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- Volume 10, 2015
Annual Review of Pathology: Mechanisms of Disease - Volume 10, 2015
Volume 10, 2015
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The Roles of Cellular and Organismal Aging in the Development of Late-Onset Maladies
Vol. 10 (2015), pp. 1–23More LessNumerous disorders, including neurodegenerative diseases and certain types of cancer, manifest late in life. This common feature raises the prospect that an aging-associated decline in the activity of cellular and organismal maintenance mechanisms enables the emergence of these maladies in late life stages. Accordingly, the alteration of aging bears the promise of harnessing the mechanisms that protect the young organism to prevent illness in the elderly. The identification of aging-regulatory pathways has enabled scrutiny of this hypothesis and revealed that the alteration of aging protects invertebrates and mammals from toxic protein aggregation linked to neurodegeneration and from cancer. Here we review the current knowledge on the regulation of aging at the cellular and organismal levels, delineate the mechanistic links between aging and late-onset disorders, describe efforts to develop compounds that protect from these maladies by selectively manipulating aging, and discuss future research directions and possible therapeutic implications of this approach.
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Driver and Passenger Mutations in Cancer
Vol. 10 (2015), pp. 25–50More LessNext-generation sequencing has allowed identification of millions of somatic mutations and epigenetic changes in cancer cells. A key challenge in interpreting cancer genomes and epigenomes is distinguishing which genetic and epigenetic changes are drivers of cancer development. Frequency-based and function-based approaches have been developed to identify candidate drivers; we discuss the advantages and drawbacks of these methods as well as their latest refinements. We focus particularly on identification of the types of drivers most likely to be missed, such as genes affected by copy number alterations, mutations in noncoding regions, dysregulation of microRNA, epigenetic changes, and mutations in chromatin modifiers.
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Leukocyte Chemoattractant Receptors in Human Disease Pathogenesis
Vol. 10 (2015), pp. 51–81More LessCombinations of leukocyte attractant ligands and cognate heptahelical receptors specify the systemic recruitment of circulating cells by triggering integrin-dependent adhesion to endothelial cells, supporting extravasation, and directing specific intratissue localization via gradient-driven chemotaxis. Chemoattractant receptors also control leukocyte egress from lymphoid organs and peripheral tissues. In this article, we summarize the fundamental mechanics of leukocyte trafficking, from the evolution of multistep models of leukocyte recruitment and navigation to the regulation of chemoattractant availability and function by atypical heptahelical receptors. To provide a more complete picture of the migratory circuits involved in leukocyte trafficking, we integrate a number of nonchemokine chemoattractant receptors into our discussion. Leukocyte chemoattractant receptors play key roles in the pathogenesis of autoimmune diseases, allergy, inflammatory disorders, and cancer. We review recent advances in our understanding of chemoattractant receptors in disease pathogenesis, with a focus on genome-wide association studies in humans and the translational implications of mechanistic studies in animal disease models.
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Pathobiology of Transfusion Reactions
Vol. 10 (2015), pp. 83–110More LessAntibody-induced hemolytic transfusion reactions were first described over 300 years ago. Indeed, during its early evolution, transfusion medicine focused almost exclusively on issues in immunohematology to prevent such events. However, despite the best of efforts to avoid them, incompatible transfusions still occur, through both error and an inability to obtain compatible red blood cells for patients who are alloimmunized against multiple antigens. Because transfusing units of incompatible blood is potentially lethal, studies on human volunteers are not ethical. Thus, understanding of hemolytic transfusion reactions is generated through clinical cases, animal models, inference from related human pathologies, or studies using small volumes of transfused red blood cells. Over the past several decades, substantial new knowledge has been accumulated regarding the mechanisms of hemolysis, the metabolism of products of hemolysis, and the effects of both on recipient biology. Using these data sources, this article traces the historical generation of this knowledge and describes recent advances.
