Mini Reviews
Artificial Intelligence and Cellular Segmentation in Tissue Microscopy Images
With applications in object detection, image feature extraction, image classification, and image segmentation, artificial intelligence is facilitating high-throughput analysis of image data in a variety of biomedical imaging disciplines, ranging from radiology and pathology to cancer biology and immunology. Specifically, a growth in research on deep learning has led to the widespread application of computer-visualization techniques for analyzing and mining data from biomedical images. The availability of open-source software packages and the development of novel, trainable deep neural network architectures has led to increased accuracy in cell detection and segmentation algorithms.Dealing with Multi-Dimensional Data and the Burden of Annotation: Easing the Burden of Annotation
The need for huge data sets represents a bottleneck for the application of artificial intelligence. Substantially fewer annotated target lesions than normal tissues for comparison present an additional problem in the field of pathology. Organic brains overcome these limitations by utilizing large numbers of specialized neural nets arranged in both linear and parallel fashion, with each solving a restricted classification problem. They rely on local Hebbian error corrections as compared to the nonlocal back-propagation used in most artificial neural nets, and leverage reinforcement.Machine-Learning–Based Evaluation of Intratumoral Heterogeneity and Tumor-Stroma Interface for Clinical Guidance
Assessment of intratumoral heterogeneity and tumor-host interaction within the tumor microenvironment is becoming increasingly important for innovative cancer therapy decisions because of the unique information it can generate about the state of the disease. However, its assessment and quantification are limited by ambiguous definitions of the tumor-host interface and by human cognitive capacity in current pathology practice. Advances in machine learning and artificial intelligence have opened the field of digital pathology to novel tissue image analytics and feature extraction for generation of high-capacity computational disease management models.Generative Deep Learning in Digital Pathology Workflows
Many modern histopathology laboratories are in the process of digitizing their workflows. Digitization of tissue images has made it feasible to research the augmentation or automation of clinical reporting and diagnosis. The application of modern computer vision techniques, based on deep learning, promises systems that can identify pathologies in slide images with a high degree of accuracy. Generative modeling is an approach to machine learning and deep learning that can be used to transform and generate data.Extracellular Vesicles and Renal Endothelial Cells: A Fatal Attraction in Hemolytic Uremic Syndrome
This review focuses on typical hemolytic uremic syndrome (HUS), a life-threatening sequela of human infections caused, particularly in children, by Shiga toxin–producing Escherichia coli strains. Thrombotic microangiopathy of the brain and the kidney is the end point of toxin action, resulting in the hallmarks of HUS (ie, thrombocytopenia, anemia, and acute renal failure). A growing body of evidence points to the role of extracellular vesicles released in the blood of patients by toxin-challenged circulating cells (monocytes, neutrophils, and erythrocytes) and platelets, as a key factor in the pathogenesis of HUS.Searching Images for Consensus: Can AI Remove Observer Variability in Pathology?
One of the major obstacles in reaching diagnostic consensus is observer variability. With the recent success of artificial intelligence, particularly the deep networks, the question emerges as to whether the fundamental challenge of diagnostic imaging can now be resolved. This article briefly reviews the problem and how eventually both supervised and unsupervised AI technologies could help to overcome it.White Matter Lesions in Migraine
Migraine, the third most common disease worldwide, is a well-known independent risk factor for subclinical focal deep white matter lesions (WMLs), even in young and otherwise healthy individuals with no cardiovascular risk factors. These WMLs are more commonly seen in migraine patients with transient neurologic symptoms preceding their headaches, the so-called aura, and those with a high attack frequency. The pathophysiology of migraine-related deep white matter hyperintensities remains poorly understood despite their prevalence.Challenges in the Development, Deployment, and Regulation of Artificial Intelligence in Anatomic Pathology
Significant advances in artificial intelligence (AI), deep learning, and other machine-learning approaches have been made in recent years, with applications found in almost every industry, including health care. AI is capable of completing a spectrum of mundane to complex medically oriented tasks previously performed only by boarded physicians, most recently assisting with the detection of cancers difficult to find on histopathology slides. Although computers will likely not replace pathologists any time soon, properly designed AI-based tools hold great potential for increasing workflow efficiency and diagnostic accuracy in pathology.Endoplasmic Reticulum Calcium Homeostasis in Kidney Disease: Pathogenesis and Therapeutic Targets
Calcium (Ca2+) homeostasis is a crucial determinant of cellular function and survival. Endoplasmic reticulum (ER) acts as the largest intracellular Ca2+ store that maintains Ca2+ homeostasis through the ER Ca2+ uptake pump, sarco/ER Ca2+ ATPase, ER Ca2+ release channels, inositol 1,4,5-trisphosphate receptor channel, ryanodine receptor, and Ca2+-binding proteins inside of the ER lumen. Alterations in ER homeostasis trigger ER Ca2+ depletion and ER stress, which have been associated with the development of a variety of diseases.Angiotensin-Converting Enzyme Gene Polymorphism and Severe Lung Injury in Patients with Coronavirus Disease 2019
Coronavirus disease 2019 has markedly varied clinical presentations, with most patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by ACE 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury.Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)?
