Cardiovascular Disease, Aging, and Clonal Hematopoiesis.
Abstract Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoi...
Source: Annual Review of Pathology - November 5, 2019 Category: Pathology Authors: Evans MA, Sano S, Walsh K Tags: Annu Rev Pathol Source Type: research

DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation.
Abstract Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes in the context of sterile inflammation, a process caused by sterile (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind specific receptors to activate inflammation and start a highly optimized sequence of immune cell recruitment of neutrophils and monocytes to initiate effective tissue repair. When DAMPs are cleared, the recruited leukocytes change from a...
Source: Annual Review of Pathology - November 1, 2019 Category: Pathology Authors: Zindel J, Kubes P Tags: Annu Rev Pathol Source Type: research

Legionnaires' Disease: State of the Art Knowledge of Pathogenesis Mechanisms of Legionella.
Abstract Legionella species are environmental gram-negative bacteria able to cause a severe form of pneumonia in humans known as Legionnaires' disease. Since the identification of Legionella pneumophila in 1977, four decades of research on Legionella biology and Legionnaires' disease have brought important insights into the biology of the bacteria and the molecular mechanisms that these intracellular pathogens use to cause disease in humans. Nowadays, Legionella species constitute a remarkable model of bacterial adaptation, with a genus genome shaped by their close coevolution with amoebae and an ability to exploi...
Source: Annual Review of Pathology - October 28, 2019 Category: Pathology Authors: Mondino S, Schmidt S, Rolando M, Escoll P, Gomez-Valero L, Buchrieser C Tags: Annu Rev Pathol Source Type: research

New Insights into Malaria Pathogenesis.
Abstract Malaria remains a major public health threat in tropical and subtropical regions across the world. Even though less than 1% of malaria infections are fatal, this leads to about 430,000 deaths per year, predominantly in young children in sub-Saharan Africa. Therefore, it is imperative to understand why a subset of infected individuals develop severe syndromes and some of them die and what differentiates these cases from the majority that recovers. Here, we discuss progress made during the past decade in our understanding of malaria pathogenesis, focusing on the major human parasite Plasmodium falciparum. E...
Source: Annual Review of Pathology - October 24, 2019 Category: Pathology Authors: Moxon CA, Gibbins MP, McGuinness D, Milner DA, Marti M Tags: Annu Rev Pathol Source Type: research

Microbial Contribution to the Human Metabolome: Implications for Health and Disease.
Abstract The human gastrointestinal tract is home to an incredibly dense population of microbes. These microbes employ unique strategies to capture energy in this largely anaerobic environment. In the process of breaking down dietary- and host-derived substrates, the gut microbiota produce a broad range of metabolic products that accumulate to high levels in the gut. Increasingly, studies are revealing that these chemicals impact host biology, either by acting on cells within the gastrointestinal tract or entering circulation and exerting their effects at distal sites within the body. Given the high level of funct...
Source: Annual Review of Pathology - October 17, 2019 Category: Pathology Authors: Van Treuren W, Dodd D Tags: Annu Rev Pathol Source Type: research

Molecular Pathogenesis of Membranous Nephropathy.
Abstract Membranous nephropathy is a noninflammatory autoimmune disease of the kidney glomerulus, characterized by the formation of immune deposits, complement-mediated proteinuria, and risk of renal failure. Considerable advances in understanding the molecular pathogenesis have occurred with the identification of several antigens [neutral endopeptidase, phospholipase A2 receptor (PLA2R), thrombospondin domain-containing 7A (THSD7A)] in cases arising from the neonatal period to adulthood and the characterization of antibody-binding domains (that is, epitopes). Immunization against PLA2R occurs in 70% to 80% of adu...
Source: Annual Review of Pathology - October 17, 2019 Category: Pathology Authors: Ronco P, Debiec H Tags: Annu Rev Pathol Source Type: research

