Reviews
Pathogenesis of Pulmonary Calcification and Homologies with Biomineralization in Other Tissues
Lungs often present tissue calcifications and even ossifications, both in the context of high or normal serum calcium levels. Precise mechanisms governing lung calcifications have not been explored. Herein, we emphasize recent advances about calcification processes in other tissues (especially vascular and bone calcifications) and discuss potential sources of calcium precipitates in the lungs, involvement of mineralization promoters and crystallization inhibitors, as well as specific cytokine milieu and cellular phenotypes characteristic for lung diseases, which may be involved in pulmonary calcifications.Natural Language Processing in Pathology: Current Trends and Future Insights
Natural language processing (NLP) plays a key role in advancing health care, being key to extracting structured information from electronic health reports. In the last decade, several advances in the field of pathology have been derived from the application of NLP to pathology reports. Herein, a comprehensive review of the most used NLP methods for extracting, coding, and organizing information from pathology reports is presented, including how the development of tools is used to improve workflow.The Inflammasome NLR Family Pyrin Domain-Containing Protein 3 (NLRP3) as a Novel Therapeutic Target for Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a dramatic disease without cure. The US Food and Drug Administration–approved drugs, pirfenidone and nintedanib, only slow disease progression. The clinical investigation of novel therapeutic approaches for IPF is an unmet clinical need. Nucleotide-binding oligomerization domain-like receptor or NOD-like receptors are pattern recognition receptors capable of binding a large variety of stress factors. NLR family pyrin domain-containing protein 3 (NLRP3), once activated, promotes IL-1β, IL-18 production, and innate immune responses.The Functional Roles of Immune Cells in Primary Liver Cancer
Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Incidence of liver cancer has been increasing in recent years, and the 5-year survival is <20%. HCC and CCA are often accompanied with a dense stroma coupled with infiltrated immune cells, which is referred to as the tumor microenvironment. Populations of specific immune cells, such as high density of CD163+ macrophages and low density of CD8+ T cells, are associated with prognosis and survival rates in both HCC and CCA.NELL-1 in Genome-Wide Association Studies across Human Diseases
Neural epidermal growth factor–like (EGFL)-like protein (NELL)-1 is a potent and key osteogenic factor in the development and regeneration of skeletal tissues. Intriguingly, accumulative data from genome-wide association studies (GWASs) have started unveiling potential broader roles of NELL-1 beyond its functions in bone and cartilage. With exploration of the genetic variants of the entire genome in large-scale disease cohorts, GWASs have been used for establishing the connection between specific single-nucleotide polymorphisms of NELL1, in addition to osteoporosis, metabolic diseases, inflammatory conditions, neuropsychiatric diseases, neurodegenerative disorders, and malignant tumors.Osteochondroma Pathogenesis: Mouse Models and Mechanistic Insights into Interactions with Retinoid Signaling
Osteochondromas are cartilage-capped tumors that arise near growing physes and are the most common benign bone tumor in children. Osteochondromas can lead to skeletal deformity, pain, loss of motion, and neurovascular compression. Currently, surgery is the only available treatment for symptomatic osteochondromas. Osteochondroma mouse models have been developed to understand the pathology and the origin of osteochondromas and develop therapeutic drugs. Several cartilage regulatory pathways have been implicated in the development of osteochondromas, such as bone morphogenetic protein, hedgehog, and WNT/β-catenin signaling.Slide Over: Advances in Slide-Free Optical Microscopy as Drivers of Diagnostic Pathology
Conventional analysis using clinical histopathology is based on bright-field microscopy of thinly sliced tissue specimens. Although bright-field microscopy is a simple and robust method of examining microscope slides, the preparation of the slides needed is a lengthy and labor-intensive process. Slide-free histopathology, however, uses direct imaging of intact, minimally processed tissue samples using advanced optical-imaging systems, bypassing the extended workflow now required for the preparation of tissue sections.Targeting Lymphangiogenesis and Lymph Node Metastasis in Liver Cancer
Increased lymphangiogenesis and lymph node metastasis, the important prognostic indicators of aggressive hepatobiliary malignancies such as hepatocellular cancer and cholangiocarcinoma, are associated with poor patient outcome. The liver produces 25% to 50% of total lymphatic fluid in the body and has a dense network of lymphatic vessels. The lymphatic system plays critical roles in fluid homeostasis and inflammation and immune response. Yet, lymphatic vessel alterations and function are grossly understudied in the context of liver pathology.Interplay between Brain Pericytes and Endothelial Cells in Dementia
Prevalence of dementia continues to increase because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit, in particular the blood-brain barrier (BBB), is required for maintaining brain homeostasis. A complex interaction exists among the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit.Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease
Alzheimer disease (AD) is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology, and neurodegeneration. However, current evidence suggests that various features of small vessel disease (SVD) are part of and covertly modify both sporadic and familial AD. Neuroimaging studies suggest that white matter hyperintensities explained by vascular mechanisms occurs frequently in the AD spectrum. Recent advances have further emphasized that frontal periventricular and posterior white matter hyperintensities are associated with cerebral amyloid angiopathy in familial AD.Ethics of AI in Pathology: Current Paradigms and Emerging Issues
Deep learning has rapidly advanced artificial intelligence (AI) and algorithmic decision-making (ADM) paradigms, affecting many traditional fields of medicine, including pathology, which is a heavily data-centric specialty of medicine. The structured nature of pathology data repositories makes it highly attractive to AI researchers to train deep learning models to improve health care delivery. Additionally, there are enormous financial incentives driving adoption of AI and ADM due to promise of increased efficiency of the health care delivery process.Understanding the Role of Blood Vessels in the Neurologic Manifestations of Coronavirus Disease 2019 (COVID-19)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally identified as an outbreak in Wuhan, China, toward the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and Middle East respiratory syndrome (MERS), concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain barrier.The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change
