[PERSPECTIVES] Comparative Pathology of Hepatitis A Virus and Hepatitis E Virus Infection
Hepatitis A virus (HAV) and hepatitis E virus (HEV) cause acute, self-limiting hepatic infections that are usually spread by the fecal–oral route in humans. Naturally occurring and experimental infections are possible in a variety of nonhuman primates and, in the case of HEV, a number of other species. Many advances in understanding the pathogenesis of these viruses have come from studies in experimental animals. In general, animals infected with these viruses recapitulate the histologic lesions seen in infected humans, but typically with less severe clinical and histopathological manifestations. This review describe...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Cullen, J. M., Lemon, S. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Epidemiology and Transmission of Hepatitis A Virus and Hepatitis E Virus Infections in the United States
There are many similarities in the epidemiology and transmission of hepatitis A virus (HAV) and hepatitis E virus (HEV) genotype (gt)3 infections in the United States. Both viruses are enterically transmitted, although specific routes of transmission are more clearly established for HAV than for HEV: HAV is restricted to humans and primarily spread through the fecal–oral route, while HEV is zoonotic with poorly understood modes of transmission in the United States. New cases of HAV infection have decreased dramatically in the United States since infant vaccination was recommended in 1996. In recent years, however, ou...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Hofmeister, M. G., Foster, M. A., Teshale, E. H. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Stem Cells and the Bird Cochlea--Where Is Everybody?
In sharp contrast to the adult mammalian cochlea, which lacks regenerative ability, the mature avian cochlea, or basilar papilla (BP) is capable of complete recovery from hearing loss after damage. Avian sensory hair cell regeneration relies on rousing quiescent supporting cells to proliferate or transdifferentiate after hair cell death. Unlike mammalian cochlear supporting cells, which have clearly defined subtypes, avian BP supporting cells are deceptively indistinguishable and molecular markers have yet to be identified. Despite the importance of supporting cells as the putative stem cells in avian regeneration, it is u...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Janesick, A. S., Heller, S. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Prostate Cancer Epigenetics: From Basic Mechanisms to Clinical Implications
A level of epigenetic programming, encoded by complex sets of chemical marks on DNA and histones, and by context-specific DNA, RNA, protein interactions, that all regulate the structure, organization, and function of the genome, is critical to establish both normal and neoplastic cell identities and functions. This structure–function relationship of the genome encoded by the epigenetic programming can be thought of as an epigenetic cityscape that is built on the underlying genetic landscape. Alterations in the epigenetic cityscape of prostate cancer cells compared with normal prostate tissues have a complex interplay...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Yegnasubramanian, S., De Marzo, A. M., Nelson, W. G. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Pathology of High-Grade Prostatic Intraepithelial Neoplasia: Challenges and Opportunities
A better understanding of the early stages of prostate cancer initiation, potentially arising from precursor lesions, may fuel development of powerful approaches for prostate cancer prevention or interception. The best-known candidate for such a precursor lesion has been referred to as high-grade prostatic intraepithelial neoplasia (HGPIN). Although there is significant evidence supporting the notion that such HGPIN lesions can give rise to invasive adenocarcinomas of the prostate, there are also numerous complicating considerations and evidence that cloud the picture in many instances. Notably, recent evidence has suggest...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Trabzonlu, L., Kulac, I., Zheng, Q., Hicks, J. L., Haffner, M. C., Nelson, W. G., Sfanos, K. S., Ertunc, O., Lotan, T. L., Heaphy, C. M., Meeker, A. K., Yegnasubramanian, S., De Marzo, A. M. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Multiple Roles of B Cells in Multiple Sclerosis and Their Implications in Multiple Sclerosis Therapies
Increasing evidence has suggested that both antibody-dependent and antibody-independent functions of B cells are involved in multiple sclerosis (MS). The contrasting results of distinct B-cell targeting therapies in MS patients underscores the importance of elucidating these multiple B-cell functions. In this review, we discuss the generation of autoreactive B cells, migration of B cells into the central nervous system (CNS), and how different functions of B cells may contribute to MS disease activity and potentially mitigation in both the periphery and CNS compartments. In addition, we propose several future therapeutic s...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Li, R., Bar-Or, A. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Lifestyle and Environmental Factors in Multiple Sclerosis