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The Emerging Picture of Autism Spectrum Disorder: Genetics and Pathology
Vol. 10 (2015), pp. 111–144More LessAutism spectrum disorder (ASD) is defined by impaired social interaction and communication accompanied by stereotyped behaviors and restricted interests. Although ASD is common, its genetic and clinical features are highly heterogeneous. A number of recent breakthroughs have dramatically advanced our understanding of ASD from the standpoint of human genetics and neuropathology. These studies highlight the period of fetal development and the processes of chromatin structure, synaptic function, and neuron-glial signaling. The initial efforts to systematically integrate findings of multiple levels of genomic data and studies of mouse models have yielded new clues regarding ASD pathophysiology. This early work points to an emerging convergence of disease mechanisms in this complex and etiologically heterogeneous disorder.
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SWI/SNF Chromatin Remodeling and Human Malignancies
Vol. 10 (2015), pp. 145–171More LessThe SWI/SNF complexes, initially identified in yeast 20 years ago, are a family of multi-subunit complexes that use the energy of adenosine triphosphate (ATP) hydrolysis to remodel nucleosomes. Chromatin remodeling processes mediated by the SWI/SNF complexes are critical to the modulation of gene expression across a variety of cellular processes, including stemness, differentiation, and proliferation. The first evidence of the involvement of these complexes in carcinogenesis was provided by the identification of biallelic, truncating mutations of the SMARCB1 gene in malignant rhabdoid tumors, a highly aggressive childhood cancer. Subsequently, genome-wide sequencing technologies have identified mutations in genes encoding different subunits of the SWI/SNF complexes in a large number of tumors. SWI/SNF mutations, and the subsequent abnormal function of SWI/SNF complexes, are among the most frequent gene alterations in cancer. The mechanisms by which perturbation of the SWI/SNF complexes promote oncogenesis are not fully elucidated; however, alterations of SWI/SNF genes obviously play a major part in cancer development, progression, and/or resistance to therapy.
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The Role of Endoplasmic Reticulum Stress in Human Pathology
Vol. 10 (2015), pp. 173–194More LessNumerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle—a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress–associated pathologies.
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Engineered In Vitro Disease Models
Vol. 10 (2015), pp. 195–262More LessThe ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition. In addition, it is difficult to identify critical cellular and molecular contributors to disease or to vary them independently in whole-animal models. This challenge has attracted the interest of engineers, who have begun to collaborate with biologists to leverage recent advances in tissue engineering and microfabrication to develop novel in vitro models of disease. As these models are synthetic systems, specific molecular factors and individual cell types, including parenchymal cells, vascular cells, and immune cells, can be varied independently while simultaneously measuring system-level responses in real time. In this article, we provide some examples of these efforts, including engineered models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer. We also describe how engineered in vitro models can be combined with human inducible pluripotent stem cells to enable new insights into a broad variety of disease mechanisms, as well as provide a test bed for screening new therapies.
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A Clearer View of the Molecular Complexity of Clear Cell Renal Cell Carcinoma
Ian J. Frew, and Holger MochVol. 10 (2015), pp. 263–289More LessThe von Hippel–Lindau (VHL) tumor suppressor gene is mutated as an early event in almost all cases of clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer. In this review we discuss recent advances in understanding how dysregulation of the many hypoxia-inducible factor α–dependent and –independent functions of the VHL tumor suppressor protein (pVHL) can contribute to tumor initiation and progression. Recent evidence showing extensive inter- and intratumoral genetic diversity has given rise to the idea that ccRCC should actually be considered as a series of molecularly related, yet distinct, diseases defined by the pattern of combinatorial genetic alterations present within the cells of the tumor. We highlight the range of genetic and epigenetic alterations that recur in ccRCC and discuss the mechanisms through which these events appear to function cooperatively with a loss of pVHL function in tumorigenesis.
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Emerging Concepts in Alzheimer's Disease
Vol. 10 (2015), pp. 291–319More LessAlzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.
