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The Pathogenesis of Acute Pulmonary Viral and Bacterial Infections: Investigations in Animal Models.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Acute viral and bacterial infections in the lower respiratory tract are major causes of morbidity and mortality worldwide. The proper study of pulmonary infections requires interdisciplinary collaboration among physicians and biomedical scientists to develop rational hypotheses based on clinical studies and to test these hypotheses in relevant animal models. Animal models for common lung infections are essential to understand pathogenic mechanisms and to clarify general mechanisms for host protection in pulmonary infections, as well as to develop vaccines and therapeutics. Animal models for uncommon pulmonary infection...
Source: Annual Review of Pathology - October 12, 2009 Category: Pathology Authors: Lipscomb MF, Hutt J, Lovchik J, Wu T, Lyons CR Tags: Annu Rev Pathol Source Type: journals

Preinvasive Breast Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Preinvasive breast cancer accounts for approximately one-third of all newly diagnosed breast cancer cases in the United States and constitutes a spectrum of neoplastic lesions with varying degrees of differentiation and clinical behavior. High-throughput genetic, epigenetic, and gene-expression analyses have enhanced our understanding of the relationship of these early neoplastic lesions to normal breast tissue, and they strongly suggest that preinvasive breast cancer develops and evolves along two distinct molecular genetic and biological pathways that correlate with tumor grade. Although unique epigenetic and gene-ex...
Source: Annual Review of Pathology - October 12, 2009 Category: Pathology Authors: Sgroi DC Tags: Annu Rev Pathol Source Type: journals

Mutational Heterogeneity in Human Cancers: Origin and Consequences.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cancer recapitulates Darwinian evolution. Mutations acquired during life that provide cells with a growth or survival advantage will preferentially multiply to form a tumor. As a result of The Cancer Genome Atlas Project, we have gathered detailed information on the nucleotide sequence changes in a number of human cancers. The sources of mutations in cancer are diverse, and the complexity of those found to be clonally present in tumors has increasingly made it difficult to identify key rate-limiting genes for tumor growth that could serve as potential targets for directed therapies. The impact of DNA sequencing on futu...
Source: Annual Review of Pathology - September 9, 2009 Category: Pathology Authors: Salk JJ, Fox EJ, Loeb LA Tags: Annu Rev Pathol Source Type: journals

Molecular Pathogenesis of Necrotizing Fasciitis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Necrotizing fasciitis, also known as the flesh-eating disease, is a severe invasive infection associated with very high rates of human morbidity and mortality. It is most commonly caused by group A Streptococcus (GAS), a versatile human pathogen that causes diseases ranging in severity from uncomplicated pharyngitis (or strep throat) to life-threatening infections such as necrotizing fasciitis. Herein, we review recent discoveries bearing on the molecular pathogenesis of GAS necrotizing fasciitis. Importantly, the integration of new technologies and the development of human-relevant animal models have markedly expanded...
Source: Annual Review of Pathology - September 7, 2009 Category: Pathology Authors: Olsen RJ, Musser JM Tags: Annu Rev Pathol Source Type: journals

The Pathobiology of Glioma Tumors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 5 is January 24, 2010. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. PMID: 19737106 [PubMed - as supplied by publisher] (Source: Annual Review of Pathology)
Source: Annual Review of Pathology - September 7, 2009 Category: Pathology Authors: Gladson CL, Prayson RA, Lu WM Tags: Annu Rev Pathol Source Type: journals

Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) and lymphocytic and histiocytic (L&H) cells in nodular lymphocyte-predominant HL (NLPHL) are derived from germinal-center B cells. HRS cells have, however, largely lost their B cell phenotype and aberrantly express markers and transcriptional regulators of other hematolymphoid cell types. Deregulation of multiple signaling pathways and downstream transcription factors, including receptor tyrosine kinases, nuclear factor-kappa B (NF-kappaB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT), is a further hallmark of ...
Source: Annual Review of Pathology - June 27, 2009 Category: Pathology Authors: Schmitz R, Stanelle J, Hansmann ML, Küppers R Tags: Annu Rev Pathol Source Type: journals