Autophagy Defects in Skeletal Myopathies.
Abstract Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and misfolded protein aggregates) for lysosomal degradation. Autophagy is activated in response to biological stress and also plays a critical role in the maintenance of normal cellular homeostasis; the latter function is particularly important for the integrity of postmitotic, metabolically active tissues, such as skeletal muscle. Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different s...
Source: Annual Review of Pathology - October 8, 2019 Category: Pathology Authors: Margeta M Tags: Annu Rev Pathol Source Type: research

Mitochondrial Dynamics and Its Involvement in Disease.
Abstract The dynamic properties of mitochondria-including their fusion, fission, and degradation-are critical for their optimal function in energy generation. The interplay of fusion and fission confers widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery me...
Source: Annual Review of Pathology - October 4, 2019 Category: Pathology Authors: Chan DC Tags: Annu Rev Pathol Source Type: research

Human Organoids: Tools for Understanding Biology and Treating Diseases.
Abstract Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and from adult stem cells, the latter being the subject of this review. Organoids derived from adult stem cells exploit the tissue regeneration process that is driven by these cells, and they can be established directly from the healthy or diseased epithelium of many organs. Organoids are amenable to any experimental approach that has been developed for cell lines. Applications in experimental biology involve the modeling of tissue physiology and...
Source: Annual Review of Pathology - September 24, 2019 Category: Pathology Authors: Schutgens F, Clevers H Tags: Annu Rev Pathol Source Type: research

Diversity, Mechanisms, and Significance of Macrophage Plasticity.
Abstract Macrophages are a diverse set of cells present in all body compartments. This diversity is imprinted by their ontogenetic origin (embryonal versus adult bone marrow-derived cells); the organ context; the activation or deactivation of various signals in the contexts of microbial invasion, tissue damage, and metabolic derangement; and by polarization of adaptive T cell responses. Classic adaptive responses of macrophages include tolerance, priming, and a wide spectrum of activation states, including M1, M2, or M2-like. Moreover, macrophages can retain long-term imprinting of microbial encounters (trained in...
Source: Annual Review of Pathology - September 17, 2019 Category: Pathology Authors: Locati M, Curtale G, Mantovani A Tags: Annu Rev Pathol Source Type: research

Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns.
Abstract The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent l...
Source: Annual Review of Pathology - August 9, 2019 Category: Pathology Authors: Ko S, Russell JO, Molina LM, Monga SP Tags: Annu Rev Pathol Source Type: research

Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases.
Abstract The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zeb...
Source: Annual Review of Pathology - July 12, 2019 Category: Pathology Authors: Lemaigre FP Tags: Annu Rev Pathol Source Type: research

Malformations of Cerebral Cortex Development: Molecules and Mechanisms.
Abstract Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on br...
Source: Annual Review of Pathology - January 24, 2019 Category: Pathology Authors: Juric-Sekhar G, Hevner RF Tags: Annu Rev Pathol Source Type: research

Systems-Wide Approaches in Induced Pluripotent Stem Cell Models.
Abstract Human induced pluripotent stem cells (iPSCs) provide a renewable supply of patient-specific and tissue-specific cells for cellular and molecular studies of disease mechanisms. Combined with advances in various omics technologies, iPSC models can be used to profile the expression of genes, transcripts, proteins, and metabolites in relevant tissues. In the past 2 years, large panels of iPSC lines have been derived from hundreds of genetically heterogeneous individuals, further enabling genome-wide mapping to identify coexpression networks and elucidate gene regulatory networks. Here, we review recent develo...
Source: Annual Review of Pathology - October 31, 2018 Category: Pathology Authors: Lau E, Paik DT, Wu JC Tags: Annu Rev Pathol Source Type: research

Cellular and Molecular Mechanisms of Prion Disease.
Abstract Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized agg...
Source: Annual Review of Pathology - October 24, 2018 Category: Pathology Authors: Sigurdson CJ, Bartz JC, Glatzel M Tags: Annu Rev Pathol Source Type: research

RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration.
Abstract Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique propert...
Source: Annual Review of Pathology - October 24, 2018 Category: Pathology Authors: Hofmann JW, Seeley WW, Huang EJ Tags: Annu Rev Pathol Source Type: research

Pathology and Pathogenesis of Chagas Heart Disease.
Abstract Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite...
Source: Annual Review of Pathology - October 24, 2018 Category: Pathology Authors: Bonney KM, Luthringer DJ, Kim SA, Garg NJ, Engman DM Tags: Annu Rev Pathol Source Type: research

Modeling Disease with Inducible Pluripotent Stem Cells.
Abstract Understanding the physiopathology of disease remains an essential step in developing novel therapeutics. Although animal models have certainly contributed to advancing this enterprise, their limitation in modeling all the aspects of complex human disorders is one of the major challenges faced by the biomedical research field. Human induced pluripotent stem cells (hiPSCs) derived from patients represent a great opportunity to overcome this deficiency because these cells cover the genetic diversity needed to fully model human diseases. Here, we provide an overview of the history of hiPSC technology and disc...
Source: Annual Review of Pathology - October 24, 2018 Category: Pathology Authors: Grandy R, Tomaz R, Vallier L Tags: Annu Rev Pathol Source Type: research

Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection.
Abstract Nearly all infectious agents contain DNA or RNA genomes, making sequencing an attractive approach for pathogen detection. The cost of high-throughput or next-generation sequencing has been reduced by several orders of magnitude since its advent in 2004, and it has emerged as an enabling technological platform for the detection and taxonomic characterization of microorganisms in clinical samples from patients. This review focuses on the application of untargeted metagenomic next-generation sequencing to the clinical diagnosis of infectious diseases, particularly in areas in which conventional diagnostic ap...
Source: Annual Review of Pathology - October 24, 2018 Category: Pathology Authors: Gu W, Miller S, Chiu CY Tags: Annu Rev Pathol Source Type: research

Molecular Pathogenesis of the Tauopathies.
RM Abstract The tauopathies constitute a group of diseases that have Tau inclusions in neurons or glia as their common denominator. In this review, we describe the biochemical and histological differences in Tau pathology that are characteristic of the spectrum of frontotemporal lobar degeneration as primary tauopathies and of Alzheimer's disease as a secondary tauopathy, as well as the commonalities and differences between the familial and sporadic forms. Furthermore, we discuss selected advances in transgenic animal models in delineating the pathomechanisms of Tau in the different subtypes. Expected final onlin...
Source: Annual Review of Pathology - October 24, 2018 Category: Pathology Authors: Götz J, Halliday G, Nisbet RM Tags: Annu Rev Pathol Source Type: research

Type I Interferons in Autoimmune Disease.
Abstract Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of ...
Source: Annual Review of Pathology - October 17, 2018 Category: Pathology Authors: Crow MK, Olferiev M, Kirou KA Tags: Annu Rev Pathol Source Type: research

Opportunities for microRNAs in the Crowded Field of Cardiovascular Biomarkers.
We describe the current state of cardiovascular disease biomarkers across a range of diseases, including myocardial infarction, acute coronary syndrome, myocarditis, hypertension, heart failure, heart transplantation, aortic stenosis, diabetic cardiomyopathy, atrial fibrillation, and sepsis. We present the current understanding of microRNAs as possible biomarkers in these categories and where their best opportunities exist to enter clinical practic Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/jour...
Source: Annual Review of Pathology - October 17, 2018 Category: Pathology Authors: Halushka PV, Goodwin AJ, Halushka MK Tags: Annu Rev Pathol Source Type: research

Pathophysiology of Sickle Cell Disease.
Abstract Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD, manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to endorgan ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular he...
Source: Annual Review of Pathology - October 17, 2018 Category: Pathology Authors: Sundd P, Gladwin MT, Novelli EM Tags: Annu Rev Pathol Source Type: research