Lifestyle and environmental factors potently influence the risk of multiple sclerosis (MS), because genetic predisposition only explains a fraction of the risk increase. There is strong evidence for associations of Epstein–Barr virus (EBV) infection, smoking, sun exposure/vitamin D, and adolescent obesity to risk of MS. There is also circumstantial evidence on organic solvents and shift work, all associate with greater risk, although certain factors like nicotine, alcohol, and a high coffee consumption associate with a reduced risk. Certain factors, smoking, EBV infection, and obesity interact with human leukocyte an...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Alfredsson, L., Olsson, T. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[TECHNIQUE] Characterizing the Cancer Genome in Blood
Cell-free circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) can be found in the bloodstream of individuals with cancer and are increasingly being explored as biomarkers in various aspects of cancer management. The application of next-generation sequencing (NGS) technologies to ctDNA and CTC analysis are providing new opportunities to characterize the cancer genome from a simple blood test and can facilitate the ease with which tumor-specific genomic changes can be followed over time. The serial analysis of ctDNA and CTCs has enormous potential to provide insights into intratumor heterogeneity and clonal evol...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2019 Category: Research Authors: Dawson, S.-J. Tags: Next-Generation Sequencing in Medicine TECHNIQUE Source Type: research

[RETROSPECTIVE] The Genomics of Prostate Cancer: A Historic Perspective
The genomics of prostate cancer (PCA) has been difficult to study compared with some other cancer types for a multitude of reasons, despite significant efforts since the early 1980s. Overcoming some of these obstacles has paved the way for greater insight into the genomics of PCA. The advent of high-throughput technologies coming from the initial use of microsatellite and oligonucleotide probes gave rise to techniques like comparative genomic hybridization (CGH). With the introduction of massively parallel genomic sequencing, referred to as next-generation sequencing (NGS), a deeper understanding of cancer genomics in gene...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Rubin, M. A., Demichelis, F. Tags: Prostate Cancer RETROSPECTIVE Source Type: research

[PERSPECTIVES] Whole-Genome Sequencing in Cancer
Genome sequencing of cancer has fundamentally advanced our understanding of the underlying biology of this disease, and more recently has provided approaches to characterize and monitor tumors in the clinic, guiding and evaluating treatment. Although cancer research is relying more on whole-genome characterization, the clinical application of genomics is largely limited to targeted sequencing approaches, tailored to capture specific clinically relevant biomarkers. However, as sequencing costs reduce, and the tools to effectively analyze complex and large-scale data improve, the ability to effectively characterize whole gen...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Zhao, E. Y., Jones, M., Jones, S. J. M. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Metastases in Prostate Cancer
Prostate cancer (PCa) prognosis and clinical outcome is directly dependent on metastatic occurrence. The bone microenvironment is a favorable metastatic niche. Different biological processes have been suggested to contribute to the osteotropism of PCa such as hemodynamics, bone-specific signaling interactions, and the "seed and soil" hypothesis. However, prevalence of disseminating tumor cells in the bone is not proportional to the actual occurrence of metastases, as not all patients will develop bone metastases. The fate and tumor-reforming ability of a metastatic cell is greatly influenced by the microenvironme...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Manna, F. L., Karkampouna, S., Zoni, E., De Menna, M., Hensel, J., Thalmann, G. N., Kruithof-de Julio, M. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Innate Immunity to Enteric Hepatitis Viruses
Although hepatitis A virus (HAV) and hepatitis E virus (HEV) are both positive-strand RNA viruses that replicate in the cytoplasm of hepatocytes, there are important differences in the ways they induce and counteract host innate immune responses. HAV is remarkably stealthy because of its ability to evade and disrupt innate signaling pathways that lead to interferon production. In contrast, HEV does not block interferon production. Instead, it persists in the presence of an interferon response. These differences may provide insight into HEV persistence in immunocompromised patients, an emerging health problem in developed c...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Feng, Z., Lemon, S. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Stem Cell-Derived Culture Models of Hepatitis E Virus Infection
Similar to other hepatotropic viruses, hepatitis E virus (HEV) has been notoriously difficult to propagate in cell culture, limiting studies to unravel its biology. Recently, major advances have been made by passaging primary HEV isolates and selecting variants that replicate efficiently in carcinoma cells. These adaptations, however, can alter HEV biology. We have explored human embryonic or induced pluripotent stem cell (hESC/iPSC)-derived hepatocyte-like cells (HLCs) as an alternative to conventional hepatoma and hepatocyte cell culture systems for HEV studies. HLCs are permissive for nonadapted HEV isolate genotypes (g...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Dao Thi, V. L., Wu, X., Rice, C. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Ras-Specific GTPase-Activating Proteins--Structures, Mechanisms, and Interactions