The pathogenesis of pituitary tumors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Recently there has been significant progress in our understanding of pituitary development, physiology, and pathology. New information has helped to clarify the classification of pituitary tumors. Epidemiologic analyses have identified a much higher incidence of pituitary tumors than previously thought. We review the pathogenetic factors that have been implicated in pituitary tumorigenesis and the application of novel targeted therapies that underscore the increasingly important role of the pathologist in determining accurate diagnoses and facilitating appropriate treatment of patients with these disorders. PMID: 1...
Source: Annual Review of Pathology - June 27, 2009 Category: Pathology Authors: Asa SL, Ezzat S Tags: Annu Rev Pathol Source Type: journals

Serrated polyps and colorectal cancer: new pathway to malignancy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Until recently, two major forms of colorectal epithelial polyp were recognized: the adenoma and the hyperplastic polyp. Adenomas were perceived to represent the precursor to colorectal cancer, whereas hyperplastic polyps were viewed as innocuous lesions with no potential for progression to malignancy. We now recognize, however, that the lesions formerly classified as hyperplastic actually represent a heterogeneous group of polyps, some of which have a significant risk for neoplastic transformation. These serrated polyps include not only hyperplastic polyps but also traditional serrated adenomas and sessile serrated ade...
Source: Annual Review of Pathology - June 27, 2009 Category: Pathology Authors: Noffsinger AE Tags: Annu Rev Pathol Source Type: journals

Regulation of hepcidin and iron-overload disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hepcidin, a 25-amino-acid antimicrobial peptide, is the central regulator of iron homeostasis. Hepcidin transcription is upregulated by inflammatory cytokines, iron, and bone morphogenetic proteins and is downregulated by iron deficiency, ineffective erythropoiesis, and hypoxia. The iron transporter ferroportin is the cognate receptor of hepcidin and is destroyed as a result of interaction with the peptide. Except for inherited defects of ferroportin and hepcidin itself, all forms of iron-storage disease appear to arise from hepcidin dysregulation. Studies using multiple approaches have begun to delineate the molecular...
Source: Annual Review of Pathology - June 27, 2009 Category: Pathology Authors: Lee PL, Beutler E Tags: Annu Rev Pathol Source Type: journals

The brainstem and serotonin in the sudden infant death syndrome.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The sudden infant death syndrome (SIDS) is the sudden death of an infant under one year of age that is typically associated with sleep and that remains unexplained after a complete autopsy and death scene investigation. A leading hypothesis about its pathogenesis is that many cases result from defects in brainstem-mediated protective responses to homeostatic stressors occurring during sleep in a critical developmental period. Here we review the evidence for the brainstem hypothesis in SIDS with a focus upon abnormalities related to the neurotransmitter serotonin in the medulla oblongata, as these are the most robust pa...
Source: Annual Review of Pathology - June 27, 2009 Category: Pathology Authors: Kinney HC, Richerson GB, Dymecki SM, Darnall RA, Nattie EE Tags: Annu Rev Pathol Source Type: journals

Molecular pathogenesis of cutaneous melanocytic neoplasms.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Melanoma is the deadliest form of skin cancer without an effective treatment. An understanding of the genetic basis of melanoma has recently shed light on some of the mechanisms of melanomagenesis. This review explores the major genes involved in familial and sporadic cutaneous melanoma with an emphasis on CDKN2A, CDK4, MC1R, and MAPK pathway targets (e.g., RAS and BRAF), apoptosis regulators (e.g., BCL-2, AKT, and APAF-1), and the tumor-suppressor genes TP53 and PTEN. New directions for therapeutics based on our current knowledge of the genes implicated in melanoma are also discussed. PMID: 19400696 [PubMed - inde...
Source: Annual Review of Pathology - June 27, 2009 Category: Pathology Authors: Ibrahim N, Haluska FG Tags: Annu Rev Pathol Source Type: journals