Molecular Genetics of Endometrial Carcinoma.
Abstract Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Endometrioid endometrial carcinomas constitute approximately 85% of newly diagnosed cases; serous carcinomas represent approximately 3-10% of diagnoses; clear cell carcinoma accounts for
Source: Annual Review of Pathology - October 17, 2018 Category: Pathology Authors: Bell DW, Ellenson LH Tags: Annu Rev Pathol Source Type: research

Innate Immune Signaling in Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases.
Abstract The physiological significance of innate immune signaling lies primarily in its role in host defense against invading pathogens. It is becoming increasingly clear that innate immune signaling also modulates the development of metabolic diseases, especially nonalcoholic fatty liver disease and cardiovascular diseases, which are characterized by chronic, low-grade inflammation due to a disarrangement of innate immune signaling. Notably, recent studies indicate that in addition to regulating canonical innate immune-mediated inflammatory responses (or immune-dependent signaling-induced responses), molecules o...
Source: Annual Review of Pathology - September 19, 2018 Category: Pathology Authors: Cai J, Xu M, Zhang X, Li H Tags: Annu Rev Pathol Source Type: research

Immunological Basis for Recurrent Fetal Loss and Pregnancy Complications.
Abstract Pregnancy stimulates an elaborate assortment of dynamic changes, allowing intimate approximation of genetically discordant maternal and fetal tissues. Although the cellular and molecular details about how this works remain largely undefined, important clues arise from evaluating how a prior pregnancy influences the outcome of a future pregnancy. The risk of complications is consistently increased when complications occurred in a prior pregnancy. Reciprocally, a prior successful pregnancy protects against complications in a future pregnancy. Here, we summarize immunological perturbations associated with fe...
Source: Annual Review of Pathology - September 5, 2018 Category: Pathology Authors: Deshmukh H, Way SS Tags: Annu Rev Pathol Source Type: research

Pathological Issues in Dystrophinopathy in the Age of Genetic Therapies.
Abstract Dystrophinopathy is a class of genetic skeletal muscle disease characterized by myofiber degeneration and regeneration due to insufficient levels or functioning of dystrophin. Pathological evaluation for dystrophinopathy includes the identification of dystrophic skeletal muscle pathology and the immuno-histochemical evaluation of dystrophin epitopes, but biopsies have become rare in recent years. However, the evaluation of dystrophin expression in the research setting has become critically important due to recent advances in genetic therapies, including exon skipping and gene therapy. Given the number of ...
Source: Annual Review of Pathology - August 27, 2018 Category: Pathology Authors: Shahnoor N, Siebers EM, Brown KJ, Lawlor MW Tags: Annu Rev Pathol Source Type: research

Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection.
Abstract Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction. Endothelial cells and mononuclear phagocytes have important roles in the intracellular killing of rickettsiae upon activation by the effector molecules of innate and adaptive immunity. In overwhelming infection, immuno-suppressive effects contribute to the severity of illness. Rickettsia-host cell interactions involve host cell receptors for rickettsial ligands that mediate cel...
Source: Annual Review of Pathology - August 27, 2018 Category: Pathology Authors: Sahni A, Fang R, Sahni SK, Walker DH Tags: Annu Rev Pathol Source Type: research

Exposure to Ultraviolet Radiation in the Modulation of Human Diseases.
Abstract This review focuses primarily on the beneficial effects for human health of exposure to ultraviolet radiation (UVR). UVR stimulates anti-inflammatory and immunosuppressive pathways in skin that modulate psoriasis, atopic dermatitis, and vitiligo; suppresses cutaneous lesions of graft-versus-host disease; and regulates some infection and vaccination outcomes. While polymorphic light eruption and the cutaneous photosensitivity of systemic lupus erythematosus are triggered by UVR, polymorphic light eruption also frequently benefits from UVR-induced immunomodulation. For systemic diseases such as multiple scl...
Source: Annual Review of Pathology - August 20, 2018 Category: Pathology Authors: Hart PH, Norval M, Byrne SN, Rhodes LE Tags: Annu Rev Pathol Source Type: research

Epstein-Barr Virus and Cancer.
Abstract Epstein-Barr virus (EBV) contributes to about 1.5% of all cases of human cancer worldwide, and viral genes are expressed in the malignant cells. EBV also very efficiently causes the proliferation of infected human B lymphocytes. The functions of the viral proteins and small RNAs that may contribute to EBV-associated cancers are becoming increasingly clear, and a broader understanding of the sequence variation of the virus genome has helped to interpret their roles. The improved understanding of the mechanisms of these cancers means that there are great opportunities for the early diagnosis of treatable st...
Source: Annual Review of Pathology - August 20, 2018 Category: Pathology Authors: Farrell PJ Tags: Annu Rev Pathol Source Type: research

Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology.
Abstract Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prost...
Source: Annual Review of Pathology - August 20, 2018 Category: Pathology Authors: Ogino S, Nowak JA, Hamada T, Milner DA, Nishihara R Tags: Annu Rev Pathol Source Type: research

Polyglutamine Repeats in Neurodegenerative Diseases.
Abstract Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific ma...
Source: Annual Review of Pathology - August 8, 2018 Category: Pathology Authors: Lieberman AP, Shakkottai VG, Albin RL Tags: Annu Rev Pathol Source Type: research

Perspectives from a Pathologist: My Journey on the Path to Women's Health Research, Sex and Gender Policy, and Practice Implications.
Abstract These words reflect my recollections of major transition points in my life and career: as I first became dedicated to becoming a physician, being introduced to the field of pathology and research, and then transitioning to a somewhat different career focus by becoming the first director of the National Institutes of Health Office of Research on Women's Health. Many of the experiences that I gained during my years in pathology served me well as I made efforts to establish women's health research and sex and gender based studies as scientific endeavors. Participating in research and teaching as an academic ...
Source: Annual Review of Pathology - January 24, 2018 Category: Pathology Authors: Pinn VW Tags: Annu Rev Pathol Source Type: research

Intrinsic Neuronal Stress Response Pathways in Injury and Disease.
Abstract From injury to disease to aging, neurons, like all cells, may face various insults that can impact their function and survival. Although the consequences are substantially dictated by the type, context, and severity of insult, distressed neurons are far from passive. Activation of cellular stress responses aids in the preservation or restoration of nervous system function. However, stress responses themselves can further advance neuropathology and contribute significantly to neuronal dysfunction and neurodegeneration. Here we explore the recent advances in defining the cellular stress responses within neu...
Source: Annual Review of Pathology - January 24, 2018 Category: Pathology Authors: Farley MM, Watkins TA Tags: Annu Rev Pathol Source Type: research

Epithelial Mesenchymal Transition in Tumor Metastasis.
Abstract Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hall...
Source: Annual Review of Pathology - January 24, 2018 Category: Pathology Authors: Mittal V Tags: Annu Rev Pathol Source Type: research

Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease.
Abstract Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic varian...
Source: Annual Review of Pathology - January 24, 2018 Category: Pathology Authors: Arab JP, Arrese M, Trauner M Tags: Annu Rev Pathol Source Type: research

Desmosomes in Human Disease.
Abstract Tissue integrity is crucial for maintaining the homeostasis of living organisms. Abnormalities that affect sites of cell-cell contact can cause a variety of debilitating disorders. The desmosome is an essential cell-cell junctional protein complex in tissues that undergo stress, and it orchestrates intracellular signal transduction. Desmosome assembly and junctional integrity are required to maintain the overall homeostasis of a tissue, organ, and organism. This review discusses the desmosome and the human diseases associated with its disruption. PMID: 29414250 [PubMed - in process] (Source: Annual Review of Pathology)
Source: Annual Review of Pathology - January 24, 2018 Category: Pathology Authors: Najor NA Tags: Annu Rev Pathol Source Type: research

