Annual Review of Pathology-Mechanisms of Disease最新文献

Infections, cardiovascular disease, and cancer are major causes of disease and death worldwide. Neutrophils are inescapably associated with each of these health concerns, by either protecting from, instigating, or aggravating their impact on the host. However, each of these disorders has a very different etiology, and understanding how neutrophils contribute to each of them requires understanding the intricacies of this immune cell type, including their immune and nonimmune contributions to physiology and pathology. Here, we review some of these intricacies, from basic concepts in neutrophil biology, such as their production and acquisition of functional diversity, to the variety of mechanisms by which they contribute to preventing or aggravating infections, cardiovascular events, and cancer. We also review poorly explored aspects of how neutrophils promote health by favoring tissue repair and discuss how discoveries about their basic biology inform the development of new therapeutic strategies.

The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP_i) 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.

Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.

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.

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.

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.

The rapid development of precision medicine in recent years has started to challenge diagnostic pathology with respect to its ability to analyze histological images and increasingly large molecular profiling data in a quantitative, integrative, and standardized way. Artificial intelligence (AI) and, more precisely, deep learning technologies have recently demonstrated the potential to facilitate complex data analysis tasks, including clinical, histological, and molecular data for disease classification; tissue biomarker quantification; and clinical outcome prediction. This review provides a general introduction to AI and describes recent developments with a focus on applications in diagnostic pathology and beyond. We explain limitations including the black-box character of conventional AI and describe solutions to make machine learning decisions more transparent with so-called explainable AI. The purpose of the review is to foster a mutual understanding of both the biomedical and the AI side. To that end, in addition to providing an overview of the relevant foundations in pathology and machine learning, we present worked-through examples for a better practical understanding of what AI can achieve and how it should be done.

Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.

Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging.

Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells lose their characteristics and acquire mesenchymal traits to promote cell movement. This program is aberrantly activated in human cancers and endows tumor cells with increased abilities in tumor initiation, cell migration, invasion, metastasis, and therapy resistance. The EMT program in tumors is rarely binary and often leads to a series of gradual or intermediate epithelial-mesenchymal states. Functionally, epithelial-mesenchymal plasticity (EMP) improves the fitness of cancer cells during tumor progression and in response to therapies. Here, we discuss the most recent advances in our understanding of the diverse roles of EMP in tumor initiation, progression, metastasis, and therapy resistance and address major clinical challenges due to EMP-driven phenotypic heterogeneity in cancer. Uncovering novel molecular markers and key regulators of EMP in cancer will aid the development of new therapeutic strategies to prevent cancer recurrence and overcome therapy resistance.