Linking the Cellular Functions of BRCA Genes to Cancer Pathogenesis and Treatment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Single-gene disorders that predispose to cancer afford a unique window into the mechanisms of carcinogenesis. I argue here that the instability in chromosome structure and number provoked by inactivation of the breast cancer-susceptibility genes BRCA1 and BRCA2 arises from the distinct functions served by their products in DNA repair or mitosis, explains many features of cancer pathogenesis in this setting, and has important implications for treatment. The chromosomal instability model proposed here suggests a conceptual framework for the connections between chromosomal aberrations and cancer. Expected final online pub...
Source: Annual Review of Pathology - October 27, 2008 Category: Pathology Authors: Venkitaraman AR Tags: Annu Rev Pathol Source Type: journals

The Immunopathogenesis of Rheumatoid Arthritis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Rheumatoid arthritis is a chronic inflammatory polyarthritis whose etiology remains uncertain. Recently we have learned that autoimmunity to citrullinated protein antigens has specificity for rheumatoid arthritis and defines a clinically and genetically distinct form of the disease. Multiple genes contribute to disease susceptibility, with the HLA locus accounting for 30% to 50% of overall genetic risk. Five risk loci have been identified and validated: HLA-DRB1, PTPN22, STAT4, a region in 6q23, and the TRAF1/C5 locus. Also, there is renewed interest in the contribution of T cells to ongoing inflammation in rheumatoid ...
Source: Annual Review of Pathology - October 27, 2008 Category: Pathology Authors: Imboden JB Tags: Annu Rev Pathol Source Type: journals

The Pathology of Chronic Obstructive Pulmonary Disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the resp...
Source: Annual Review of Pathology - October 27, 2008 Category: Pathology Authors: Hogg JC, Timens W Tags: Annu Rev Pathol Source Type: journals

Nod-like Receptors: Role in Innate Immunity and Inflammatory Disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The NOD-like receptors (NLRs) are a specialized group of intracellular receptors that represent a key component of the host innate immune system. Since the discovery of the first NLR almost 10 years ago, the study of this special class of microbial sensors has burgeoned; consequently, a better understanding of the mechanism by which these receptors recognize microbes and other danger signals and of how they activate inflammatory signaling pathways has emerged. Moreover, in addition to their primary role in host defense against invading pathogens, their ability to regulate nuclear factor-kappa B (NF-kappaB) signaling, i...
Source: Annual Review of Pathology - October 17, 2008 Category: Pathology Authors: Chen G, Shaw MH, Kim YG, Nuñez G Tags: Annu Rev Pathol Source Type: journals

Tumor Suppressors, Chromosomal Instability, and Hepatitis C Virus-Associated Liver Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hepatitis C virus (HCV) is the only known RNA virus with an exclusively cytoplasmic life cycle that is associated with cancer. The mechanisms by which it causes cancer are unclear, but chronic immunemediated inflammation and associated oxidative chromosomal DNA damage probably play a role. Compelling data suggest that the path to hepatocellular carcinoma in chronic hepatitis C shares some important features with the mechanisms of transformation employed by DNA tumor viruses. Interactions of viral proteins with key regulators of the cell cycle, the retinoblastoma-susceptibility protein, p53, and possibly DDX5 and DDX3 l...
Source: Annual Review of Pathology - October 17, 2008 Category: Pathology Authors: McGivern DR, Lemon SM Tags: Annu Rev Pathol Source Type: journals

Drosophila Models of Neurodegenerative Diseases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insight...
Source: Annual Review of Pathology - October 8, 2008 Category: Pathology Authors: Lu B, Vogel H Tags: Annu Rev Pathol Source Type: journals

Ovarian Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ovarian carcinomas are a heterogeneous group of neoplasms and are traditionally subclassified based on type and degree of differentiation. Although current clinical management of ovarian carcinoma largely fails to take this heterogeneity into account, it is becoming evident that each major histological type has characteristic genetic defects that deregulate specific signaling pathways in the tumor cells. Moreover, within the most common histological types, the molecular pathogenesis of low-grade versus high-grade tumors appears to be largely distinct. Mouse models of ovarian carcinoma have been developed that recapitul...
Source: Annual Review of Pathology - October 8, 2008 Category: Pathology Authors: Cho KR, Shih IM Tags: Annu Rev Pathol Source Type: journals

Molecular Pathogenesis and Diagnostics of Bladder Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Despite elaborate characterization of the risk factors, bladder cancer is still a major epidemiological problem whose incidence continues to rise each year. Urothelial carcinoma is now recognized as a disease of alterations in several cellular processes. The more prevalent, less aggressive, recurrent, noninvasive tumors are characterized by constitutive activation of the Ras-MAPK pathway. The less common but more aggressive invasive tumors, which have a higher mortality rate, are characterized by alterations in the p53 and retinoblastoma pathways. Several diagnostic tests have attempted to identify these molecular alte...
Source: Annual Review of Pathology - October 7, 2008 Category: Pathology Authors: Mitra AP, Cote RJ Tags: Annu Rev Pathol Source Type: journals

Epigenetic Changes in Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Normal epigenetic modifications of DNA encompass three types of changes: chromatin modifications, DNA methylation, and genomic imprinting, each of which is altered in cancer cells. This review addresses the various epigenetic modifications that are pervasive among human tumors and traces the history of cancer epigenetics from the first observations of altered global methylation content to the recently proposed epigenetic progenitor model, which provides a commo...
Source: Annual Review of Pathology - October 7, 2008 Category: Pathology Authors: Iacobuzio-Donahue CA Tags: Annu Rev Pathol Source Type: journals

MicroRNAs in Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Within the past few years, studies on microRNA (miRNA) and cancer have burst onto the scene. Profiling of the miRNome (global miRNA expression levels) has become prevalent, and abundant miRNome data are currently available for various cancers. The pattern of miRNA expression can be correlated with cancer type, stage, and other clinical variables, so miRNA profiling can be used as a tool for cancer diagnosis and prognosis. miRNA expression analyses also suggest oncogenic (or tumor-suppressive) roles of miRNAs. miRNAs play roles in almost all aspects of cancer biology, such as proliferation, apoptosis, invasion/metastasi...
Source: Annual Review of Pathology - September 25, 2008 Category: Pathology Authors: Lee YS, Dutta A Tags: Annu Rev Pathol Source Type: journals

Molecular Genetics of Acute Lymphoblastic Leukemia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Acute lymphoblastic leukemia (ALL) is mainly a disease of childhood that arises from recurrent genetic insults that block precursor B and T cell differentiation and drive aberrant cell proliferation and survival. Recurrent defects including chromosomal translocations, aneuploidies, and gene-specific alterations generate molecular subgroups of B- and T-ALL with differing clinical courses and distinct responses to therapy. Recent discoveries arising from genome-wide surveys and adoptive transfer of leukemia-initiating cells have uncovered multiple gene copy number aberrations and have yielded new insight into at least on...
Source: Annual Review of Pathology - September 10, 2008 Category: Pathology Authors: Teitell MA, Pandolfi PP Tags: Annu Rev Pathol Source Type: journals

PTEN and the PI3-Kinase Pathway in Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PI3-kinase and PTEN are major positive and negative regulators, respectively, of the PI3-kinase pathway, which regulates growth, survival, and proliferation. These key signaling components are two of the most frequently mutated proteins in human cancers, resulting in unregulated activation of PI3K signaling and providing irrefutable genetic evidence of the central role of this pathway in tumorigenesis. PTEN regulates PI3K signaling by dephosphorylating the lipid signaling intermediate PIP3, but PTEN may have additional phosphatase-independent activities, as well as other functions in the nucleus. In this review, we hig...
Source: Annual Review of Pathology - September 3, 2008 Category: Pathology Authors: Chalhoub N, Baker SJ Tags: Annu Rev Pathol Source Type: journals

Mechanisms of Endothelial Dysfunction, Injury, and Death.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Vascular endothelial cells normally perform several key homeostatic functions such as keeping blood fluid, regulating blood flow, regulating macromolecule and fluid exchange with the tissues, preventing leukocyte activation, and aiding in immune surveillance for pathogens. Injury or cell death impairs or prevents conduct of these activities, resulting in dysfunction. Most endothelial cell death is apoptotic, involving activation of caspases, but nonapoptotic death responses also have been described. Stimuli that can cause endothelial injury or death include environmental stresses such as oxidative stress, endoplasmic r...
Source: Annual Review of Pathology - August 28, 2008 Category: Pathology Authors: Pober JS, Min W, Bradley JR Tags: Annu Rev Pathol Source Type: journals

