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Challenges and Opportunities in the Clinical Translation of High-Resolution Spatial Transcriptomics. Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-30 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.
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RNA Damage Responses in Cellular Homeostasis, Genome Stability, and Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-30 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
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Circadian Clocks, Daily Stress, and Neurodegenerative Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-18 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
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Multiple System Atrophy: Pathology, Pathogenesis, and Path Forward Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-15 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
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Pathogenesis of Germinal Matrix Hemorrhage: Insights from Single-Cell Transcriptomics Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-15 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
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Choroid Plexus Pathophysiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-09 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
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Cysteinyl Leukotrienes in Allergic Inflammation Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-07 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
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Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-02 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
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Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-02 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
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B Cell Responses to the Placenta and Fetus Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-09-12 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
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Wnt/β-Catenin Signaling in Liver Pathobiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-09-11 Matthew D. Carson, Kari Nejak-Bowen
The liver has a critical role in regulating host metabolism, immunity, detoxification, and homeostasis. Proper liver function is essential for host health, and dysregulation of hepatic signaling pathways can lead to the onset of disease. The Wnt/β-catenin signaling pathway is an important regulator of liver homeostasis and function. Throughout life, hepatic Wnt/β-catenin signaling contributes to liver
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Somatic Mosaicism in Brain Disorders Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-09-04 Rachel R. Corrigan, Lauren M. Mashburn-Warren, Hyojung Yoon, Tracy A. Bedrosian
Research efforts over the past decade have defined the genetic landscape of somatic variation in the brain. Neurons accumulate somatic mutations from development through aging with potentially profound functional consequences. Recent studies have revealed the contribution of somatic mosaicism to various brain disorders including focal epilepsy, neuropsychiatric disease, and neurodegeneration. One notable
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Reflections on a Career in Pediatric Neuropathology, with a Note of Gratitude Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-07-17 Hannah C. Kinney
I am honored to be asked by the journal to write this personal essay about my career in pediatric neuropathology—a life of immense satisfaction, meaning, and fulfillment. My motivation to enter this discipline is highlighted, as is my decision to perform brain research in the sudden infant death syndrome, the leading cause of postneonatal infant mortality in the United States today. I also touch upon
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Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-01-24 Hartmut Jaeschke, Anup Ramachandran
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
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Chance and Opportunity: A Personal Story Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-01-24 Abul K. Abbas
This article summarizes my personal life story, from early education in India to research, teaching, and other activities in Boston and San Francisco. I have tried to illustrate how unplanned events shape one's path, and why the willingness to go with the flow is among one's most valuable attributes.
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Pediatric Cholestatic Diseases: Common and Unique Pathogenic Mechanisms Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-01-24 Harry Sutton, Saul J. Karpen, Binita M. Kamath
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
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Neutrophils in Physiology and Pathology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-01-24 Alejandra Aroca-Crevillén, Tommaso Vicanolo, Samuel Ovadia, Andrés Hidalgo
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
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Haploinsufficient Transcription Factors in Myeloid Neoplasms Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-31 Tanner C. Martinez, Megan E. McNerney
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
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ENPP1 in Blood and Bone: Skeletal and Soft Tissue Diseases Induced by ENPP1 Deficiency Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-23 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
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Toward Explainable Artificial Intelligence for Precision Pathology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-23 Frederick Klauschen, Jonas Dippel, Philipp Keyl, Philipp Jurmeister, Michael Bockmayr, Andreas Mock, Oliver Buchstab, Maximilian Alber, Lukas Ruff, Grégoire Montavon, Klaus-Robert Müller
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
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Genome Instability and DNA Repair in Somatic and Reproductive Aging Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 Stephanie Panier, Siyao Wang, Björn Schumacher
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
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Cancer as a Disease of Development Gone Awry Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 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
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Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 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
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Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 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
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Comparative Pathogenesis of Severe Acute Respiratory Syndrome Coronaviruses Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 Jingshu Zhang, Melanie Rissmann, Thijs Kuiken, Bart L. Haagmans
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
