and ribosomes, the appropriate handling of damaged RNAs is critical for maintaining cellular homeostasis. This notion is bolstered by disease states, including neurodevelopmental and neurodegenerative diseases, that may arise upon loss or misregulation of RNA quality control mechanisms.

所有细胞都会接触到可能损害其核酸的化学物质。细胞必须保护这些聚合物,因为它们编码着生命所必需的关键因子或复合物。有关核酸损伤的大部分工作自然都集中在 DNA 上,部分原因是突变与人类疾病(尤其是癌症)之间存在联系。最近的工作揭示了 RNA 损伤的重要性,它触发了一系列保守的 RNA 质量控制机制。由于许多 RNA 物种都是瞬时的,而且它们能够被重新转录,因此 RNA 损伤在很大程度上被忽视了。然而,由于转录过程中受损 RNA 与 DNA 之间的联系,以及处理或解码 RNA 的重要复合体(特别是剪接体和核糖体)之间的关联,适当处理受损 RNA 对于维持细胞平衡至关重要。包括神经发育性疾病和神经退行性疾病在内的疾病状态,可能会因 RNA 质量控制机制的缺失或失调而产生,这进一步证实了这一观点。
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引用次数: 0
Circadian Clocks, Daily Stress, and Neurodegenerative Disease 昼夜节律、日常压力与神经退行性疾病
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-18 DOI: 10.1146/annurev-pathmechdis-031521-033828
Eugene Nyamugenda, Clark Rosensweig, Ravi Allada
Disrupted circadian or 24-h rhythms are among the most common early findings in a wide range of neurodegenerative disorders. Once thought to be a mere consequence of the disease process, increasing evidence points toward a causal or contributory role of the circadian clock in neurodegenerative disease. Circadian clocks control many aspects of cellular biochemistry, including stress pathways implicated in neuronal survival and death. Given the dearth of disease-modifying therapies for these increasingly prevalent disorders, this understanding may lead to breakthroughs in the development of new treatments. In this review, we provide a background on circadian clocks and focus on some potential mechanisms that may be pivotal in neurodegeneration.
昼夜节律或 24 小时节律紊乱是多种神经退行性疾病最常见的早期症状之一。昼夜节律紊乱一度被认为只是疾病过程的结果,但越来越多的证据表明,昼夜节律在神经退行性疾病中起着因果或促成作用。昼夜节律钟控制着细胞生物化学的许多方面,包括与神经元存活和死亡有关的应激途径。鉴于针对这些日益普遍的疾病的疾病调整疗法匮乏,这种认识可能会在新疗法的开发方面带来突破。在这篇综述中,我们将介绍昼夜节律钟的背景,并重点探讨可能在神经退行性病变中起关键作用的一些潜在机制。
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引用次数: 0
Multiple System Atrophy: Pathology, Pathogenesis, and Path Forward 多系统萎缩:病理学、发病机制和前进之路
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-15 DOI: 10.1146/annurev-pathmechdis-051122-104528
Alain Ndayisaba, Glenda M. Halliday, Vikram Khurana
Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by autonomic failure and motor impairment. The hallmark pathologic finding in MSA is widespread oligodendroglial cytoplasmic inclusions rich in aggregated α-synuclein (αSyn). MSA is widely held to be an oligodendroglial synucleinopathy, and we outline lines of evidence to support this assertion, including the presence of early myelin loss. We consider emerging data that support the possibility of neuronal or immune dysfunction