Pathogenesis of Peripheral T Cell Lymphoma.
Abstract Peripheral T cell lymphomas (PTCLs) are highly heterogeneous tumors, displaying distinct clinical and biological features. The pathogenesis and normal counterpart of such entities have been elusive for decades. Recent studies have, however, disclosed key mechanisms of peripheral T cell transformation, including (a) the deregulation of signaling pathways controlling T cell development, differentiation, and maturation; (b) the remodeling of the peritumor microenvironment; and (c) the virus-mediated rewiring of T cell biology. Uncovering the molecular mechanisms of T cell transformation will help elucidate t...
Source: Annual Review of Pathology - January 24, 2018 Category: Pathology Authors: Pizzi M, Margolskee E, Inghirami G Tags: Annu Rev Pathol Source Type: research

The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future.
Abstract The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the gl...
Source: Annual Review of Pathology - December 1, 2017 Category: Pathology Authors: Plog BA, Nedergaard M Tags: Annu Rev Pathol Source Type: research

Cellular and Molecular Mechanisms of Autoimmune Hepatitis.
Abstract Autoimmune hepatitis is an uncommon idiopathic syndrome of immunemediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non- HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by se...
Source: Annual Review of Pathology - November 15, 2017 Category: Pathology Authors: Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME Tags: Annu Rev Pathol Source Type: research

New Insights into Lymphoma Pathogenesis.
Abstract Lymphomas represent clonal proliferations of lymphocytes that are broadly classified based upon their maturity (peripheral or mature versus precursor) and lineage (B cell, T cell, and natural killer cell). Insights into the pathogenetic mechanisms involved in lymphoma impact the classification of lymphoma and have significant implications for the diagnosis and clinical management of patients. Serial scientific and technologic advances over the last 30 years in immunology, cytogenetics, molecular biology, gene expression profiling, mass spectrometry-based proteomics, and, more recently, next-generation seq...
Source: Annual Review of Pathology - November 15, 2017 Category: Pathology Authors: Elenitoba-Johnson KSJ, Lim MS Tags: Annu Rev Pathol Source Type: research

Wnt/ β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology.
Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annu Rev Pathol. 2017 Nov 09;: Authors: Russell JO, Monga SS Abstract The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every fac...
Source: Annual Review of Pathology - November 9, 2017 Category: Pathology Authors: Russell JO, Monga SS Tags: Annu Rev Pathol Source Type: research

New Insights into Graft-Versus-Host Disease and Graft Rejection.
Abstract Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation, immune-mediated rejection mandates the use of prolonged global immunosuppression and limits the life span of transplanted allografts. After bone marrow transplantation, donor-derived immune cells can trigger life-threatening graft-versus-host disease. T cells are central mediators of alloimmune complications and the target of most existing therapeutic interventions. We review recent progress identifying multiple cell types in addition to T cells and ne...
Source: Annual Review of Pathology - November 3, 2017 Category: Pathology Authors: Perkey E, Maillard I Tags: Annu Rev Pathol Source Type: research

Nutritional Interventions for Mitochondrial OXPHOS Deficiencies: Mechanisms and Model Systems.
Abstract Multisystem metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are severe and often lethal, conditions. Inborn errors of OXPHOS function are termed primary mitochondrial disorders (PMDs), and the use of nutritional interventions is routine in their supportive management. However, detailed mechanistic understanding and evidence for efficacy and safety of these interventions are limited. Preclinical cellular and animal model systems are important tools to investigate PMD metabolic mechanisms and therapeutic strategies. This review assesses the mechanistic rationale and experimental ...
Source: Annual Review of Pathology - November 3, 2017 Category: Pathology Authors: Kuszak AJ, Espey MG, Falk MJ, Holmbeck MA, Manfredi G, Shadel GS, Vernon HJ, Zolkipli-Cunningham Z Tags: Annu Rev Pathol Source Type: research