Molecular Pathology of Head and Neck Cancer: Implications for Diagnosis, Prognosis, and Treatment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The prototypic head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract, demonstrates squamous differentiation microscopically, involves older men with a long history of cigarette smoking and alcohol consumption, and is treated by multimodality therapy. HNSCC has long been regarded as a uniform disease process requiring a methodical and unwavering therapeutic approach. Divergence in epidemiologic trends among HNSCCs arising from different anatomic sites has introduced a view that, morphologic repetition aside, head and neck cancers form a heterogeneous group. This vi...
Source: Annual Review of Pathology - August 26, 2008 Category: Pathology Authors: Pai SI, Westra WH Tags: Annu Rev Pathol Source Type: journals

Graft Vascular Disease: Immune Response Meets the Vessel Wall.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Graft vascular disease (GVD) is the single most important long-term limitation to solid-organ transplantation. It is a concentric vascular intimal hyperplastic lesion composed of smooth muscle-like cells and associated matrix. GVD diffusely involves allograft vessels, eventually compromising perfusion and resulting in graft ischemia and failure. Animal models and an increasing sophistication in analyzing human GVD have provided important new insights into GVD pathogenesis. Innate and specific immune responses both participate in the initial vascular injury; GVD develops as a consequence of downstream chemokineand cytok...
Source: Annual Review of Pathology - August 21, 2008 Category: Pathology Authors: Mitchell RN Tags: Annu Rev Pathol Source Type: journals

The First Fifty Years in Research.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
It has been an honor for me to write the prefatory article for Volume 4 of the Annual Review of Pathology: Mechanisms of Disease. I decided to describe the first 50 years of my career in research, which started with my entry into medical school. I have tried to outline the numerous scientific mentors who played such an important role in my development as an independent scientific investigator. In general, I have tried to avoid mention in the text of the many, many colleagues who carried out the scientific work, as I would inevitably fail to cite many of them. Rather, I have cited what I think are my most important publ...
Source: Annual Review of Pathology - August 14, 2008 Category: Pathology Authors: Ward PA Tags: Annu Rev Pathol Source Type: journals

Modeling morphogenesis and oncogenesis in three-dimensional breast epithelial cultures.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Three-dimensional (3D) epithelial culture systems recreate the cardinal features of glandular epithelium in vivo and represent a valuable tool for modeling breast cancer initiation and progression in a structurally appropriate context. 3D models have emerged as a powerful method to interrogate the biological activities of cancer genes and oncogenic pathways, and recent studies have poignantly illustrated their utility in dissecting the emerging role of tensional force in regulating epithelial tissue homeostasis. We review how 3D models are being used to investigate fundamental cellular and biophysical mechanisms associ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Hebner C, Weaver VM, Debnath J Tags: Annu Rev Pathol Source Type: journals

Notch signaling in leukemia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Recent discoveries indicate that gain-of-function mutations in the Notch1 receptor are very common in human T cell acute lymphoblastic leukemia/lymphoma. This review discusses what these mutations have taught us about normal and pathophysiologic Notch1 signaling, and how these insights may lead to new targeted therapies for patients with this aggressive form of cancer. PMID: 18039126 [PubMed - indexed for MEDLINE] (Source: Annual Review of Pathology)
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Aster JC, Pear WS, Blacklow SC Tags: Annu Rev Pathol Source Type: journals

The origins of medulloblastoma subtypes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Childhood tumors containing cells that are morphologically and functionally similar to normal progenitor cells provide fertile ground for investigating the links between development and cancer. In this respect, integrated studies of normal cerebellar development and the medulloblastoma, a malignant embryonal tumor of the cerebellum, have proven especially fruitful. Emerging evidence indicates that the different precursor cell populations that form the cerebellum and the cell signaling pathways that regulate its development likely represent distinct compartments from which the various subtypes of medulloblastoma arise. ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Gilbertson RJ, Ellison DW Tags: Annu Rev Pathol Source Type: journals