as primary drivers of MSA. These hypotheses are placed in the context of a major recent discovery that αSyn is conformationally distinct in MSA versus other synucleinopathies such as Parkinson's disease. We outline emerging techniques in epidemiology, genetics, and molecular pathology that will shed more light on this mysterious disease. We anticipate a future in which cutting-edge developments in personalized disease modeling, including with pluripotent stem cells, bridge mechanistic developments at the bench and real benefits at the bedside.
多系统萎缩症(MSA)是一种致命的神经退行性疾病,以自主神经功能衰竭和运动障碍为特征。MSA的标志性病理发现是广泛的少突胶质细胞质包涵体富含聚集的α-突触核蛋白(αSyn)。人们普遍认为 MSA 是一种少突胶质突触核蛋白病,我们概述了支持这一观点的证据,包括早期髓鞘脱失的存在。我们考虑了新出现的数据,这些数据支持神经元或免疫功能障碍作为 MSA 主要驱动因素的可能性。最近的一项重大发现表明,αSyn 在 MSA 中的构象与帕金森病等其他突触核蛋白病不同。我们概述了流行病学、遗传学和分子病理学方面的新兴技术,这些技术将为这一神秘疾病带来更多启示。我们预计,未来个性化疾病建模的前沿发展,包括多能干细胞,将为工作台的机理发展和床边的实际获益架起桥梁。
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引用次数: 0
Pathogenesis of Germinal Matrix Hemorrhage: Insights from Single-Cell Transcriptomics. 胚芽基质出血的发病机制:单细胞转录组学的启示。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-14 DOI: 10.1146/annurev-pathmechdis-111523-023446
Jiapei Chen,Jennifer Ja-Yoon Choi,Pin-Yeh Lin,Eric J Huang
The germinal matrix harbors neurogenic niches in the subpallium of the prenatal human brain that produce abundant GABAergic neurons. In preterm infants, the germinal matrix is particularly vulnerable to developing hemorrhage, which disrupts neurogenesis and causes severe neurodevelopmental sequelae. However, the disease mechanisms that promote germinal matrix hemorrhage remain unclear. Here, we review recent advances using single-cell transcriptomics to uncover novel mechanisms that govern neurogenesis and angiogenesis in the germinal matrix of the prenatal human brain. These approaches also reveal the critical role of immune-vascular interaction that promotes vascular morphogenesis in the germinal matrix and how proinflammatory factors from activated neutrophils and monocytes can disrupt this process, leading to hemorrhage. Collectively, these results reveal fundamental disease mechanisms and therapeutic interventions for germinal matrix hemorrhage.
胚芽基质蕴藏着产前人脑表皮下的神经源龛,可产生丰富的 GABA 能神经元。在早产儿中,胚芽基质特别容易发生出血,从而破坏神经发生并导致严重的神经发育后遗症。然而,促进胚芽基质出血的疾病机制仍不清楚。在此,我们回顾了利用单细胞转录组学揭示支配产前人脑生发基质中神经发生和血管生成的新机制的最新进展。这些方法还揭示了免疫-血管相互作用在促进胚芽基质中血管形态发生方面的关键作用,以及活化的中性粒细胞和单核细胞产生的促炎因子如何破坏这一过程并导致出血。这些结果共同揭示了胚芽基质出血的基本疾病机制和治疗干预措施。
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引用次数: 0
Choroid Plexus Pathophysiology. 脉络丛病理生理学
IF 28.4 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-09 DOI: 10.1146/annurev-pathmechdis-051222-114051
Ya'el Courtney, Alexandra Hochstetler, Maria K Lehtinen