Genomic Hallmarks of Thyroid Neoplasia.
Abstract The genomic landscape of thyroid cancers that are derived from follicular cells has been substantially elucidated through the coordinated application of high-throughput genomic technologies. Here, I review the common genetic alterations across the spectrum of thyroid neoplasia and present the resulting model of thyroid cancer initiation and progression. This model illustrates the striking correlation between tumor differentiation and overall somatic mutational burden, which also likely explains the highly variable clinical behavior and outcome of patients with thyroid cancers. These advances are yielding ...
Source: Annual Review of Pathology - October 30, 2017 Category: Pathology Authors: Giordano TJ Tags: Annu Rev Pathol Source Type: research

Cancer Metastasis: A Reappraisal of Its Underlying Mechanisms and Their Relevance to Treatment.
Abstract Metastases are responsible for the vast majority of cancer-related deaths, but, despite intense efforts to understand their underlying mechanisms with the goal of uncovering effective therapeutic targets, treatment of metastatic cancer has progressed minimally. In this review, we examine the biological programs currently proposed to be key drivers of metastasis. On the basis of evidence from a growing body of research, we discuss to what extent the cellular and molecular mechanisms that are suggested to underlie cancer cell dissemination are specific to the metastatic process, as opposed to representing n...
Source: Annual Review of Pathology - October 25, 2017 Category: Pathology Authors: Riggi N, Aguet M, Stamenkovic I Tags: Annu Rev Pathol Source Type: research

Stem Cell Pathology.
Abstract Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurat...
Source: Annual Review of Pathology - October 20, 2017 Category: Pathology Authors: Fu DJ, Miller AD, Southard TL, Flesken-Nikitin A, Ellenson LH, Nikitin AY Tags: Annu Rev Pathol Source Type: research

Hemophagocytic Lymphohistiocytosis.
Abstract Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by unbridled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages resulting in hypercytokinemia and immunemediated injury of multiple organ systems. It is seen in both children and adults and is recognized as primary (driven by underlying genetic mutations that abolish critical proteins required for normal function of cytotoxic T cells and NK cells) or secondary (resulting from a malignant, infectious, or autoimmune stimulus without an identifiable underlying genetic trigger). Clinical and laborato...
Source: Annual Review of Pathology - September 13, 2017 Category: Pathology Authors: Al-Samkari H, Berliner N Tags: Annu Rev Pathol Source Type: research

Hydatidiform Moles: Genetic Basis and Precision Diagnosis.
Abstract Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. Overrepresentation of the paternal genome in sporadic hydatidiform moles (purely androgenetic in complete hydatidiform moles and diandric triploid in partial hydatidiform moles) is a fundamental genetic event leading to global alteration of imprinting gene expression in the molar trophoblast. Rare familial biparental hydatidiform moles (due to NLRP7 or KHDC3L mutations) share such global im...
Source: Annual Review of Pathology - January 24, 2017 Category: Pathology Authors: Hui P, Buza N, Murphy KM, Ronnett BM Tags: Annu Rev Pathol Source Type: research

Focal Cortical Dysplasia: Gene Mutations, Cell Signaling, and Therapeutic Implications.
Abstract Focal cortical dysplasias (FCDs) are malformations of cortical development (MCDs) that are highly associated with medication-resistant epilepsy and are the most common cause of neocortical epilepsy in children. FCDs are a heterogeneous group of developmental disorders caused by germline or somatic mutations that occur in genes regulating the PI3K/Akt/mTOR pathway-a key pathway in neuronal growth and migration. Accordingly, FCDs are characterized by abnormal cortical lamination, cell morphology (e.g., cytomegaly), and cellular polarity. In some FCD subtypes, balloon cells express proteins typically seen in...
Source: Annual Review of Pathology - January 24, 2017 Category: Pathology Authors: Iffland PH, Crino PB Tags: Annu Rev Pathol Source Type: research