Ras-specific GTPase-activating proteins (RasGAPs) down-regulate the biological activity of Ras proteins by accelerating their intrinsic rate of GTP hydrolysis, basically by a transition state stabilizing mechanism. Oncogenic Ras is commonly not sensitive to RasGAPs caused by interference of mutants with the electronic or steric requirements of the transition state, resulting in up-regulation of activated Ras in respective cells. RasGAPs are modular proteins containing a helical catalytic RasGAP module surrounded by smaller domains that are frequently involved in the subcellular localization or contributing to regulatory fe...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Scheffzek, K., Shivalingaiah, G. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune disorder that typically affects young people during their most productive years, causing irreversible damage and accumulation of disability. Treatments over time have had modest effects at completely controlling or suppressing disease activity, but are generally aimed at controlling early dominating inflammation that, over time, accumulates damage and leads to progressive disability. Some unfortunate patients are destined to deteriorate despite even newer and more effective agents because of the inability of these drugs to fully curb the inflammatory component of the disease. These ...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Rush, C. A., Atkins, H. L., Freedman, M. S. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Biomarkers in Multiple Sclerosis
Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease with a complex clinical course characterized by inflammation, demyelination, and axonal degeneration. Diagnosis of MS most commonly includes finding lesions in at least two separate areas of the central nervous system (CNS), including the brain, spinal cord, and optic nerves. In recent years, there has been a remarkable increase in the number of available treatments for MS. An optimal treatment is usually based on a personalized approach determined by an individual patient’s prognosis and treatment risks. Biomarkers that can predict disability ...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2019 Category: Research Authors: Paul, A., Comabella, M., Gandhi, R. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Cochlear Frequency Tuning and Otoacoustic Emissions
Otoacoustic emissions (OAEs) evoked from the inner ear are the barely audible, signature byproduct of the delicate hydromechanical amplifier that evolved within its bony walls. Compared to the sounds evoked from the ears of common laboratory animals, OAEs from human ears have exceptionally long delays, typically exceeding those of cats, guinea pigs, and chinchillas by a factor of two to three. This review asks "Why are human OAE delays so long?" and recounts efforts to locate answers in the characteristics of mechanical frequency selectivity in the inner ear. The road to understanding species differences in OAE d...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Shera, C. A., Charaziak, K. K. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Next-Generation Sequencing in Pharmacogenetics and Pharmacogenomics
Inherited genetic variations in pharmacogenetic loci are widely acknowledged as important determinants of phenotypic differences in drug response, and may be actionable in the clinic. However, recent studies suggest that a considerable number of novel rare variants in pharmacogenes likely contribute to a still unexplained fraction of the observed interindividual variability. Next-generation sequencing (NGS) represents a rapid, relatively inexpensive, large-scale DNA sequencing technology with potential relevance as a comprehensive pharmacogenetic genotyping platform to identify genetic variation related to drug therapy. Ho...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Schwarz, U. I., Gulilat, M., Kim, R. B. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] B-Cell Therapies in Multiple Sclerosis
B cells play a vital function in multiple sclerosis (MS) pathogenesis through an array of effector functions. All currently approved MS disease–modifying therapies alter the frequency, phenotype, or homing of B cells in one way or another. The importance of this mechanism of action has been reinforced with the successful development and clinical testing of B-cell-depleting monoclonal antibodies that target the CD20 surface antigen. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved by the Food and Drug Administration (FDA) in March 2017 after pivotal trials showed dramatic reductions in inflammatory...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Sabatino, J. J., Zamvil, S. S., Hauser, S. L. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Nonhuman Primate Models of Hepatitis A Virus and Hepatitis E Virus Infections
Although phylogenetically unrelated, human hepatitis viruses share an exclusive or near exclusive tropism for replication in differentiated hepatocytes. This narrow tissue tropism may contribute to the restriction of the host ranges of these viruses to relatively few host species, mostly nonhuman primates. Nonhuman primate models thus figure prominently in our current understanding of the replication and pathogenesis of these viruses, including the enterically transmitted hepatitis A virus (HAV) and hepatitis E virus (HEV), and have also played major roles in vaccine development. This review draws comparisons of HAV and HE...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Lanford, R. E., Walker, C. M., Lemon, S. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Immunization against Hepatitis A
