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Hypoxia-Induced Signaling in Gut and Liver Pathobiology. 缺氧诱导的肠道信号传导和肝脏病理生物学。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-13 DOI: 10.1146/annurev-pathmechdis-051122-094743
Sumeet Solanki, Yatrik M Shah

Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.

氧气(O2)对细胞代谢和生物化学反应至关重要。当氧气的需求超过供应时,就会发生缺氧。缺氧诱导因子(HIFs)对激活缺氧应激后的适应性和生存反应至关重要。在肠道和肝脏中,氧气梯度或生理性缺氧是维持正常稳态所必需的。虽然生理性缺氧是有益的,有助于正常功能,但病理性缺氧是有害的,因为它会加剧炎症反应和组织功能障碍,是许多癌症的标志。在这篇综述中,我们讨论了肠道和肝脏缺氧诱导的信号传导,主要集中在HIFs,在肠道和肝脏疾病的生理学和病理生物学中的作用。此外,我们还检测了HIFs在肠道和肝脏疾病期间各种细胞类型中的功能,而不仅仅是肠上皮和肝细胞HIFs。这篇综述强调了理解缺氧诱导的信号在肠道和肝脏疾病发病机制中的重要性,并强调了HIFs作为治疗靶点的潜力。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection. 急性和慢性感染中细菌病原体的宿主内进化。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-13 DOI: 10.1146/annurev-pathmechdis-051122-111408
John P Dekker

Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity. The host immune response provides another critical component of the fitness landscapes guiding adaptation, and selection operating on pathogens at this level may lead to immune evasion and the establishment of chronic infection. This review summarizes recent advances in this field, with a special focus on different forms of bacterial genome plasticity in the context of infection, and considers clinical consequences of adaptive changes for the host.

细菌病原体在宿主定植和感染过程中遇到选择性力,会发生显著的适应性变化。过去几十年的研究表明,在宿主适应过程中,可以识别出许多一般的进化过程,包括谱系的遗传多样性、克隆演替事件、趋同进化和平衡适应度权衡。在某些情况下,错配修复或校对缺陷导致的突变率升高会加速进化,而活跃的可移动遗传元件或噬菌体可能有助于基因组的可塑性。宿主免疫反应提供了指导适应的适应景观的另一个关键组成部分,在这个水平上对病原体进行选择可能导致免疫逃避和慢性感染的建立。这篇综述总结了该领域的最新进展,特别关注感染背景下不同形式的细菌基因组可塑性,并考虑了宿主适应性变化的临床后果。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Control of Cell Death in Health and Disease. 控制健康和疾病中的细胞死亡。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-03 DOI: 10.1146/annurev-pathmechdis-051022-014433
Nobuhiko Kayagaki, Joshua D Webster, Kim Newton

Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.

细胞凋亡、坏死和pyroptosis是基因编程的细胞死亡机制,可消除过时、受损、感染和自我反应的细胞。细胞凋亡以限制免疫细胞激活的方式使细胞碎片化,而坏死和焦下垂的裂解性死亡程序释放促炎细胞内内容物。细胞凋亡在哺乳动物发育过程中微调组织结构,促进组织稳态,对避免癌症和自身免疫至关重要。所有三种细胞死亡机制都是为了阻止病原体的传播。禁用小鼠细胞死亡信号的调节因子揭示了过度的细胞死亡如何助长急性或慢性炎症。在这里,我们回顾了在疾病背景下调节细胞死亡的策略。例如,BCL-2抑制剂venetoclax,一种细胞凋亡诱导剂,被批准用于治疗某些血液系统恶性肿瘤。相反,抑制RIPK1、NLRP3、GSDMD或NINJ1以限制促炎细胞死亡和/或从垂死细胞释放大的促炎分子可能有益于炎症性疾病患者。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy. 克隆性造血、炎症和血液系统恶性肿瘤。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-13 DOI: 10.1146/annurev-pathmechdis-051222-122724
Rashmi Kanagal-Shamanna, David B Beck, Katherine R Calvo

Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.