The relevance of research on red cell membranes to the understanding of complex human disease: a personal perspective.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Molecular analysis in the service of research on human disease has finally come of age, as the chapters within this volume testify. Many technical advances, among them the development of recombinant DNA and its many applications, opened the way to study cells and processes that were unapproachable in the 1960s, when I first began my research career. The state of molecular biological studies at that time limited studies of human cell membrane proteins to experimental material most available and accessible, making the human erythrocyte membrane the favored target. I describe here how studies of red blood cell membrane pr...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Marchesi VT Tags: Annu Rev Pathol Source Type: journals

Autophagy: basic principles and relevance to disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Autophagy is a process by which cytoplasmic components are sequestered in double membrane vesicles and degraded upon fusion with lysosomal compartments. In yeast, autophagy is activated in response to changes in the extracellular milieu. Depending upon the stimulus, autophagy can degrade cytoplasmic contents nonspecifically or can target the degradation of specific cellular components. Both of these have been adopted in higher eukaryotes and account for the expanding role of autophagy in various cellular processes, as well as contribute to the variation in cellular outcomes after induction of autophagy. In some cases, ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Kundu M, Thompson CB Tags: Annu Rev Pathol Source Type: journals

The aging brain.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aging is accompanied by cognitive decline in a major segment of the population and is the primary risk factor for Alzheimer's disease and other prevalent neurodegenerative disorders. Despite this central role in disease pathogenesis and morbidity, the aging of the brain has not been well understood at a molecular level. This review seeks to integrate what is known about age-related cognitive and neuroanatomical changes with recent advances in understanding basic molecular mechanisms that underlie aging. An important issue is how normal brain aging transitions to pathological aging, giving rise to neurodegenerative diso...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Yankner BA, Lu T, Loerch P Tags: Annu Rev Pathol Source Type: journals

Molecular biology and pathogenesis of viral myocarditis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. Several viruses have been associated with myocarditis in humans. However, coxsackievirus B3 is still considered the dominant etiological agent. The observed pathology in viral myocarditis is a result of cooperation or teamwork between viral processes and host immune responses at various stages of disease. Both innate and adaptive immune responses are crucial determinants of the severity of myocardial damage, and contribute to the development of chronic myocarditis and dilated cardiomyopathy following acute viral myocarditis. Adv...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Esfandiarei M, McManus BM Tags: Annu Rev Pathol Source Type: journals

The role of hypoxia in vascular injury and repair.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Although the terms ischemia and hypoxia are often used interchangeably, they represent distinct processes that result in different modulatory effects at the cellular level. Hypoxia is a reduction in oxygen delivery below tissue demand, whereas ischemia is a lack of perfusion, characterized not only by hypoxia but also by insufficient nutrient supply. Hypoxia can be either acute or chronic, and both are centrally regulated by hypoxia-inducible factor, a transcription factor that governs the expression of key response genes such as vascular endothelial growth factor and erythropoietin. Whereas severe chronic hypoxia can ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Walshe TE, D'Amore PA Tags: Annu Rev Pathol Source Type: journals

Airway smooth muscle in asthma.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Airway smooth muscle plays a multifaceted role in the pathogenesis of asthma. We review the current understanding of the contribution of airway myocytes to airway inflammation, airway wall remodeling, and airflow obstruction in this prevalent disease syndrome. Together, these roles make airway smooth muscle an attractive target for asthma therapy. PMID: 18039134 [PubMed - indexed for MEDLINE] (Source: Annual Review of Pathology)
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Hershenson MB, Brown M, Camoretti-Mercado B, Solway J Tags: Annu Rev Pathol Source Type: journals

The osteoclast: friend or foe?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Bone is a dynamic organ constantly remodeled to support calcium homeostasis and structural needs. The osteoclast is the cell responsible for removing both the organic and inorganic components of bone. It is derived from hematopoietic progenitors in the macrophage lineage and differentiates in response to the tumor necrosis factor family cytokine receptor activator of NF kappa B ligand. alpha v beta 3 integrin mediates cell adhesion necessary for polarization and formation of an isolated, acidified resorptive microenvironment. Defects in osteoclast function, whether genetic or iatrogenic, may increase bone mass but lead...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Novack DV, Teitelbaum SL Tags: Annu Rev Pathol Source Type: journals

