[PERSPECTIVES] Outer Hair Cells and Electromotility
Outer hair cells (OHCs) of the mammalian cochlea behave like actuators: they feed energy into the cochlear partition and determine the overall mechanics of hearing. They do this by generating voltage-dependent axial forces. The resulting change in the cell length, observed by microscopy, has been termed "electromotility." The mechanism of force generation OHCs can be traced to a specific protein, prestin, a member of a superfamily SLC26 of transporters. This short review will identify some of the more recent findings on prestin. Although the tertiary structure of prestin has yet to be determined, results from the...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Ashmore, J. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Inner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear Function
Connexin 26 and connexin 30 are the prevailing isoforms in the epithelial and connective tissue gap junction systems of the developing and mature cochlea. The most frequently encountered variants of the genes that encode these connexins, which are transcriptionally coregulated, determine complete loss of protein function and are the predominant cause of prelingual hereditary deafness. Reducing connexin 26 expression by Cre/loxP recombination in the inner ear of adult mice results in a decreased endocochlear potential, increased hearing thresholds, and loss of>90% of outer hair cells, indicating that this connexin is ess...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Mammano, F. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis E Virus Genotype 1 and 2 Infections
Infection with genotype 1 or 2 hepatitis E virus (HEV) results primarily from human-to-human transmission through the fecal–oral route in low-resource countries. It presents primarily as "acute viral hepatitis" syndrome, usually a self-limiting illness. A few cases progress to acute liver failure, a serious illness with high fatality. Clinical disease is infrequent among children. Infection during pregnancy is associated with a higher risk of symptomatic disease, severe liver injury, and mortality. Severe disease is also encountered in persons with preexisting chronic liver disease. Some cases have associat...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Aggarwal, R., Goel, A. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment
Hepatitis E virus (HEV) genotype (gt)3 and 4 infections are prevalent in industrialized and high-income countries. Although most HEV gt3 and gt4 infections are clinically silent, acute infection may be symptomatic in some patients. In persons with underlying liver disease and in elderly men, HEV infections may present as acute or acute-on-chronic liver failure. Chronic hepatitis may develop in immunosuppressed individuals, including transplant recipients, human immunodeficiency virus (HIV)-infected patients, and persons with hematologic malignancy undergoing chemotherapy, and may progress to life-threatening liver cirrhosi...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Kamar, N., Pischke, S. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[TECHNIQUES] Next-Generation Sequencing Strategies
More than a decade ago, the term "next-generation" sequencing was coined to describe what was, at the time, revolutionary new methods to sequence RNA and DNA at a faster pace and cheaper cost than could be performed by standard bench-top protocols. Since then, the field of DNA sequencing has evolved at a rapid pace, with new breakthroughs allowing capacity to exponentially increase and cost to dramatically decrease. As genome-scale sequencing has become routine, a paradigm shift is occurring in genomics, which uses the power of high-throughput, rapid sequencing power with large-scale studies. These new approaches...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Levy, S. E., Boone, B. E. Tags: Next-Generation Sequencing in Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Diabetes Technology: Monitoring, Analytics, and Optimal Control
In conclusion, engineering lessons learned from AP research, and the clinical need for AP systems to prove their safety and efficacy in large-scale clinical trials, are outlined. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Kovatchev, B. Tags: Bioelectronic Medicine PERSPECTIVES Source Type: research

[TECHNIQUE] Bioelectronic Approaches to Control Neuroimmune Interactions in Acute Kidney Injury
Recent studies have shown renal protective effects of bioelectric approaches, including ultrasound treatment, electrical vagus nerve stimulation, and optogenetic brainstem C1 neuron stimulation. The renal protection acquired by all three modalities was lost in splenectomized mice and/or α7 subunit of the nicotinic acetylcholine receptor–deficient mice. C1 neuron-mediated renal protection was blocked by β2-adrenergic receptor antagonist. These findings indicate that all three methods commonly, at least partially, activate the cholinergic anti-inflammatory pathway, a well-studied neuroimmune pathway. In this...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Inoue, T., Tanaka, S., Rosin, D. L., Okusa, M. D. Tags: Bioelectronic Medicine TECHNIQUE Source Type: research

[PERSPECTIVES] Interactions between Macrophages and the Sensory Cells of the Inner Ear