Worldwide, there are multiple formaldehyde-inactivated and at least two live attenuated hepatitis A vaccines now in clinical use. The impressive immunogenicity of inactivated vaccines is reflected in rapid seroconversion rates, enabling both preexposure and postexposure prophylaxis. Universal childhood vaccination programs targeting young children have led to significant drops in the incidence of hepatitis A both in toddlers and in susceptible nonimmune adults in regions with intermediate endemicity for hepatitis A. Although the safety of inactivated vaccines is well established, further studies are needed concerning the i...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Shouval, D. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] The Interdependent Activation of Son-of-Sevenless and Ras
The guanine-nucleotide exchange factor (GEF) Son-of-Sevenless (SOS) plays a critical role in metazoan signaling by converting Ras•GDP (guanosine diphosphate) to Ras•GTP (guanosine triphosphate) in response to tyrosine kinase activation. Structural studies have shown that SOS differs from other Ras-specific GEFs in that SOS is itself activated by Ras•GTP binding to an allosteric site, distal to the site of nucleotide exchange. The activation of SOS involves membrane recruitment and conformational changes, triggered by lipid binding, that open the allosteric binding site for Ras•GTP. This is in contrast t...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Bandaru, P., Kondo, Y., Kuriyan, J. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Neuroendocrine Differentiation in Prostate Cancer: Emerging Biology, Models, and Therapies
Although a de novo clinical presentation of small cell neuroendocrine carcinoma of the prostate is rare, a subset of patients previously diagnosed with prostate adenocarcinoma may develop neuroendocrine features in later stages of castration-resistant prostate cancer (CRPC) progression as a result of treatment resistance. Despite sharing clinical, histologic, and some molecular features with other neuroendocrine carcinomas, including small cell lung cancer, castration-resistant neuroendocrine prostate cancer (CRPC-NE) is clonally derived from prostate adenocarcinoma. CRPC-NE therefore retains early prostate cancer genomic ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Puca, L., Vlachostergios, P. J., Beltran, H. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetically Engineered Mouse Models of Prostate Cancer in the Postgenomic Era
Recent genomic sequencing analyses have unveiled the spectrum of genomic alterations that occur in primary and advanced prostate cancer, raising the question of whether the corresponding genes are functionally relevant for prostate tumorigenesis, and whether such functions are associated with particular disease stages. In this review, we describe genetically engineered mouse models (GEMMs) of prostate cancer, focusing on those that model genomic alterations known to occur in human prostate cancer. We consider whether the phenotypes of GEMMs based on gain or loss of function of the relevant genes provide reliable counterpar...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Arriaga, J. M., Abate-Shen, C. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Evolving Mechanisms of Action of Glatiramer Acetate
Glatiramer acetate (GA) is a synthetic amino acid copolymer that is approved for treatment of relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS). GA reduces multiple sclerosis (MS) disease activity and has shown comparable efficacy with high-dose interferon-β. The mechanism of action (MOA) of GA has long been an enigma. Originally, it was recognized that GA treatment promoted expansion of GA-reactive T-helper 2 and regulatory T cells, and induced the release of neurotrophic factors. However, GA treatment influences both innate and adaptive immune compartments, and it is now recognized...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2019 Category: Research Authors: Prodhomme, T., Zamvil, S. S. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Ras-Mediated Activation of the Raf Family Kinases
The extracellular signal-regulated kinase (ERK) cascade comprised of the Raf, MEK, and ERK protein kinases constitutes a key effector cascade used by the Ras GTPases to relay signals regulating cell growth, survival, proliferation, and differentiation. Of the ERK cascade components, the regulation of the Raf kinases is by far the most complex, involving changes in subcellular localization, protein and lipid interactions, as well as alterations in the Raf phosphorylation state. The Raf kinases interact directly with active, membrane-localized Ras, and this interaction is often the first step in the Raf activation process, w...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Terrell, E. M., Morrison, D. K. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Composition of Vestibular Hair Bundles
The vertebrate hair bundle, responsible for transduction of mechanical signals into receptor potentials in sensory hair cells, is an evolutionary masterpiece. Composed of actin-filled stereocilia of precisely regulated length, width, and number, the structure of the hair bundle is optimized for sensing auditory and vestibular stimuli. Recent developments in identifying the lipids and proteins constituting the hair bundle, obtained through genetics, biochemistry, and imaging, now permit a description of the consensus composition of vestibular bundles of mouse, rat, and chick. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Krey, J. F., Barr-Gillespie, P. G. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Oral Therapies for Multiple Sclerosis
Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties. In addition, there are three more specific S1P agonists in late stages of...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Faissner, S., Gold, R. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis E Virus Genome Structure and Replication Strategy
Hepatitis E virus (HEV) possesses many of the features of other positive-stranded RNA viruses but also adds HEV-specific nuances, making its virus–host interactions unique. Slow virus replication kinetics and fastidious growth conditions, coupled with the historical lack of an efficient cell culture system to propagate the virus, have left many gaps in our understanding of its structure and replication cycle. Recent advances in culturing selected strains of HEV and resolving the 3D structure of the viral capsid are filling in knowledge gaps, but HEV remains an extremely understudied pathogen. Many steps in the HEV li...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Kenney, S. P., Meng, X.-J. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Murine Models of Hepatitis A Virus Infection
Mechanistic analyses of hepatitis A virus (HAV)-induced pathogenesis have long been thwarted by the lack of tractable small animal models that recapitulate disease observed in humans. Several approaches have shown success, including infection of chimeric mice with human liver cells. Other recent studies show that HAV can replicate to high titer in mice lacking expression of the type I interferon (IFN) receptor (IFN-α/β receptor) or mitochondrial antiviral signaling (MAVS) protein. Mice deficient in the IFN receptor show critical features of type A hepatitis in humans when challenged with human HAV, including his...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Hirai-Yuki, A., Whitmire, J. K., Joyce, M., Tyrrell, D. L., Lemon, S. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Osteoimmunology
Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory molecules, including cytokines and signaling molecules. Osteoimmunology was created as an interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, the importance of an inseparable link between the two systems has been highlighted by studies on the pathogenesis of rheumatoid arthritis (RA), in which path...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Okamoto, K., Takayanagi, H. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] DNA Damage Response in Prostate Cancer
Prostatic adenocarcinoma (PCa) remains a significant health concern. Although localized PCa can be effectively treated, disseminated disease remains uniformly fatal. PCa is reliant on androgen receptor (AR); as such, first-line therapy for metastatic PCa entails suppression of AR signaling. Although initially effective, recurrent tumors reactivate AR function, leading to a lethal stage of disease termed castration-resistant PCa (CRPC). Recent findings implicate AR signaling in control of DNA repair and show that alterations in DNA damage repair pathways are strongly associated with disease progression and poor outcome. Thi...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Schiewer, M. J., Knudsen, K. E. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Regulation of Astrocyte Functions in Multiple Sclerosis
Astrocytes play complex roles in health and disease. Here, we review recent findings on molecular pathways that control astrocyte function in multiple sclerosis (MS) as well as new tools for their investigation. In particular, we describe positive and negative regulators of astrocyte-mediated pathogenesis in MS, such as sphingolipid metabolism and aryl hydrocarbon receptor signaling, respectively. In addition, we also discuss the issue of astrocyte heterogeneity and its relevance for the contribution of astrocytes to MS pathogenesis. Finally, we discuss how new genomic tools could transform the study of astrocyte biology i...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Wheeler, M. A., Quintana, F. J. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] High Throughput Sequencing and Assessing Disease Risk
High-throughput sequencing has dramatically improved our ability to determine and diagnose the underlying causes of human disease. The use of whole-genome and whole-exome sequencing has facilitated faster and more cost-effective identification of new genes implicated in Mendelian disease. It has also improved our ability to identify disease-causing mutations for Mendelian diseases whose associated genes are already known. These benefits apply not only in cases in which the objective is to assess genetic disease risk in adults and children, but also for prenatal genetic testing and embryonic testing. High-throughput sequenc...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2019 Category: Research Authors: Rego, S. M., Snyder, M. P. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] MRAS: A Close but Understudied Member of the RAS Family
MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a phosphatase regulatory subunit when in complex with SHOC2 and protein phosphatase 1 (PP1). This phosphatase complex regulates a crucial step in the activation cycle of RAF kinases and provides a key coordinate input required for efficient ERK pathway activation and transformation by RAS. MRAS mutations rarely occur in cancer but deregulated expression may play a role in tumorigenesis in some settings. Activating mutations in MRAS (...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Young, L. C., Rodriguez-Viciana, P. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis A Virus Genome Organization and Replication Strategy