体细胞或获得性突变是合子后的遗传变异,可以发生在任何组织中。这些突变在衰老过程中积累,通常与恶性过程有关。过去几年的巨大进步使人们对体细胞突变在良性和恶性年龄相关疾病中的作用有了更深入的了解。在这里,我们回顾了血液中积累的体细胞突变及其与疾病状态的联系,特别关注炎症性疾病和骨髓增生异常综合征。我们包括克隆性造血(CH)的定义,以及这些突变的起源和意义的概述。此外,我们强调具有重叠炎症的躯体疾病和CH以外的血液系统疾病,包括阵发性夜间血红蛋白尿和再生障碍性贫血,重点关注VEXAS(液泡、E1酶、X-连锁、自身炎症、躯体)综合征。最后,我们对体细胞突变在临床血液学、病理学及其他方面的意义提供了一个实用的观点。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Role of the Microenvironment in Glioma Pathogenesis. 微环境在胶质瘤发病机制中的作用。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-13 DOI: 10.1146/annurev-pathmechdis-051122-110348
Maya Anjali Jayaram, Joanna J Phillips

Gliomas are a diverse group of primary central nervous system tumors that affect both children and adults. Recent studies have revealed a dynamic cross talk that occurs between glioma cells and components of their microenvironment, including neurons, astrocytes, immune cells, and the extracellular matrix. This cross talk regulates fundamental aspects of glioma development and growth. In this review, we discuss recent discoveries about the impact of these interactions on gliomas and highlight how tumor cells actively remodel their microenvironment to promote disease. These studies provide a better understanding of the interactions in the microenvironment that are important in gliomas, offer insight into the cross talk that occurs, and identify potential therapeutic vulnerabilities that can be utilized to improve clinical outcomes.

胶质瘤是一组多样的原发性中枢神经系统肿瘤,影响儿童和成人。最近的研究揭示了神经胶质瘤细胞与其微环境组成部分之间发生的动态串扰,包括神经元、星形胶质细胞、免疫细胞和细胞外基质。这种串扰调节神经胶质瘤发育和生长的基本方面。在这篇综述中,我们讨论了这些相互作用对胶质瘤影响的最新发现,并强调了肿瘤细胞如何主动重塑其微环境以促进疾病。这些研究更好地了解了胶质瘤中重要的微环境中的相互作用,深入了解了发生的串扰,并确定了可用于改善临床结果的潜在治疗漏洞。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Epigenomic Characterization of Lymphoid Neoplasms. 淋巴肿瘤的表观基因组特征。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-13 DOI: 10.1146/annurev-pathmechdis-051122-100856
Martí Duran-Ferrer, José Ignacio Martín-Subero

Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.

淋巴肿瘤代表了一组具有明显不同分子和临床特征的异质性疾病实体和亚型。除了基因改变外,淋巴肿瘤还表现出广泛的表观基因组变化。这些严重影响DNA甲基化、组蛋白修饰、染色质可及性和三维基因组相互作用的水平和分布。DNA甲基化是细胞身份和记忆的示踪剂,因为B细胞肿瘤显示出其细胞起源和增殖史的表观遗传印记,这可以通过表观遗传有丝分裂时钟来量化。染色质相关标记有助于揭示导致不同淋巴肿瘤发展的调节区和转录因子网络的改变。肿瘤内在的表观遗传和遗传畸变与微环境细胞合作并相互作用,在淋巴瘤进化的不同阶段形成转录组,现在可以通过单细胞图谱来表征克隆内的异质性。最后,表观遗传学提供了多种临床应用,包括强大的诊断和预后生物标志物以及治疗靶点。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
ENPP1 in Blood and Bone: Skeletal and Soft Tissue Diseases Induced by ENPP1 Deficiency. 血液和骨骼中的ENPP1:由ENPP1缺乏引起的骨骼和软组织疾病。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-23 DOI: 10.1146/annurev-pathmechdis-051222-121126
Carlos R Ferreira, Thomas O Carpenter, Demetrios T Braddock

The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PPi) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.

外核苷酸焦磷酸酶/磷酸二酯酶-1(ENPP1)编码2型跨膜糖蛋白,该糖蛋白水解细胞外ATP产生焦磷酸(PPi)和单磷酸腺苷,从而促进下游嘌呤能信号通路。ENPP1缺乏引起的临床表型似乎是矛盾的,包括中年人的早发性骨质疏松症和婴儿大动脉中危及生命的血管钙化以及婴儿期的广泛动脉钙化。软组织的渐进性过度矿化和骨骼的同时矿化不足也发生在普通医学人群中,这被称为反常矿化,以突出令人困惑的病理生理学。这篇综述总结了ENPP1缺乏引起的反常矿化的临床表现和病理生理学,以及一种新的ENPP1生物制剂的研发,该制剂旨在治疗罕见病和普通医学人群中的矿化障碍。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Antibody and B Cell Responses to SARS-CoV-2 Infection and Vaccination: The End of the Beginning. 抗体和B细胞对严重急性呼吸系统综合征冠状病毒2型感染的反应和疫苗接种:开始的结束。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-09-22 DOI: 10.1146/annurev-pathmechdis-031521-042754
Katharina Röltgen, Scott D Boyd