Macrophages are present in most somatic tissues, where they detect and attack invading pathogens. Macrophages also participate in many nonimmune functions, particularly those related to tissue maintenance and injury response. The sensory organs of the inner ear contain resident populations of macrophages, and additional macrophages enter the ear after acoustic trauma or ototoxicity. As expected, such macrophages participate in the clearance of cellular debris. However, otic macrophages can also influence the long-term survival of both hair cells and afferent neurons after injury. The signals that recruit macrophages into t...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Warchol, M. E. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] A Functional Perspective on the Evolution of the Cochlea
This review summarizes paleontological data as well as studies on the morphology, function, and molecular evolution of the cochlea of living mammals (monotremes, marsupials, and placentals). The most parsimonious scenario is an early evolution of the characteristic organ of Corti, with inner and outer hair cells and nascent electromotility. Most remaining unique features, such as loss of the lagenar macula, coiling of the cochlea, and bony laminae supporting the basilar membrane, arose later, after the separation of the monotreme lineage, but before marsupial and placental mammals diverged. The question of when hearing sen...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Köppl, C., Manley, G. A. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Sequencing in High Definition Drives a Changing Worldview of the Epigenome
Single-molecule sequencing approaches have transformed the study of the human epigenome, accelerating efforts to describe genome function beyond the sequences that encode proteins. The post-genome era has ignited strong interest in the noncoding genome and profiling epigenetic signatures genome-wide have been critical for the identification and characterization of noncoding gene-regulatory sequences in various cellular and developmental contexts. These technologies enable quantification of epigenetic marks through digital assessment of DNA fragments. With the capacity to probe both the DNA sequence and count DNA molecules ...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Hodges, E. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis A Virus and Hepatitis E Virus: Emerging and Re-Emerging Enterically Transmitted Hepatitis Viruses
Over the past two decades, progress in understanding human infections with hepatitis A virus (HAV) and hepatitis E virus (HEV) has been eclipsed by the priority of combating persistent hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. During that time, the global burden of liver disease caused by enteric hepatitis viruses has not abated. Because of vaccines, hepatitis A has become increasingly a disease of adults instead of early childhood in many regions of the world, resulting in an age-related shift toward more severe disease. HEV has remained endemic in many developing countries, and in well-developed, ec...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Lemon, S. M., Walker, C. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Epidemiology of Genotype 1 and 2 Hepatitis E Virus Infections
Hepatitis E virus (HEV) genotypes 1 and 2 are responsible for the majority of acute viral hepatitis infections in endemic areas in South Asia and sub-Saharan Africa. In addition to frequent sporadic illnesses throughout the year, these viruses often cause large epidemics in association with monsoon rains in Asia or during humanitarian crises in Africa. Clinical hepatitis commonly involves adults more often than young children, with an overall mortality of ~1%. However, the mortality among pregnant women is often 30% or higher. HEV infection in pregnant women frequently leads to infant mortality or premature delivery. Hepat...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Nelson, K. E., Labrique, A. B., Kmush, B. L. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Prostate Stem Cells and Cancer Stem Cells
Stem/progenitor cells play central roles in processes of organogenesis and tissue maintenance, whereas cancer stem cells (CSCs) are thought to drive tumor malignancy. Here, we review recent progress in the identification and analysis of normal prostate stem/progenitor cells as well as putative CSCs in both genetically engineered mouse models as well as in human tissue. We also discuss studies that have investigated the cell type of origin for prostate cancer. In addition, we provide a critical assessment of methodologies used in stem cell analyses and outline directions for future research. (Source: Cold Spring Harbor pers...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Li, J. J., Shen, M. M. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Daclizumab Therapy for Multiple Sclerosis
In conclusion, daclizumab has complex immunomodulatory effects with resultant inhibition of central nervous system inflammation in MS. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Bielekova, B. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[TECHNIQUES] Electromagnetic Regulation of Cell Activity