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AA Amyloidosis: Pathogenesis and Targeted Therapy
Vol. 10 (2015), pp. 321–344More LessThe understanding of why and how proteins misfold and aggregate into amyloid fibrils has increased considerably during recent years. Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation. Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules. In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood. Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease. This review summarizes current knowledge about AA amyloidosis. The systemic amyloidoses have been regarded as intractable conditions, but improvements in the understanding of fibril composition and pathogenesis over the past decade have led to the development of a number of different therapeutic approaches with promising results.
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Hepatitis C Virus–Associated Cancer
Vol. 10 (2015), pp. 345–370More LessHepatitis C virus (HCV) is one of the major etiologic agents of liver cancer. HCV is an RNA virus that, unlike hepatitis B virus, is unable to integrate into the host genome. Through complex interactions between viral and host proteins that induce host responses and promote inflammation, fibrosis, and ultimately cirrhosis, HCV infection can result in the development of hepatocellular carcinoma (HCC). The HCV oncogenic process involves genetic and epigenetic alterations and oncogenic effects mediated by viral proteins in the activation of cellular oncogenes, inactivation of tumor-suppressor genes, and dysregulation of multiple signal-transduction pathways. Advances in genetics and gene expression profiling have enhanced our current understanding of the pathways involved in HCV-associated liver cancer development. In this review, we summarize the current understanding of mechanisms of hepatocarcinogenesis induced by HCV infection.
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Diseases of Pulmonary Surfactant Homeostasis
Vol. 10 (2015), pp. 371–393More LessAdvances in physiology and biochemistry have provided fundamental insights into the role of pulmonary surfactant in the pathogenesis and treatment of preterm infants with respiratory distress syndrome. Identification of the surfactant proteins, lipid transporters, and transcriptional networks regulating their expression has provided the tools and insights needed to discern the molecular and cellular processes regulating the production and function of pulmonary surfactant prior to and after birth. Mutations in genes regulating surfactant homeostasis have been associated with severe lung disease in neonates and older infants. Biophysical and transgenic mouse models have provided insight into the mechanisms underlying surfactant protein and alveolar homeostasis. These studies have provided the framework for understanding the structure and function of pulmonary surfactant, which has informed understanding of the pathogenesis of diverse pulmonary disorders previously considered idiopathic. This review considers the pulmonary surfactant system and the genetic causes of acute and chronic lung disease caused by disruption of alveolar homeostasis.
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The Inflammasomes and Autoinflammatory Syndromes
Vol. 10 (2015), pp. 395–424More LessInflammation, a vital response of the immune system to infection and damage to tissues, can be initiated by various germline-encoded innate immune-signaling receptors. Among these, the inflammasomes are critical for activation of the potent proinflammatory interleukin-1 cytokine family. Additionally, inflammasomes can trigger and maintain inflammatory responses aimed toward excess nutrients and the numerous danger signals that appear in a variety of chronic inflammatory diseases. We discuss our understanding of how inflammasomes assemble to trigger caspase-1 activation and subsequent cytokine release, describe how genetic mutations in inflammasome-related genes lead to autoinflammatory syndromes, and review the contribution of inflammasome activation to various pathologies arising from metabolic dysfunction. Insights into the mechanisms that govern inflammasome activation will help in the development of novel therapeutic strategies, not only for managing genetic diseases associated with overactive inflammasomes, but also for treating common metabolic diseases for which effective therapies are currently lacking.
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DNA Replication Stress as a Hallmark of Cancer
Vol. 10 (2015), pp. 425–448More LessHuman cancers share properties referred to as hallmarks, among which sustained proliferation, escape from apoptosis, and genomic instability are the most pervasive. The sustained proliferation hallmark can be explained by mutations in oncogenes and tumor suppressors that regulate cell growth, whereas the escape from apoptosis hallmark can be explained by mutations in the TP53, ATM, or MDM2 genes. A model to explain the presence of the three hallmarks listed above, as well as the patterns of genomic instability observed in human cancers, proposes that the genes driving cell proliferation induce DNA replication stress, which, in turn, generates genomic instability and selects for escape from apoptosis. Here, we review the data that support this model, as well as the mechanisms by which oncogenes induce replication stress. Further, we argue that DNA replication stress should be considered as a hallmark of cancer because it likely drives cancer development and is very prevalent.