As the COVID-19 pandemic has evolved during the past years, interactions between human immune systems, rapidly mutating and selected SARS-CoV-2 viral variants, and effective vaccines have complicated the landscape of individual immunological histories. Here, we review some key findings for antibody and B cell-mediated immunity, including responses to the highly mutated omicron variants; immunological imprinting and other impacts of successive viral antigenic variant exposures on antibody and B cell memory; responses in secondary lymphoid and mucosal tissues and non-neutralizing antibody-mediated immunity; responses in populations vulnerable to severe disease such as those with cancer, immunodeficiencies, and other comorbidities, as well as populations showing apparent resistance to severe disease such as many African populations; and evidence of antibody involvement in postacute sequelae of infection or long COVID. Despite the initial phase of the pandemic ending, human populations will continue to face challenges presented by this unpredictable virus.

随着新冠肺炎大流行在过去几年的演变,人类免疫系统、快速变异和选择的SARS-CoV-2病毒变体以及有效疫苗之间的相互作用使个体免疫史的前景变得复杂。在这里,我们回顾了抗体和B细胞介导的免疫的一些关键发现,包括对高度突变的奥密克戎变体的反应;免疫印迹和连续的病毒抗原变体暴露对抗体和B细胞记忆的其他影响;次级淋巴和粘膜组织的反应以及非中和抗体介导的免疫;易患严重疾病的人群,如患有癌症、免疫缺陷和其他合并症的人群,以及对严重疾病表现出明显耐药性的人群,例如许多非洲人群的反应;以及抗体参与感染或长期新冠肺炎急性后遗症的证据。尽管疫情的最初阶段已经结束,但人类将继续面临这种不可预测的病毒带来的挑战。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Genetics and Pathogenesis of Dystonia. 营养不良的遗传学和发病机制。
IF 36.2 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-09-22 DOI: 10.1146/annurev-pathmechdis-051122-110756
Mirja Thomsen, Lara M Lange, Michael Zech, Katja Lohmann

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., KMT2B, THAP1), calcium homeostasis (e.g., ANO3, HPCA), striatal dopamine signaling (e.g., GNAL), endoplasmic reticulum stress response (e.g., EIF2AK2, PRKRA, TOR1A), autophagy (e.g., VPS16), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.

肌张力障碍是一种临床和遗传上高度异质性的神经系统疾病,其特征是由非自愿的持续或间歇性肌肉收缩引起的异常运动和姿势。最近获得了许多突破性的遗传和分子见解。尽管它们能够进行基因检测和咨询,但它们转化为新疗法的能力仍然有限。然而,我们开始了解共同的病理生理途径和分子机制。肌张力障碍是由基底神经节、小脑、丘脑和皮层的功能失调网络引起的。在分子水平上,超过少数通常相互交织的途径与肌张力障碍基因的致病性变体有关,包括神经发育过程中的基因转录(如KMT2B、THAP1)、钙稳态(如ANO3、HPCA)、纹状体多巴胺信号传导(如GNAL)、内质网应激反应(如EIF2AK2、PRKRA、TOR1A)、自噬(如VPS16)等。因此,不同形式的肌张力障碍可以在分子上进行分组,这可能有助于未来的治疗发展。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Cancer as a Disease of Development Gone Awry. 癌症作为一种发展中的疾病已经过时。
IF 28.4 1区 医学 Q1 PATHOLOGY Pub Date : 2024-01-24 Epub Date: 2023-10-13 DOI: 10.1146/annurev-pathmechdis-031621-025610
Ben Z Stanger, Geoffrey M Wahl

In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulates embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution.

Rudolf Virchow首次假设肿瘤是由调节胚胎发育的同一定律引起的,在这160年里,科学家们已经认识到癌症和胚胎所使用的分子和细胞程序之间的惊人重叠。癌症生物学和分子技术的进展进一步突出了致癌作用和胚胎发生之间的相似性,其中细胞生长、分化、运动和细胞间串扰是由共同的驱动因素和调节网络介导的。这篇综述强调了癌症生物学和发育生物学之间的许多联系,以更深入地了解组织的发育史如何既能促进又能限制癌症细胞的进化。《病理学年度评论:疾病机制》第19卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
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Annual Review of Pathology-Mechanisms of Disease
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