Hepatitis A virus (HAV) is a positive-strand RNA virus classified in the genus Hepatovirus of the family Picornaviridae. It is an ancient virus with a long evolutionary history and multiple features of its capsid structure, genome organization, and replication cycle that distinguish it from other mammalian picornaviruses. HAV proteins are produced by cap-independent translation of a single, long open reading frame under direction of an inefficient, upstream internal ribosome entry site (IRES). Genome replication occurs slowly and is noncytopathic, with transcription likely primed by a uridylated protein primer as in other ...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: McKnight, K. L., Lemon, S. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Evolutionary Origins of Enteric Hepatitis Viruses
The enterically transmitted hepatitis A (HAV) and hepatitis E viruses (HEV) are the leading causes of acute viral hepatitis in humans. Despite the discovery of HAV and HEV 40–50 years ago, their evolutionary origins remain unclear. Recent discoveries of numerous nonprimate hepatoviruses and hepeviruses allow revisiting the evolutionary history of these viruses. In this review, we provide detailed phylogenomic analyses of primate and nonprimate hepatoviruses and hepeviruses. We identify conserved and divergent genomic properties and corroborate historical interspecies transmissions by phylogenetic comparisons and reco...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Sander, A.-L., Corman, V. M., Lukashev, A. N., Drexler, J. F. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Mechanism of Bone Mineralization
Mineralized "hard" tissues of the skeleton possess unique biomechanical properties to support the body weight and movement and act as a source of essential minerals required for critical body functions. For a long time, extracellular matrix (ECM) mineralization in the vertebrate skeleton was considered as a passive process. However, the explosion of genetic studies during the past decades has established that this process is essentially controlled by multiple genetic pathways. These pathways regulate the homeostasis of ionic calcium and inorganic phosphate—two mineral components required for bone mineral fo...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Murshed, M. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] New Opportunities for Targeting the Androgen Receptor in Prostate Cancer
Recent genomic analyses of metastatic prostate cancer have provided important insight into adaptive changes in androgen receptor (AR) signaling that underpin resistance to androgen deprivation therapies. Novel strategies are required to circumvent these AR-mediated resistance mechanisms and thereby improve prostate cancer survival. In this review, we present a summary of AR structure and function and discuss mechanisms of AR-mediated therapy resistance that represent important areas of focus for the development of new therapies. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Centenera, M. M., Selth, L. A., Ebrahimie, E., Butler, L. M., Tilley, W. D. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Epidemiology of Prostate Cancer
Prostate cancer is a major cause of disease and mortality among men, and each year 1.6 million men are diagnosed with and 366,000 men die of prostate cancer. In this review, we discuss the state of evidence for specific genetic, lifestyle, and dietary factors associated with prostate cancer risk. Given the biological heterogeneity of this cancer, we focus on risk factors for advanced or fatal prostate cancer. First, we provide descriptive epidemiology statistics and patterns for prostate cancer incidence and mortality around the world. This includes discussion of the impact of prostate-specific antigen screening on prostat...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Pernar, C. H., Ebot, E. M., Wilson, K. M., Mucci, L. A. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Natalizumab: Perspectives from the Bench to Bedside
Probably no other disease-modifying drug for multiple sclerosis has a more fascinating story than natalizumab from both the bench to bedside perspective and the postmarketing experience standpoint. Natalizumab is a monoclonal antibody that inhibits the trafficking of lymphocytes from the blood into the central nervous system by blocking the adhesion molecule α4-integrin. Natalizumab was approved as a disease-modifying drug for relapsing remitting multiple sclerosis only 12 years after the discovery of its target molecule—a time line that is rather fast for drug development. However, a few months after its U.S. ...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Shirani, A., Stüve, O. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Regulatory T Cells: From Discovery to Autoimmunity
Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. Allelic variants lead to lower thresholds of T-cell activation resulting in activation of autoreactive T cells. Environmental factors, including, among others, diet, vitamin D, and smoking, in combination with genetic predispositions, play a substantial role in disease development and activation of autoreactive T cells. FoxP3+ regulatory T cells (Tregs) have emerged as central in the control of autoreactive T cells. A consistent finding in patients with MS is defects in Treg cell function with reduced suppression of effector...