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Hypoxia-Induced Signaling in Gut and Liver Pathobiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 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
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Neurodegenerative Disease Tauopathies Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 Benjamin C. Creekmore, Ryohei Watanabe, Edward B. Lee
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
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Role of the Microenvironment in Glioma Pathogenesis Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 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
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Epigenomic Characterization of Lymphoid Neoplasms Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-13 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
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Control of Cell Death in Health and Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-10-03 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
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Update on Epithelial-Mesenchymal Plasticity in Cancer Progression Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-09-27 Rosa Fontana, Aida Mestre-Farrera, Jing Yang
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
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Genetics and Pathogenesis of Dystonia Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-09-22 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,
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Antibody and B Cell Responses to SARS-CoV-2 Infection and Vaccination: The End of the Beginning Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-09-22 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
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Dynamic Multiplex Tissue Imaging in Inflammation Research Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-09-19 Stefan Uderhardt, Georgiana Neag, Ronald N. Germain
Inflammation is a highly dynamic process with immune cells that continuously interact with each other and parenchymal components as they migrate through tissue. The dynamic cellular responses and interaction patterns are a function of the complex tissue environment that cannot be fully reconstructed ex vivo, making it necessary to assess cell dynamics and changing spatial patterning in vivo. These
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Diffuse Pleural Mesothelioma: Advances in Molecular Pathogenesis, Diagnosis, and Treatment Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-09-19 Christopher A. Febres-Aldana, Rachel Fanaroff, Michael Offin, Marjorie G. Zauderer, Jennifer L. Sauter, Soo-Ryum Yang, Marc Ladanyi
Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in
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Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-01-24 Tomaz Martini, Felix Naef, Jan S. Tchorz
Hepatocytes are the main workers in the hepatic factory, managing metabolism of nutrients and xenobiotics, production and recycling of proteins, and glucose and lipid homeostasis. Division of labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar to distributed tasks at an assembly line. This so-called metabolic zonation has both spatial and
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My Journey Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-01-24 Lucy Balian Rorke-Adams
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
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Oropharyngeal Carcinoma with a Special Focus on HPV-Related Squamous Cell Carcinoma Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2023-01-24 Robert L. Ferris, William Westra
Human papillomavirus–positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system separates HPV-OPSCC from its HPV-negative counterpart to account for the improved prognosis seen in the former
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Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-11-09 Maya E. Kotas, Claire E. O'Leary, Richard M. Locksley
Tuft cells are found in tissues with distinct stem cell compartments, tissue architecture, and luminal exposures but converge on a shared transcriptional program, including expression of taste transduction signaling pathways. Here, we summarize seminal and recent findings on tuft cells, focusing on major categories of function—instigation of type 2 cytokine responses, orchestration of antimicrobial
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The Development and Consequences of Red Blood Cell Alloimmunization Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-11-09 Connie M. Arthur, Sean R. Stowell
While red blood cell (RBC) transfusion is the most common medical intervention in hospitalized patients, as with any therapeutic, it is not without risk. Allogeneic RBC exposure can result in recipient alloimmunization, which can limit the availability of compatible RBCs for future transfusions and increase the risk of transfusion complications. Despite these challenges and the discovery of RBC alloantigens
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Neuroepithelial Interactions in Cancer Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-11-02 Gustavo Ayala
Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of neural regulation of epithelial tissues. Cancer cells rarely develop in denervated organs, and denervation affects tumorigenesis, in vivo and in humans. Axonogenesis occurs to supply the new malignant epithelial growth with nerves. Neurogenesis
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Metabolism and Colorectal Cancer Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-11-02 Joseph C. Sedlak, Ömer H. Yilmaz, Jatin Roper
Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include
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Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-21 Xiaoqin Wu, Xiude Fan, Tatsunori Miyata, Adam Kim, Christina K. Cajigas-Du Ross, Semanti Ray, Emily Huang, Moyinoluwa Taiwo, Rakesh Arya, Jianguo Wu, Laura E. Nagy
Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the
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The Pathology of Asthma: What Is Obstructing Our View? Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-21 Helena Aegerter, Bart N. Lambrecht
Despite the advent of sophisticated and efficient new biologics to treat inflammation in asthma, the disease persists. Even following treatment, many patients still experience the well-known symptoms of wheezing, shortness of breath, and coughing. What are we missing? Here we examine the evidence that mucus plugs contribute to a substantial portion of disease, not only by physically obstructing the
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New Insights into the Pathogenesis of Mastocytosis: Emerging Concepts in Diagnosis and Therapy Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-21 Peter Valent, Cem Akin, Wolfgang R. Sperr, Hans-Peter Horny, Michel Arock, Dean D. Metcalfe, Stephen J. Galli
Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated
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After the Storm: Regeneration, Repair, and Reestablishment of Homeostasis Between the Alveolar Epithelium and Innate Immune System Following Viral Lung Injury Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-21 Joseph D. Planer, Edward E. Morrisey
The mammalian lung has an enormous environmental-epithelial interface that is optimized to accomplish the principal function of the respiratory system, gas exchange. One consequence of evolving such a large surface area is that the lung epithelium is continuously exposed to toxins, irritants, and pathogens. Maintaining homeostasis in this environment requires a delicate balance of cellular signaling
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Common Variable Immunodeficiency: More Pathways than Roads to Rome Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-21 Xiao P. Peng, Andrés Caballero-Oteyza, Bodo Grimbacher
Fifty years have elapsed since the term common variable immunodeficiency (CVID) was introduced to accommodate the many and varied antibody deficiencies being identified in patients with suspected inborn errors of immunity (IEIs). Since then, how the term is understood and applied for diagnosis and management has undergone many revisions, though controversy persists on how exactly to define and classify
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Osteoclasts, Master Sculptors of Bone Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-07 Deborah J. Veis, Charles A. O'Brien
Osteoclasts are multinucleated cells with the unique ability to resorb bone matrix. Excessive production or activation of osteoclasts leads to skeletal pathologies that affect a significant portion of the population. Although therapies that effectively target osteoclasts have been developed, they are associated with sometimes severe side effects, and a fuller understanding of osteoclast biology may
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Orchestration of Collective Migration and Metastasis by Tumor Cell Clusters Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-07 Ami Yamamoto, Andrea E. Doak, Kevin J. Cheung
Metastatic dissemination has lethal consequences for cancer patients. Accruing evidence supports the hypothesis that tumor cells can migrate and metastasize as clusters of cells while maintaining contacts with one another. Collective metastasis enables tumor cells to colonize secondary sites more efficiently, resist cell death, and evade the immune system. On the other hand, tumor cell clusters face
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Tumor-Derived Extracellular Vesicles: Multifunctional Entities in the Tumor Microenvironment Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-10-06 James W. Clancy, Crislyn D'Souza-Schorey
Tumor cells release extracellular vesicles (EVs) that can function as mediators of intercellular communication in the tumor microenvironment. EVs contain a host of bioactive cargo, including membrane, cytosolic, and nuclear proteins, in addition to noncoding RNAs, other RNA types, and double-stranded DNA fragments. These shed vesicles may deposit paracrine information and can also be taken up by stromal
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Pathogenesis of Zika Virus Infection Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-24 Maria I. Giraldo, Maria Gonzalez-Orozco, Ricardo Rajsbaum
Zika virus (ZIKV) is an emerging virus from the Flaviviridae family that is transmitted to humans by mosquito vectors and represents an important health problem. Infections in pregnant women are of major concern because of potential devastating consequences during pregnancy and have been associated with microcephaly in newborns. ZIKV has a unique ability to use the host machinery to promote viral replication
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Molecular Monitoring of Lymphomas Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-21 Joseph G. Schroers-Martin, Stefan Alig, Andrea Garofalo, Benoit Tessoulin, Takeshi Sugio, Ash A. Alizadeh
Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the
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Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-21 Mara H. Sherman, Gregory L. Beatty
Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights
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Genetics and Pathogenesis of Parkinson's Syndrome Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-13 Hui Ye, Laurie A. Robak, Meigen Yu, Matthew Cykowski, Joshua M. Shulman
Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly
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Adipose Tissue Remodeling in Pathophysiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-07 Christopher Auger, Shingo Kajimura
Rather than serving as a mere onlooker, adipose tissue is a complex endocrine organ and active participant in disease initiation and progression. Disruptions of biological processes operating within adipose can disturb healthy systemic physiology, the sequelae of which include metabolic disorders such as obesity and type 2 diabetes. A burgeoning interest in the field of adipose research has allowed
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The Immunobiology and Pathogenesis of Celiac Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-06 Rasmus Iversen, Ludvig M. Sollid
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
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The Pathogenesis of African Trypanosomiasis Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-09-03 Etienne Pays, Magdalena Radwanska, Stefan Magez
African trypanosomes are bloodstream protozoan parasites that infect mammals including humans, where they cause sleeping sickness. Long-lasting infection is required to favor parasite transmission between hosts. Therefore, trypanosomes have developed strategies to continuously escape innate and adaptive responses of the immune system, while also preventing premature death of the host. The pathology
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Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-01-24 Benjamin J. Moss, Stefan W. Ryter, Ivan O. Rosas
The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial
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Engineering β Cell Replacement Therapies for Type 1 Diabetes: Biomaterial Advances and Considerations for Macroscale Constructs Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-01-24 Michelle J. Quizon, Andrés J. García
While significant progress has been made in treatments for type 1 diabetes (T1D) based on exogenous insulin, transplantation of insulin-producing cells (islets or stem cell–derived β cells) remains a promising curative strategy. The current paradigm for T1D cell therapy is clinical islet transplantation (CIT)—the infusion of islets into the liver—although this therapeutic modality comes with its own
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Lysophospholipid Mediators in Health and Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2022-01-24 Kuniyuki Kano, Junken Aoki, Timothy Hla
Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein–coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes