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Cold Spring Harbor Perspectives in Medicine

Paul Albert Fuchs, Amanda M Lauer
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)...
August 6, 2018: Cold Spring Harbor Perspectives in Medicine
Levent Trabzonlu, Ibrahim Kulac, Qizhi Zheng, Jessica L Hicks, Michael C Haffner, William G Nelson, Karen S Sfanos, Onur Ertunc, Tamara L Lotan, Christopher M Heaphy, Alan K Meeker, Srinivasan Yegnasubramanian, Angelo M De Marzo
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...
August 6, 2018: Cold Spring Harbor Perspectives in Medicine
Christopher L Cunningham, Ulrich Müller
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...
August 6, 2018: Cold Spring Harbor Perspectives in Medicine
Christopher A Shera, Karolina K Charaziak
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...
July 23, 2018: Cold Spring Harbor Perspectives in Medicine
David I Stuart, Jingshan Ren, Xiangxi Wang, Zihe Rao, Elizabeth E Fry
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...
July 23, 2018: Cold Spring Harbor Perspectives in Medicine
Srinivasan Yegnasubramanian, Angelo M De Marzo, William G Nelson
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 with genetic alterations to drive prostate cancer initiation and progression...
June 29, 2018: Cold Spring Harbor Perspectives in Medicine
Shannon M Rego, Michael P Snyder
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...
June 29, 2018: Cold Spring Harbor Perspectives in Medicine
Federico La Manna, Sofia Karkampouna, Eugenio Zoni, Marta De Menna, Janine Hensel, George N Thalmann, Marianna Kruithof-de Julio
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...
June 14, 2018: Cold Spring Harbor Perspectives in Medicine
Eric Y Zhao, Martin Jones, Steven J M Jones
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 genomes at scale in a clinically relevant time frame is now being piloted...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Ute I Schwarz, Markus Gulilat, Richard B Kim
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...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Jocelyn F Krey, Peter G Barr-Gillespie
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...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Loredana Puca, Panagiotis J Vlachostergios, Himisha Beltran
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...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Sarah-Jane Dawson
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 evolution during disease progression, and may ultimately allow noninvasive molecular disease monitoring to guide therapeutic decisions and improve patient outcomes...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Christopher M Walker
Both hepatitis A virus (HAV) and hepatitis E virus (HEV) cause self-limited infections in humans that are preventable by vaccination. Progress in characterizing adaptive immune responses against these enteric hepatitis viruses, and how they contribute to resolution of infection or liver injury, has therefore remained largely frozen for the past two decades. How HAV and HEV infections are so effectively controlled by B- and T-cell immunity, and why they do not have the same propensity to persist as HBV and HCV infections, cannot yet be adequately explained...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Federico La Manna, Sofia Karkampouna, Eugenio Zoni, Marta De Menna, Janine Hensel, George N Thalmann, Marianna Kruithof-de Julio
No abstract text is available yet for this article.
July 2, 2018: Cold Spring Harbor Perspectives in Medicine
Nikolaos A Patsopoulos
The contribution of genetic inheritance in multiple sclerosis was established early on. Although multiple sclerosis is not a Mendelian disease, its incidence and prevalence is higher in family members of affected individuals compared with the general population. Throughout the last decade, several small studies failed to identify any robust genetic associations besides the classic associations in the major histocompatibility complex region. During the past few years, genome-wide association studies (GWAS) have revolutionized the genetics of multiple sclerosis, uncovering more than 200 implicated genetic loci...
July 2, 2018: Cold Spring Harbor Perspectives in Medicine
Jeffrey C Francis, Amanda Swain
The prostate is a male exocrine gland that secretes components of the seminal fluid. In men, prostate tumors are one of the most prevalent cancers. Studies on the development of the prostate have given a better understanding of the processes and genes that are important in the formation of this organ and have provided insights into the mechanisms of prostate tumorigenesis. These developmental studies have provided evidence that some of the genes and signaling pathways involved in development are reactivated or deregulated during prostate cancer...
July 2, 2018: Cold Spring Harbor Perspectives in Medicine
Matthew Holderfield
The high prevalence of KRAS mutations in human cancers and the lack of effective treatments for patients ranks KRAS among the most highly sought-after targets for preclinical oncologists. Pharmaceutical companies and academic laboratories have tried for decades to identify small molecule inhibitors of oncogenic KRAS proteins, but little progress has been made and many have labeled KRAS undruggable. However, recent progress in in silico screening, fragment-based drug design, disulfide tethered screening, and some emerging themes in RAS biology have caused the field to reconsider previously held notions about targeting KRAS...
July 2, 2018: Cold Spring Harbor Perspectives in Medicine
Marta Galán-Díez, Álvaro Cuesta-Domínguez, Stavroula Kousteni
Hematopoietic stem cells (HSCs) interact dynamically with an intricate network of cells in the bone marrow (BM) microenvironment or niche. These interactions provide instructive cues that influence the production and lineage determination of different types of blood cells and maintenance of HSC quiescence. They also contribute to hematopoietic deregulation and hematological myeloid malignancies. Alterations in the BM niche are commonly observed in myeloid malignancies and contribute to the aberrant function of myelodysplastic and leukemia-initiating stem cells...
July 2, 2018: Cold Spring Harbor Perspectives in Medicine
Emma C Watson, Ralf H Adams
Blood vessels are essential for the distribution of oxygen, nutrients, and immune cells, as well as the removal of waste products. In addition to this conventional role as a versatile conduit system, the endothelial cells forming the innermost layer of the vessel wall also possess important signaling capabilities and can control growth, patterning, homeostasis, and regeneration of the surrounding organ. In the skeletal system, blood vessels regulate developmental and regenerative bone formation as well as hematopoiesis by providing vascular niches for hematopoietic stem cells...
July 2, 2018: Cold Spring Harbor Perspectives in Medicine
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