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Birth and Pathogenesis of Rogue Respiratory Viruses*
Vol. 10 (2015), pp. 449–471More LessEmerging infectious diseases of zoonotic origin are shaping today's infectious disease field more than ever. In this article, we introduce and review three emerging zoonotic viruses. Novel hantaviruses emerged in the Americas in the mid-1990s as the cause of severe respiratory infections, designated hantavirus pulmonary syndrome, with case fatality rates of around 40%. Nipah virus emerged a few years later, causing respiratory infections and encephalitis in Southeast Asia, with case fatality rates ranging from 40% to more than 90%. A new coronavirus emerged in 2012 on the Arabian Peninsula with a clinical syndrome of acute respiratory infections, later designated as Middle East respiratory syndrome (MERS), and an initial case fatality rate of more than 40%. Our current state of knowledge on the pathogenicity of these three severe, emerging viral infections is discussed.
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Protein Glycosylation in Cancer
Vol. 10 (2015), pp. 473–510More LessNeoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic alterations underpin the development of neoplastic disease, epigenetic changes can exert an equally significant effect on neoplastic transformation. Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of neoplastic progression. Alterations in glycosylation appear to not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Many of these changes may support neoplastic progression, and unique alterations in tumor-associated glycosylation may also serve as a distinct feature of cancer cells and therefore provide novel diagnostic and even therapeutic targets.
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Pathobiology of Severe Asthma
Vol. 10 (2015), pp. 511–545More LessSevere asthma (SA) afflicts a heterogeneous group of asthma patients who exhibit poor responses to traditional asthma medications. SA patients likely represent 5–10% of all asthma patients; however, they have a higher economic burden when compared with milder asthmatics. Considerable research has been performed on pathological pathways and structural changes associated with SA. Although limitations of the pathological approaches, ranging from sampling, to quantitative assessments, to heterogeneity of disease, have prevented a more definitive understanding of the underlying pathobiology, studies linking pathology to molecular markers to targeted therapies are beginning to solidify the identification of select molecular phenotypes. This review addresses the pathobiology of SA and discusses the current limitations of studies, the inflammatory cells and pathways linked to emerging phenotypes, and the structural and remodeling changes associated with severe disease. In all cases, an effort is made to link pathological findings to specific clinical/molecular phenotypes.
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Genetics and Epigenetics of Human Retinoblastoma
Vol. 10 (2015), pp. 547–562More LessRetinoblastoma is a pediatric tumor of the developing retina from which the genetic basis for cancer development was first described. Inactivation of both copies of the RB1 gene is the predominant initiating genetic lesion in retinoblastoma and is rate limiting for tumorigenesis. Recent whole-genome sequencing of retinoblastoma uncovered a tumor that had no coding-region mutations or focal chromosomal lesions other than in the RB1 gene, shifting the paradigm in the field. The retinoblastoma genome can be very stable; therefore, epigenetic deregulation of tumor-promoting pathways is required for tumorigenesis. This review highlights the genetic and epigenetic changes in retinoblastoma that have been reported, with special emphasis on recent whole-genome sequencing and epigenetic analyses that have identified novel candidate genes as potential therapeutic targets.
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Previous Volumes
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Volume 20 (2025)
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Volume 19 (2024)
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Volume 18 (2023)
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Volume 17 (2022)
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Volume 16 (2021)
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Volume 15 (2020)
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Volume 14 (2019)
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Volume 13 (2018)
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Volume 12 (2017)
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Volume 11 (2016)
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Volume 10 (2015)
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Volume 9 (2014)
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Volume 8 (2013)
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Volume 7 (2012)
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Volume 6 (2011)
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Volume 5 (2010)
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Volume 4 (2009)
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Volume 3 (2008)
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Volume 2 (2007)
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Volume 1 (2006)
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Volume 0 (1932)