Pancreatic cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The past two decades have witnessed an explosion in our understanding of pancreatic cancer, and it is now clear that pancreatic cancer is a disease of inherited (germ-line) and somatic gene mutations. The genes mutated in pancreatic cancer include KRAS2, p16/CDKN2A, TP53, and SMAD4/DPC4, and these are accompanied by a substantial compendium of genomic and transcriptomic alterations that facilitate cell cycle deregulation, cell survival, invasion, and metastases. Pancreatic cancers do not arise de novo, and three distinct precursor lesions have been identified. Experimental models of pancreatic cancer have been develope...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Maitra A, Hruban RH Tags: Annu Rev Pathol Source Type: journals

Gene expression profiling of breast cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
DNA microarray platforms for gene expression profiling were invented relatively recently, and breast cancer has been among the earliest and most intensely studied diseases using this technology. The molecular signatures so identified help reveal the biologic spectrum of breast cancers, provide diagnostic tools as well as prognostic and predictive gene signatures, and may identify new therapeutic targets. Data are best presented in an open access format to facilitate external validation, the most crucial step in identifying robust, reproducible gene signatures suitable for clinical translation. Clinically practical appl...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Cheang MC, van de Rijn M, Nielsen TO Tags: Annu Rev Pathol Source Type: journals

The pathology of influenza virus infections.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic. The histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed here. Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not significantly different from the histopathology ob...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Taubenberger JK, Morens DM Tags: Annu Rev Pathol Source Type: journals

Endoplasmic reticulum stress in disease pathogenesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which, collectively, represent a large fraction of the total protein output of a mammalian cell. Therefore, the protein flux through the ER must be carefully monitored for abnormalities, including the buildup of misfolded proteins. Mammalian cells have evolved an intricate set of signaling pathways from the ER to the cytosol and nucleus, to allow the cell to respond to the presence of misfolded proteins within the ER. These pathways, known collectively as the unfolded protein response, are important for normal cellul...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Lin JH, Walter P, Yen TS Tags: Annu Rev Pathol Source Type: journals

Molecular pathobiology of gastrointestinal stromal sarcomas.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Gastrointestinal stromal tumors (GISTs) form an interesting group of sarcomas whose unique pathobiology provides a model of how molecularly targeted therapeutics can have a major impact on patient welfare. Approximately 85% of GISTs are driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT or platelet-derived growth factor receptor alpha. We review the pivotal relationship between specific mutations in these kinase genes, the origin and pathologic spectrum of GISTs, and the response of these tumors to treatment with kinase inhibitors such as imatinib and sunitinib. Mechanisms of resistance to ki...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Corless CL, Heinrich MC Tags: Annu Rev Pathol Source Type: journals

Molecular biology and pathology of lymphangiogenesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The lymphatic vasculature is essential for the maintenance of tissue fluid balance, immune surveillance, and adsorption fatty acids in the gut. The lymphatic vessels are also crucially involved in the pathogenesis of diseases such as tumor metastasis, lymphedema, and various inflammatory conditions. Attempts to control or treat these diseases have drawn a lot of interest to lymphatic vascular research during the past few years. Recently, several markers specific for lymphatic endothelium and models for lymphatic vascular research have been characterized, enabling great technical progress in lymphatic vascular biology, ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Karpanen T, Alitalo K Tags: Annu Rev Pathol Source Type: journals

Applications of proteomics to lab diagnosis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Detailed and comprehensive characterization of proteins is a major goal of proteomics. This goal has become more realistic today with the latest high-resolution mass spectrometers capable of faster sequencing in a high-throughput fashion and with the emergence of new techniques such as protein and peptide microarrays. A promising area for discovery is the application of these advanced mass spectrometric and other quantitative proteomic methodologies to laboratory diagnosis. This review focuses on the role of proteomics in the development of new laboratory diagnostics and the implications for routine diagnosis and monit...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Chaerkady R, Pandey A Tags: Annu Rev Pathol Source Type: journals