Source: Cold Spring Harbor perspectives in medicine - December 3, 2018 Category: Research Authors: Kitz, A., Singer, E., Hafler, D. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Immunization against Hepatitis E
Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in Escherichia coli. Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries wh...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Innis, B. L., Lynch, J. A. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Transmission and Epidemiology of Hepatitis E Virus Genotype 3 and 4 Infections
Following the introduction of robust serological and molecular tools, our understanding of the epidemiology of zoonotic hepatitis E virus (HEV) has improved considerably in recent years. Current thinking suggests that consumption of pork meat products is the key route of infection in humans, but it is certainly not the only one. Other routes of infection include environmental spread, contaminated water, and via the human blood supply. The epidemiology of HEV genotype (gt)3 and gt4 is complex, as there are several sources and routes of infection, and it is likely that these vary between and within countries and over time. (...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Dalton, H. R., Izopet, J. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Interferon {beta} for Multiple Sclerosis
Despite that the availability of new therapeutic options has expanded the multiple sclerosis (MS) disease-modifying therapy arsenal, interferon β (IFN-β) remains an important therapy option in the current decision-making process. This review will summarize the present knowledge of IFN-β mechanism of action, the overall safety, and the short- and long-term efficacy of its use in relapsing remitting MS and clinically isolated syndromes. Data on secondary progressive MS is also provided, although no clear benefit was identified. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Jakimovski, D., Kolb, C., Ramanathan, M., Zivadinov, R., Weinstock-Guttman, B. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Targeting the MAPK Pathway in RAS Mutant Cancers
Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Hymowitz, S. G., Malek, S. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Posttranslational Modifications of RAS Proteins
The three human RAS genes encode four proteins that play central roles in oncogenesis by acting as binary molecular switches that regulate signaling pathways for growth and differentiation. Each is subject to a set of posttranslational modifications (PTMs) that modify their activity or are required for membrane targeting. The enzymes that catalyze the various PTMs are potential targets for anti-RAS drug discovery. The PTMs of RAS proteins are the focus of this review. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Ahearn, I., Zhou, M., Philips, M. R. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Biomarkers in the Clinical Management of Prostate Cancer
Prostate cancer, one of the most common noncutaneous malignancies in men, is a heterogeneous disease with variable clinical outcome. Although the majority of patients harbor indolent tumors that are essentially cured by local therapy, subsets of patients present with aggressive disease or recur/progress after primary treatment. With this in mind, modern clinical approaches to prostate cancer emphasize the need to reduce overdiagnosis and overtreatment via personalized medicine. Advances in our understanding of prostate cancer pathogenesis, coupled with recent technologic innovations, have facilitated the development and va...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Udager, A. M., Tomlins, S. A. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Transcriptional Regulation in Prostate Cancer
Prostate cancer development involves corruption of the normal prostate transcriptional network, following deregulated expression or mutation of key transcription factors. Here, we provide an overview of the transcription factors that are important in normal prostate homeostasis (NKX3-1, p63, androgen receptor [AR]), primary prostate cancer (ETS family members, c-MYC), castration-resistant prostate cancer (AR, FOXA1), and AR-independent castration-resistant neuroendocrine prostate cancer (RB1, p53, N-MYC). We use functional (in vitro and in vivo) as well as clinical data to discuss evidence that unveils their roles in the i...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Labbe, D. P., Brown, M. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS)
Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system (CNS) leading to the progressive destruction of the myelin sheath surrounding axons. It can present with variable clinical and pathological manifestations, which might reflect the involvement of distinct pathogenic processes. Although the mechanisms leading to the development of the disease are not fully understood, numerous evidences indicate that MS is an autoimmune disease, the initiation and progression of which are dependent on an autoimmune response against myelin antigens. In addition, genetic susceptibility and environmental...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2018 Category: Research Authors: Glatigny, S., Bettelli, E. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research