The ability to observe the effects of rapidly and reversibly regulating cell activity in targeted cell populations has provided numerous physiologic insights. Over the last decade, a wide range of technologies have emerged for regulating cellular activity using optical, chemical, and, more recently, electromagnetic modalities. Electromagnetic fields can freely penetrate cells and tissue and their energy can be absorbed by metal particles. When released, the absorbed energy can in turn gate endogenous or engineered receptors and ion channels to regulate cell activity. In this manner, electromagnetic fields acting on externa...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Stanley, S. A., Friedman, J. M. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[TECHNIQUES] Microscale and Nanoscale Electrophotonic Diagnostic Devices
Detecting and identifying infectious agents and potential pathogens in complex environments and characterizing their mode of action is a critical need. Traditional diagnostics have targeted a single characteristic (e.g., spectral response, surface receptor, mass, intrinsic conductivity, etc.). However, advances in detection technologies have identified emerging approaches in which multiple modes of action are combined to obtain enhanced performance characteristics. Particularly appealing in this regard, electrophotonic devices capable of coupling light to electron translocation have experienced rapid recent growth and offe...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Fu, K., Xu, W., Hu, J., Lopez, A., Bohn, P. W. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Efferent Inhibition of the Cochlea
Cholinergic efferent neurons originating in the brainstem innervate the acoustico-lateralis organs (inner ear, lateral line) of vertebrates. These release acetylcholine (ACh) to inhibit hair cells through activation of calcium-dependent potassium channels. In the mammalian cochlea, ACh shunts and suppresses outer hair cell (OHC) electromotility, reducing the essential amplification of basilar membrane motion. Consequently, medial olivocochlear neurons that inhibit OHCs reduce the sensitivity and frequency selectivity of afferent neurons driven by cochlear vibration of inner hair cells (IHCs). The cholinergic synapse on hai...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Fuchs, P. A., Lauer, A. M. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Structure of the Hair Cell Mechanoelectrical Transduction Complex
Cochlear hair cells employ mechanically gated ion channels located in stereocilia that open in response to sound wave–induced motion of the basilar membrane, converting mechanical stimulation to graded changes in hair cell membrane potential. Membrane potential changes in hair cells cause neurotransmitter release from hair cells that initiate electrical signals in the nerve terminals of afferent fibers from spiral ganglion neurons. These signals are then propagated within the central nervous system (CNS) to mediate the sensation of hearing. Recent studies show that the mechanoelectrical transduction (MET) machinery o...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Cunningham, C. L., Müller, U. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis A Virus Capsid Structure
Hepatitis A virus (HAV) has been enigmatic, evading detailed structural analysis for many years. Its recently determined high-resolution structure revealed an angular surface without the indentations often characteristic of receptor-binding sites. The viral protein 1 (VP1) β-barrel shows no sign of a pocket factor and the amino terminus of VP2 displays a "domain swap" across the pentamer interface, as in a subset of mammalian picornaviruses and insect picorna-like viruses. Structure-based phylogeny confirms this placement. These differences suggest an uncoating mechanism distinct from that of enteroviruses. ...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Stuart, D. I., Ren, J., Wang, X., Rao, Z., Fry, E. E. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[RETROSPECTIVE] History of the Discovery of Hepatitis A Virus
Disease outbreaks resembling hepatitis A have been known since antiquity. However, it was not until World War II when two forms of viral hepatitis were clearly differentiated. After the discovery of Australia antigen and its association with hepatitis B, similar methodologies were used to find the hepatitis A virus. The virus was ultimately identified when investigators changed the focus of their search from serum to feces and applied appropriate technology. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Feinstone, S. M. Tags: Enteric Hepatitis Viruses RETROSPECTIVE Source Type: research

[PERSPECTIVES] Immunotherapy for Prostate Cancer
Immunotherapy with agents that block immune checkpoints is a mainstay of therapy for several common tumor types; so far, prostate cancer is not among those treated using this method. The observed lack of activity in prostate cancer is not due to a lack of testing; several agents have been evaluated both alone and in combination. Although several combination strategies show some promise, it appears likely that a greater understanding of the prostate cancer tumor microenvironment and baseline immune response will be required to optimize future treatment strategies. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - May 1, 2019 Category: Research Authors: Venturini, N. J., Drake, C. G. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[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