The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems.The Role of Estrogen in Insulin Resistance: A Review of Clinical and Preclinical Data
Insulin resistance results when peripheral tissues, including adipose, skeletal muscle, and liver, do not respond appropriately to insulin, causing the ineffective uptake of glucose. This represents a risk factor for the development of type 2 diabetes mellitus. Along with abdominal obesity, hypertension, high levels of triglycerides, and low levels of high-density lipoproteins, insulin resistance is a component of a condition known as the metabolic syndrome, which significantly increases the risk of developing cardiometabolic disorders.The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third leading cause of cancer-related deaths worldwide. Liver resection or liver transplantation is the most effective therapy for HCC because drugs approved by the US Food and Drug Administration to treat patients with unresectable HCC have an unfavorable overall survival rate. Therefore, the development of biomarkers for early diagnosis and effective therapy strategies are still necessary to improve patient outcomes.ACE2 Down-Regulation May Act as a Transient Molecular Disease Causing RAAS Dysregulation and Tissue Damage in the Microcirculatory Environment Among COVID-19 Patients
Severe acute respiratory syndrome coronavirus 2, the etiologic agent of coronavirus disease 2019 (COVID-19) and the cause of the current pandemic, produces multiform manifestations throughout the body, causing indiscriminate damage to multiple organ systems, particularly the lungs, heart, brain, kidney, and vasculature. The aim of this review is to provide a new assessment of the data already available for COVID-19, exploring it as a transient molecular disease that causes negative regulation of angiotensin-converting enzyme 2, and consequently, deregulates the renin-angiotensin-aldosterone system, promoting important changes in the microcirculatory environment.Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases
Mutations in the NOTCH3 gene can lead to small-vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations altering the number of cysteine residues in the extracellular domain of Notch3. Growing evidence indicates that other types of mutations in NOTCH3, including cysteine-sparing missense mutations or frameshift and premature stop codons, can lead to small-vessel disease phenotypes of variable severity or penetrance.Hepcidin and Iron Metabolism in Experimental Liver Injury
The liver plays a pivotal role in the regulation of iron metabolism through its ability to sense and respond to iron stores by release of the hormone hepcidin. Under physiologic conditions, regulation of hepcidin expression in response to iron status maintains iron homeostasis. In response to tissue injury, hepcidin expression can be modulated by other factors, such as inflammation and oxidative stress. The resulting dysregulation of hepcidin is proposed to account for alterations in iron homeostasis that are sometimes observed in patients with liver disease.Exploring the Potential of Breast Microbiota as Biomarker for Breast Cancer and Therapeutic Response
Breast cancer tissue contains its own unique microbiota. Emerging preclinical data indicates that breast microbiota dysbiosis contributes to breast cancer initiation and progression. Furthermore, the breast microbiota may be a promising biomarker for treatment selection and prognosis. Differences in breast microbiota composition have been found between breast cancer subtypes and disease severities that may contribute to immunosuppression, enabling tumor cells to evade immune destruction. Interactions between breast microbiota, gut microbiota, and immune system are proposed, all forming potential targets to increase therapeutic efficacy.Endothelial Nitric Oxide Synthase–Deficient Mice: A Model of Spontaneous Cerebral Small-Vessel Disease
Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)–deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age.Endothelial Control of Cerebral Blood Flow
Since constant perfusion of blood throughout the brain is critical for neuronal health, the regulation of cerebral blood flow is complex and highly controlled. This regulation is controlled, in part, by the cerebral endothelium. In this review, multiple modes of endothelium-derived blood flow regulation is discussed, including chemical control of vascular tone, heterotypic and homotypic cell-cell interactions, second messenger signaling, and cellular response to physical forces and inflammatory mediators.Statistical Methods in Experimental Pathology: A Review and Primer
Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests.Overlapping Protein Accumulation Profiles of CADASIL and CAA: Is There a Common Mechanism Driving Cerebral Small-Vessel Disease?
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral amyloid angiopathy (CAA) are two distinct vascular angiopathies that share several similarities in clinical presentation and vascular pathology. Given the clinical and pathologic overlap, the molecular overlap between CADASIL and CAA was explored. CADASIL and CAA protein profiles from recently published proteomics-based and immuno-based studies were compared to investigate the potential for shared disease mechanisms.Effects of Electronic Nicotine Delivery Systems and Cigarettes on Systemic Circulation and Blood-Brain Barrier: Implications for Cognitive Decline
Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are twofold, as these products may represent a novel source of tobacco-associated disease but may also provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Herein, we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and implications for blood-brain barrier dysfunction and cognitive decline.Animal and Cell Culture Models for Cystic Fibrosis: Which Model Is Right for Your Application?
Over the past 30 years, a range of cystic fibrosis (CF) animal models have been generated for research purposes. Different species, including mice, rats, ferrets, rabbits, pigs, sheep, zebrafish, and fruit flies, have all been used to model CF disease. While access to such a variety of animal models is a luxury for any research field, it also complicates the decision-making process when it comes to selecting the right model for an investigation. The purpose of this review is to provide a guide for selecting the most appropriate CF animal model for any given application.
