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Annual Review of Pathology

Matthew L Wheeler, Jose J Limon, David M Underhill
Fungi are ubiquitous in our environment, and a healthy immune system is essential to maintain adequate protection from fungal infections. When this protection breaks down, superficial and invasive fungal infections cause diseases that range from irritating to life-threatening. Millions of people worldwide develop invasive infections during their lives, and mortality for these infections often exceeds 50%. Nevertheless, we are normally colonized with many of the same disease-causing fungi (e.g., on the skin or in the gut)...
December 21, 2016: Annual Review of Pathology
Sriram Venneti, Craig B Thompson
Next-generation sequencing has substantially enhanced our understanding of the genetics of primary brain tumors by uncovering several novel driver genetic alterations. How many of these genetic modifications contribute to the pathogenesis of brain tumors is not well understood. An exciting paradigm emerging in cancer biology is that oncogenes actively reprogram cellular metabolism to enable tumors to survive and proliferate. We discuss how some of these genetic alterations in brain tumors rewire metabolism...
December 21, 2016: Annual Review of Pathology
Laura Baseler, Daniel S Chertow, Karl M Johnson, Heinz Feldmann, David M Morens
For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control...
December 7, 2016: Annual Review of Pathology
Robert P Schleimer
Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more than a million surgical interventions annually worldwide. The nose, paranasal sinuses, and associated lymphoid tissues play important roles in homeostasis and immunity, and CRS significantly impairs these normal functions. Pathogenic mechanisms of CRS have recently become the focus of intense investigations worldwide, and significant progress has been made...
December 5, 2016: Annual Review of Pathology
Ahmet Dogan
Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There are at least 30 different proteins that can cause amyloidosis. The clinical management depends entirely on the type of protein deposited, and thus on the underlying pathogenesis, and often requires high-risk therapeutic intervention. Application of mass spectrometry-based proteomic technologies for analysis of amyloid plaques has transformed the way amyloidosis is diagnosed and classified...
December 5, 2016: Annual Review of Pathology
Jon C Aster, Warren S Pear, Stephen C Blacklow
Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive...
December 5, 2016: Annual Review of Pathology
Susan Bullman, Matthew Meyerson, Aleksandar D Kostic
Established infectious agents continue to be a major cause of human morbidity and mortality worldwide. However, the causative agent remains unknown for a wide range of diseases; many of these are suspected to be attributable to yet undiscovered microorganisms. The advent of unbiased high-throughput sequencing and bioinformatics has enabled rapid identification and molecular characterization of known and novel infectious agents in human disease. An exciting era of microbe discovery, now underway, holds great promise for the improvement of global health via the development of antimicrobial therapies, vaccination strategies, targeted public health measures, and probiotic-based preventions and therapies...
December 5, 2016: Annual Review of Pathology
Jonathan H Esensten, Jeffrey A Bluestone, Wendell A Lim
Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies...
December 5, 2016: Annual Review of Pathology
Silvia Affo, Lexing Yu, Robert F Schwabe
Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver...
December 5, 2016: Annual Review of Pathology
Elaine S Jaffe
This review reflects the trajectory of my career in hematopathology, and my personal reflections on scientific advances in the field. During the course of more than 40 years, the approach to classification of hematological malignancies has evolved from descriptive approaches, based on either cytological or clinical features, to a modern approach, which incorporates cutting-edge technologies. My philosophy has focused on defining individual diseases, an approach that can best lead to an understanding of molecular pathogenesis...
December 5, 2016: Annual Review of Pathology
Lorenzo Galluzzi, Oliver Kepp, Francis Ka-Ming Chan, Guido Kroemer
Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion...
December 5, 2016: Annual Review of Pathology
M Kathryn Liszewski, Anuja Java, Elizabeth C Schramm, John P Atkinson
The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome...