Severe coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their roles in COVID-19 are poorly characterized.Chronic Kidney Disease: A Vicarious Relation to Premature Cell Senescence
Chronic kidney disease (CKD), commonly fostering nonrenal complications, themselves more life threatening than renal pathology, remains enigmatic. Despite more than a century of intense research, therapeutic options to halt or reverse renal disease are rather limited. Recently, similarity between manifestations of progressive CKD and aging kidney has attracted investigative attention that revealed senescent cells and secreting proinflammatory and profibrotic mediators in all renal compartments, even at young age, in patients with kidney maladies.Cortactin Expression in Hematopoietic Cells: Implications for Hematological Malignancies
Cortactin is an actin-binding protein expressed in virtually all cell types. It regulates several cell functions, including adhesion and migration. Cortactin overexpression is associated with increased metastasis formation and worse outcome in different types of solid tumors, thus highlighting a critical role of cortactin in cancer progression. Mechanistically, this is due to increased invadopodia formation and matrix metalloproteinase secretion. Cortactin has been until recently considered absent in hematopoietic cells because these cells express the cortactin homolog hematopoietic cell-specific lyn substrate-1.Endothelial Cell Calcium Signaling during Barrier Function and Inflammation
Calcium is an essential second messenger in endothelial cells and plays a pivotal role in regulating a number of physiologic processes, including cell migration, angiogenesis, barrier function, and inflammation. An increase in intracellular Ca2+ concentration can trigger a number of diverse signaling pathways under both physiologic and pathologic conditions. In this review, we discuss how calcium signaling pathways in endothelial cells play an essential role in affecting barrier function and facilitating inflammation.The Major Histocompatibility Complex Class II–CD4 Immunologic Synapse in Alcoholic Hepatitis and Autoimmune Liver Pathology: The Role of Aberrant Major Histocompatibility Complex Class II in Hepatocytes
The major histocompatibility complex class II (MHC II)–CD4 immunologic synapse is classically described between the T-cell receptor of CD4-positive lymphocytes and MHC II on antigen-presenting cells. This interaction and others between surrounding costimulatory and checkpoint molecules promote differentiation of naïve CD4 T lymphocytes into helper T cells subtypes, including types 1, 2, and 17 helper T cells, that have more tailored immunologic responses. Although MHC II is mainly produced by professional antigen-presenting cells, it can be aberrantly produced by other cell types, including hepatocytes in various liver pathologies, such as autoimmune hepatitis and alcoholic hepatitis.Molecular Evaluation of Breast Ductal Carcinoma in Situ with Oncotype DX DCIS
A subset of patients with ductal carcinoma in situ (DCIS) of the breast develop ipsilateral invasive breast cancer after breast-conserving surgery with or without adjuvant radiotherapy. Risk assessment and prediction of adverse outcomes for individual patients based on traditional clinical and pathological parameters are limited. The Oncotype DCIS Score is a commercially available multigene assay that has been independently validated in a prospective clinical trial and a population-based cohort.Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development
Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multisystem clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI), characterized by severe, early-onset mineralization of the cardiovascular system, often with early postnatal demise.Functional Role of miRNAs in the Progression of Breast Ductal Carcinoma in Situ
miRNAs are small RNAs that influence gene expression by targeting mRNAs. Depending on the function of their target genes, miRNAs may regulate the expression of oncogenes and tumor suppressors, thereby contributing to the promotion or inhibition of tumor progression. Ductal carcinoma in situ (DCIS), although often diagnosed as breast cancer, is a potential precursor to invasive ductal carcinoma. Many of the genetic events required for the invasive progression of DCIS occur at the preinvasive stage, and these events include changes in the expression of miRNAs.Strategies to Reduce the Immunogenicity of Recombinant Immunotoxins
Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a fragment of a bacterial toxin that kills tumor cells. Because the toxin is a foreign protein, it is immunogenic. The clinical success of RITs in patients with a normal immune system is limited by their immunogenicity. In this review, we discuss our progress in therapeutic protein deimmunization and the balancing act between immunogenicity and therapeutic potency.Adventitial Activation in the Pathogenesis of Injury-Induced Arterial Remodeling: Potential Implications in Transplant Vasculopathy
Transplant vasculopathy is one of the major causes of chronic rejection after solid organ transplantation. The pathogenic mechanisms of transplant vasculopathy are still poorly understood. Herein, we summarize current evidence suggesting that activation of the tunica adventitia may be involved in the pathogenesis of transplant vasculopathy. Adventitia is an early responder to various vascular injuries and plays an integral role in eliciting vascular inflammation and remodeling. Accumulation of macrophages in the adventitia promotes the development of vascular remodeling by releasing a variety of paracrine factors that have profound impacts on vascular mural cells.miRNAs as Biomarkers for Predicting the Progression of Ductal Carcinoma in Situ
Ductal carcinoma in situ (DCIS) is defined as a proliferation of neoplastic cells within the duct of the mammary gland that have not invaded into the surrounding stroma. DCIS is considered a precursor to invasive ductal carcinoma (IDC); however, approximately half of DCIS may progress to IDC, if left untreated. Current research has shown that the genomic and transcriptomic changes are present in DCIS before the emergence of invasive disease, indicating that the malignant nature of the DCIS is defined before invasion.Pathomechanisms of Altered Wound Healing in Recessive Dystrophic Epidermolysis Bullosa
Individuals with recessive dystrophic epidermolysis bullosa (RDEB), a rare genetic skin disease, carry mutations in the COL7A1 gene that codes for type VII collagen, an extracellular matrix component of the basement membrane zone forming the anchoring fibrils. As a consequence, RDEB individuals manifest unremitting skin blistering that evolves into chronic wounds, inflammation, and fibrosis. These features play a central role in the development of more severe disease complications, such as mitten deformities of hands and feet and aggressive epithelial cancers.Modulation of Antiviral Immunity by Heme Oxygenase-1
Heme oxygenase-1 (HO-1) is a stress-inducible, anti-inflammatory, and cytoprotective enzyme expressed in most cell types in the organism. Under several stress stimuli, HO-1 expression and activity is up-regulated to catalyze the rate-limiting enzymatic step of heme degradation into carbon monoxide, free iron, and biliverdin. Besides its effects on cell metabolism, HO-1 is also capable of modulating host innate and adaptive immune responses in response to sepsis, transplantation, and autoimmunity, and preventing oxidative damage associated with inflammation.Stem Cells in Lung Injury and Repair
In this review, we summarize the recent literature on the biology of endogenous stem cells in adult lung injury repair. We focus on in vivo studies in mice with an emphasis on data generated using cell-specific Cre-dependent lineage-tracing systems. These studies provide new information on the identification of lung stem cells, their hierarchical relationships, the plasticity of their behavior in different types of injury, and the molecular signals that control their fates. Although most of this work has been on epithelial hierarchies, we expect that further development of robust genetic tools will foster meaningful investigations into how nonepithelial cell populations are controlled during lung injury repair in adults.The Role of the Fibroblast in Inflammatory Upper Airway Conditions
Upper airway inflammation is one of the most frequent health care presentations. This is perhaps not surprising with our exposure to a myriad of environmental microbes, pollutants, and allergens. The precise pathophysiological mechanisms that cause persistent, exaggerated, upper airway inflammation rather than acute resolving illness remain unclear. Analysis of upper airway specimens identifies specific inflammatory cells, cytokine signatures, and fibrotic airway remodeling. Recent research has highlighted the role of stromal cells in the generation and persistence of chronic inflammation.
