Annual Review of Pathology-Mechanisms of Disease最新文献

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.

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.

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.

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.

Tauopathies are a diverse group of progressive and fatal neurodegenerative diseases characterized by aberrant tau inclusions in the central nervous system. Tau protein forms pathologic fibrillar aggregates that are typically closely associated with neuronal cell death, leading to varied clinical phenotypes including dementia, movement disorders, and motor neuron disease. In this review, we describe the clinicopathologic features of tauopathies and highlight recent advances in understanding the mechanisms that lead to spread of pathologic aggregates through interconnected neuronal pathways. The cell-to-cell propagation of tauopathy is then linked to posttranslational modifications, tau fibril structural variants, and the breakdown of cellular protein quality control.

Over the last two decades the world has witnessed the global spread of two genetically related highly pathogenic coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. However, the impact of these outbreaks differed significantly with respect to the hospitalizations and fatalities seen worldwide. While many studies have been performed recently on SARS-CoV-2, a comparative pathogenesis analysis with SARS-CoV may further provide critical insights into the mechanisms of disease that drive coronavirus-induced respiratory disease. In this review, we comprehensively describe clinical and experimental observations related to transmission and pathogenesis of SARS-CoV-2 in comparison with SARS-CoV, focusing on human, animal, and in vitro studies. By deciphering the similarities and disparities of SARS-CoV and SARS-CoV-2, in terms of transmission and pathogenesis mechanisms, we offer insights into the divergent characteristics of these two viruses. This information may also be relevant to assessing potential novel introductions of genetically related highly pathogenic coronaviruses.

Many transcription factors (TFs) function as tumor suppressor genes with heterozygous phenotypes, yet haploinsufficiency generally has an underappreciated role in neoplasia. This is no less true in myeloid cells, which are normally regulated by a delicately balanced and interconnected transcriptional network. Detailed understanding of TF dose in this circuitry sheds light on the leukemic transcriptome. In this review, we discuss the emerging features of haploinsufficient transcription factors (HITFs). We posit that: (a) monoallelic and biallelic losses can have distinct cellular outcomes; (b) the activity of a TF exists in a greater range than the traditional Mendelian genetic doses; and (c) how a TF is deleted or mutated impacts the cellular phenotype. The net effect of a HITF is a myeloid differentiation block and increased intercellular heterogeneity in the course of myeloid neoplasia.

Among human leukocyte antigen (HLA)-associated disorders, celiac disease has an immunopathogenesis that is particularly well understood. The condition is characterized by hypersensitivity to cereal gluten proteins, and the disease lesion is localized in the gut. Still, the diagnosis can be made by detection of highly disease-specific autoantibodies to transglutaminase 2 in the blood. We now have mechanistic insights into how the disease-predisposing HLA-DQ molecules, via presentation of posttranslationally modified gluten peptides, are connected to the generation of these autoantibodies. This review presents our current understanding of the immunobiology of this common disorder that is positioned in the border zone between food hypersensitivity and autoimmunity.

This is the life story of Dr. Lucy B. Rorke-Adams, who was raised in the rural Midwest of the United States by Armenian immigrant parents during the Depression. The youngest in a family of five girls, she was lovingly nurtured by her parents and sisters. She was encouraged to become educated in order to lead a worthwhile life and contribute to society. She chose medicine, specifically the specialty of pediatric neuropathology, and over her long career succeeded in advancing the field. In particular, she made major contributions to understanding childhood brain tumors, central nervous system (CNS) malformations, and pathophysiology of abusive CNS injury in infants and children.