This review examines the crucial roles of the choroid plexus (ChP) in central nervous system (CNS) pathology, emphasizing its involvement in disease mechanisms and therapeutic potential. Structural changes in the human ChP have been reported across various diseases in case reports and descriptive work, but studies have yet to pin down the physiological relevance of these changes. We highlight primary pathologies of the ChP, as well as their significance in neurologic disorders, including stroke, hydrocephalus, infectious diseases, and neurodegeneration. Synthesizing recent research, this review positions the ChP as a critical player in CNS homeostasis and pathology, advocating for enhanced focus on its mechanisms to unlock new diagnostic and treatment strategies and ultimately improve patient outcomes in CNS diseases. Whether acting as a principal driver of disease, a gateway for pathogens into the CNS, or an orchestrator of neuroimmune processes, the ChP holds tremendous promise as a therapeutic target to attenuate a multitude of CNS conditions.

这篇综述探讨了脉络丛(ChP)在中枢神经系统(CNS)病理学中的关键作用,强调了脉络丛在疾病机制和治疗潜力中的参与。在病例报告和描述性工作中,人类脉络丛的结构变化已在各种疾病中有所报道,但研究尚未明确这些变化的生理相关性。我们重点介绍了 ChP 的主要病理变化及其在神经系统疾病(包括中风、脑积水、感染性疾病和神经变性)中的重要性。综合近期的研究,本综述将胆碱酯酶定位为中枢神经系统稳态和病理学中的关键角色,主张加强对胆碱酯酶机制的关注,以开启新的诊断和治疗策略,最终改善中枢神经系统疾病患者的预后。无论是作为疾病的主要驱动因素、病原体进入中枢神经系统的通道,还是神经免疫过程的协调者,胆碱酯酶都有望成为减轻多种中枢神经系统疾病的治疗靶点。
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引用次数: 0
Cysteinyl Leukotrienes in Allergic Inflammation 过敏性炎症中的胱氨酰白三烯
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-07 DOI: 10.1146/annurev-pathmechdis-111523-023509
Minkyu Lee, Joshua A. Boyce, Nora A. Barrett
The cysteinyl leukotrienes (CysLTs), LTC4, LTD4, and LTE4, are potent lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway. These mediators produce both inflammation and bronchoconstriction through three distinct G protein–coupled receptors (GPCRs)—CysLT1, CysLT2, and OXGR1 (also known as CysLT3 or GPR99). While CysLT-mediated functions in the effector phase of allergic inflammation and asthma have been established for some time, recent work has demonstrated novel roles for these mediators and their receptors in the induction and amplification of type 2 inflammation. Additionally, in vitro studies and murine models have uncovered diverse regulatory mechanisms that restrain or amplify CysLT receptor activation and CysLT receptor function. This review provides an overview of CysLT biosynthesis and its regulation, the molecular and functional pharmacology of CysLT receptors, and an overview of the established and emerging roles of CysLTs in asthma, aspirin-exacerbated respiratory disease, and type 2 inflammation.
半胱氨酰白三烯(CysLTs)、LTC4、LTD4 和 LTE4 是花生四烯酸通过 5-脂氧合酶途径产生的强效脂质介质。这些介质通过三种不同的 G 蛋白偶联受体(GPCR)--CysLT1、CysLT2 和 OXGR1(又称 CysLT3 或 GPR99)--产生炎症和支气管收缩。虽然 CysLT 在过敏性炎症和哮喘的效应阶段所介导的功能已经确立了一段时间,但最近的研究表明,这些介质及其受体在诱导和扩大 2 型炎症方面发挥了新的作用。此外,体外研究和小鼠模型揭示了抑制或放大 CysLT 受体活化和 CysLT 受体功能的多种调节机制。本综述概述了 CysLT 的生物合成及其调控、CysLT 受体的分子和功能药理学,并概述了 CysLTs 在哮喘、阿司匹林加重的呼吸道疾病和 2 型炎症中的既有和新出现的作用。
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引用次数: 0
Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications. 髓样肿瘤的遗传倾向:发病机制和临床意义。
IF 28.4 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-02 DOI: 10.1146/annurev-pathmechdis-111523-023420
Yen-Chun Liu, Mohammad K Eldomery, Jamie L Maciaszek, Jeffery M Klco

Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.