December 5, 2016: Annual Review of Pathology
William M Lin, David E Fisher
Melanoma is a complex and genomically diverse malignancy, and new genes and signaling pathways involved in pathogenesis continue to be discovered. Mechanistic insights into gene and immune regulation in melanoma have led to the development of numerous successful and innovative pharmacologic agents over recent years. Multiple targeted therapies and immunotherapies have already entered the clinic, becoming new standards of care and transforming the prognosis for many patients with malignant melanoma. In this review, we provide an overview of the current understanding of signaling and immune regulation in melanoma and implications for responses to treatment, organized in the framework of hallmark characteristics in cancer...
December 5, 2016: Annual Review of Pathology
Nicole C Walsh, Laurie L Kenney, Sonal Jangalwe, Ken-Edwin Aryee, Dale L Greiner, Michael A Brehm, Leonard D Shultz
Immunodeficient mice engrafted with functional human cells and tissues, that is, humanized mice have become increasingly important as small, preclinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rg(null)) in the early 2000s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers...
December 5, 2016: Annual Review of Pathology
Andreas Schober, Christian Weber
The maladaptation of endothelial cells to disturbed flow at arterial bifurcations increases permeability for lipoproteins. Additional injury by chemically modified lipoproteins disrupts the continuous repair of maladapted endothelial cells and triggers intimal macrophage accumulation. Macrophages remove modified lipoproteins from the extracellular space until the cholesterol overload leads to macrophage death and insufficient efferocytosis. This macrophage failure promotes the progression to advanced lesions by formation of a lipid-rich necrotic core, which may rupture and cause myocardial infarction and stroke...
May 23, 2016: Annual Review of Pathology
Jonathan Hoggatt, Youmna Kfoury, David T Scadden
Regulation of stem cells in adult tissues is a key determinant of how well an organism can respond to the stresses of physiological challenge and disease. This is particularly true of the hematopoietic system, where demands on host defenses can call for an acute increase in cell production. Hematopoietic stem cells receive the regulatory signals for cell production in adult mammals in the bone marrow, a tissue with higher-order architectural and functional organization than previously appreciated. Here, we review the data defining particular structural components and heterologous cells in the bone marrow that participate in hematopoietic stem cell function...
May 23, 2016: Annual Review of Pathology
Tuo Deng, Christopher J Lyon, Stephen Bergin, Michael A Caligiuri, Willa A Hsueh
Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment...
May 23, 2016: Annual Review of Pathology
Scott B Lovitch, Scott J Rodig
The recognition that the immune system can identify and destroy tumor cells has driven a paradigm shift in our understanding of human cancer. Therapies designed to enhance this capacity, including cancer vaccines and coinhibitory receptor blockade, have demonstrated clinical efficacy in treating tumors refractory to conventional therapy. In this review, we discuss how the analysis of the immune microenvironment in primary tissue biopsy samples can be used to stratify patients according to clinical outcome, identify patients likely to benefit from specific immunotherapies, and tailor combination immunotherapy to individual patients and tumor types...
May 23, 2016: Annual Review of Pathology
Jyoti Nangalia, Jacob Grinfeld, Anthony R Green
Myeloproliferative neoplasms (MPNs) are a set of chronic hematopoietic neoplasms with overlapping clinical and molecular features. Recent years have witnessed considerable advances in our understanding of their pathogenetic basis. Due to their protracted clinical course, the evolution to advanced hematological malignancies, and the accessibility of neoplastic tissue, the study of MPNs has provided a window into the earliest stages of tumorigenesis. With the discovery of mutations in CALR, the majority of MPN patients now bear an identifiable marker of clonal disease; however, the mechanism by which mutated CALR perturbs megakaryopoiesis is currently unresolved...
May 23, 2016: Annual Review of Pathology
Sean P Colgan, Eric L Campbell, Douglas J Kominsky
Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O2 metabolism and hypoxia play a prominent role in inflammation so-called "inflammatory hypoxia," which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O2-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution...
May 23, 2016: Annual Review of Pathology
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