The inflammatory response to cell death.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
When cells die in vivo, they trigger an inflammatory response. The ensuing hyperemia, leak of plasma proteins, and recruitment of leukocytes serve a number of useful functions in host defense and tissue repair. However, this response can also cause tissue damage and contribute to the pathogenesis of a number of diseases. Given the key role of inflammation in these processes, it is important to understand the underlying mechanisms that drive this response. Injured cells release danger signals that alert the host to cell death. Some of these molecules are recognized by cellular receptors that stimulate the generation of ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Rock KL, Kono H Tags: Annu Rev Pathol Source Type: journals

Kidney transplantation: mechanisms of rejection and acceptance.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe the molecular and cellular mechanisms believed to be responsible for the rejection of renal allografts, including acute T cell-mediated rejection, acute antibody-mediated (humoral) rejection, rejection mediated by the innate immune system, and chronic rejection. We present mechanisms of graft acceptance, including accommodation, regulation, and tolerance. Studies in animals have replicated many pathologic features of acute and chronic rejection. We illuminate the pathogenesis of human pathology by reflection from experimental models. PMID: 18039144 [PubMed - indexed for MEDLINE] (Source: Annual Review of Pathology)
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Cornell LD, Smith RN, Colvin RB Tags: Annu Rev Pathol Source Type: journals

Pathogenesis of thrombotic microangiopathies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Profound thrombocytopenia and microangiopathic hemolytic anemia characterize thrombotic microangiopathy, which includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP has at least three types: congenital or familial, idiopathic, and nonidiopathic. The congenital and idiopathic TTP syndromes are caused primarily by deficiency of ADAMTS13, owing to mutations in the ADAMTS13 gene or autoantibodies that inhibit ADAMTS13 activity. HUS is similar to TTP, but is associated with acute renal failure. Diarrhea-associated HUS accounts for more than 90% of cases and is usual...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Zheng XL, Sadler JE Tags: Annu Rev Pathol Source Type: journals

Molecular mechanisms of prion pathogenesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Prion diseases are infectious neurodegenerative diseases occurring in humans and animals with an invariably lethal outcome. One fundamental mechanistic event in prion diseases is the aggregation of aberrantly folded prion protein into large amyloid plaques and fibrous structures associated with neurodegeneration. The cellular prion protein (PrPC) is absolutely required for disease development, and prion knockout mice are not susceptible to prion disease. Prions accumulate not only in the central nervous system but also in lymphoid organs, as shown for new variant and sporadic Creutzfeldt-Jakob patients and for some ani...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Aguzzi A, Sigurdson C, Heikenwaelder M Tags: Annu Rev Pathol Source Type: journals

Metastatic cancer cell.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Metastasis is the result of cancer cell adaptation to a tissue microenvironment at a distance from the primary tumor. Metastatic cancer cells require properties that allow them not only to adapt to a foreign microenvironment but to subvert it in a way that is conducive to their continued proliferation and survival. Recent conceptual and technological advances have contributed to our understanding of the role of the host tissue stroma in promoting tumor cell growth and dissemination and have provided new insight into the genetic makeup of cancers with high metastatic proclivity. PMID: 18233952 [PubMed - indexed for ...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Bacac M, Stamenkovic I Tags: Annu Rev Pathol Source Type: journals

Anti-inflammatory and proresolving lipid mediators.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The popular view that all lipid mediators are pro-inflammatory arises largely from the finding that nonsteroidal anti-inflammatory drugs block the biosynthesis of prostaglandins. The resolution of inflammation was widely held as a passive event until recently, with the characterization of novel biochemical pathways and lipid-derived mediators that are actively turned on in resolution and that possess potent anti-inflammatory and proresolving actions. A lipid-mediator informatics approach was employed to systematically identify new families of endogenous local-acting mediators from omega-3 polyunsaturated fatty acids (e...
Source: Annual Review of Pathology - July 7, 2008 Category: Pathology Authors: Serhan CN, Yacoubian S, Yang R Tags: Annu Rev Pathol Source Type: journals