伴有或不伴有先天性血小板紊乱的髓样肿瘤常常与潜在的种系易感性有关。影响 ANKRD26、CEBPA、DDX41、ETV6 和 RUNX1 的种系改变与髓系肿瘤(包括急性髓系白血病和骨髓增生异常综合征)的非综合征易感性有关。然而,髓样肿瘤的种系易感性还与其他多种综合征有关,包括 SAMD9/9L 相关易感性、GATA2 缺乏症、RAS 病、核糖体病、端粒生物学紊乱、范可尼贫血症、严重先天性中性粒细胞减少症、唐氏综合征等。在世界卫生组织(WHO)关于造血和淋巴组织肿瘤分类的第五版系列中,与种系易感性相关的髓系肿瘤已被确认为一个独立的实体。在此,我们回顾了世界卫生组织这一实体中的几种疾病以及其他相关疾病,重点是疾病的分子发病机制和伴随的体细胞改变。最后,我们概述了如何对这些种系遗传病进行分子诊断,并对相关血液病的筛查和管理提出了一般性建议。
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引用次数: 0
Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction. 炎症对射血分数保留型心脏代谢性心力衰竭的影响
IF 28.4 1区 医学 Q1 PATHOLOGY Pub Date : 2024-10-02 DOI: 10.1146/annurev-pathmechdis-111523-023405
Edward B Thorp, Mallory Filipp

The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.

最常见的心力衰竭是射血分数保留型心力衰竭(HFpEF)。虽然起源各异,但最常见的 HFpEF 是心脏代谢性表现。肥胖和衰老会促进全身炎症,这似乎与心脏代谢性 HFpEF 的病理生理学密不可分。心脏内免疫细胞的积聚,再加上代谢组的改变,导致了心脏炎症和纤维化。尽管如此,广泛的抗炎治疗并未显示出对患者预后的显著益处。因此,了解 HFpEF 期间与代谢和年龄相关的炎症的细微差别对于采取更有针对性的干预措施至关重要。在此,我们回顾了高频低氧血症(HFpEF)中炎症的临床证据,并总结了我们对免疫代谢炎症的机理认识,同时强调了具有治疗潜力的途径。
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引用次数: 0
B Cell Responses to the Placenta and Fetus B 细胞对胎盘和胎儿的反应
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-09-12 DOI: 10.1146/annurev-pathmechdis-111523-023459
Gabrielle Rizzuto
Pregnancy has fascinated immunologists ever since Peter Medawar's observation that reproduction runs contrary to the founding tenets of immunology. During healthy pregnancy, maternal B cells interact with antigens of the foreign conceptus (placenta and fetus) yet do not elicit rejection. Instead, robust, and redundant fetomaternal tolerance pathways generally prevent maternal B cells and antibodies from harming the placenta and fetus. Fetomaternal tolerance is not absolute, and unfortunately there exist several pregnancy complications that arise from breaks therein. Here, important historic and recent developments in the field of fetomaternal tolerance pertaining to maternal B cells and antibodies are reviewed. General rules from which to conceptualize humoral tolerance to the placenta and fetus are proposed. Significant but underexplored ideas are highlighted and topics for future research are suggested, findings from which are predicted to provide insight into the fundamental nature of tolerance and bolster efforts to combat immune-mediated pregnancy complications.
自从彼得-梅达瓦(Peter Medawar)发现生殖与免疫学的基本原理相悖之后,妊娠就一直吸引着免疫学家。在健康妊娠期间,母体 B 细胞与外来胎儿(胎盘和胎儿)的抗原相互作用,但不会引起排斥反应。相反,强大且冗余的母胎耐受途径通常会阻止母体 B 细胞和抗体对胎盘和胎儿造成伤害。母体对胎儿的耐受性并非绝对,不幸的是,有几种妊娠并发症就是由于母体对胎儿的耐受性被破坏而引起的。在此,我们将回顾与母体 B 细胞和抗体有关的胎儿-母体耐受性领域的重要历史和最新进展。提出了胎盘和胎儿体液耐受性概念的一般规则。其中强调了一些重要但未被充分探索的观点,并提出了未来研究的主题,预计这些研究结果将有助于深入了解耐受性的基本性质,并为防治免疫介导的妊娠并发症做出贡献。
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引用次数: 0
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Annual Review of Pathology-Mechanisms of Disease
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