[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

[PERSPECTIVES] Alemtuzumab as Treatment for Multiple Sclerosis
Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after its successful use in hematology, oncology, and transplantation medicine. One phase 2 and two phase 3 trials of this lymphocyte-depleting agent have established alemtuzumab’s superior efficacy to interferon β-1a over the short term (2–3 years) with greater relapse rate reduction, reduced accumulation of disability, and more frequent sustained improvement in disability. Longer-term extension studies show durable effects on slowing cerebral at...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Katsavos, S., Coles, A. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Ras and the Plasma Membrane: A Complicated Relationship
The primary site of Ras signal transduction is the plasma membrane (PM). On the PM, the ubiquitously expressed Ras isoforms, H-, N-, and K-Ras, spatially segregate to nonoverlapping nanometer-sized domains, called nanoclusters, with further lateral segregation into nonoverlapping guanosine triphosphate (GTP)-bound and guanosine diphosphate (GDP)-bound nanoclusters. Effector binding and activation is restricted to GTP nanoclusters, rendering the underlying assembly mechanism essential to Ras signaling. Ras nanoclusters have distinct lipid compositions as a result of lipid-sorting specificity encoded in each Ras carboxy-term...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Zhou, Y., Prakash, P., Gorfe, A. A., Hancock, J. F. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis A Virus Codon Usage: Implications for Translation Kinetics and Capsid Folding
Codon usage bias is universal to all genomes. Hepatitis A virus (HAV) codon usage is highly biased and deoptimized with respect to its host. Accordingly, HAV is unable to induce cellular translational shutoff and its internal ribosome entry site (IRES) is inefficient. Codon usage deoptimization may be seen as a hawk (host cell) versus dove (HAV) game strategy for accessing transfer RNA (tRNA). HAV avoids use of abundant host cell codons and thereby eludes competition for the corresponding tRNAs. Instead, codons that are abundant or rare in cellular messenger RNAs (mRNAs) are used relatively rarely in its genome, although i...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Pinto, R. M., Perez-Rodriguez, F.-J., DAndrea, L., de Castellarnau, M., Guix, S., Bosch, A. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Globalization and the Changing Epidemiology of Hepatitis A Virus
Increased economic interdependence, social integration, and other aspects of globalization are contributing to significant changes in hepatitis A epidemiology. Globally, the incidence of hepatitis A virus (HAV) infection is decreasing, the age at midpoint of population immunity (AMPI) is increasing, and the proportion of symptomatic cases is increasing as the average age at infection increases. In low-income countries, HAV remains endemic but improved water and sanitation systems are reducing transmission rates among young children. In high-income countries, most adults remain susceptible to HAV and foodborne outbreaks are...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Jacobsen, K. H. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[TECHNIQUE] Kras in Organoids
Oncogenic Kras are genetic dependencies for the majority of pancreatic and colorectal adenocarcinomas; however, much remains to be understood regarding its tropism to these carcinomas. Recently developed organoid technology presents a more representative model culture system for pancreatic and colon epithelial tissues as well as better fostering the culture of nonimmortalized cells than two-dimensional culture. These advantages enable cancer researchers to directly compare tumor and normal tissue models to better study tumor initiation as well as therapeutic efficacy. Although in vivo models better model the complexity of ...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Cheng, D., Tuveson, D. Tags: Ras and Cancer in the 21st Century TECHNIQUE Source Type: research

[PERSPECTIVES] Metabolic Vulnerabilities of Prostate Cancer: Diagnostic and Therapeutic Opportunities
Cancer cells hijack metabolic pathways to support bioenergetics and biosynthetic requirements for their uncontrolled growth. Thus, cancer can be considered as a metabolic disease. In this review, we discuss the main metabolic features of prostate cancer with a particular focus on the link between oncogene-directed cancer metabolic regulation, metabolism rewiring, and epigenetic regulation. The potential of using metabolic profiling as a means to predict disease behavior and to identify novel therapeutic targets and new diagnostic markers will be addressed as well as the current challenges in metabolomics analyses. Finally,...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Zadra, G., Loda, M. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Chemoprevention in Prostate Cancer: Current Perspective and Future Directions
Chemoprevention of prostate cancer aims to reduce the mortality as well as the public burden of overdetection, which increases anxiety, cost, and morbidity related to the disease. The role of 5-α-reductase inhibitors has been well investigated and shown to decrease the risk of prostate cancer. No current evidence exists to encourage the use of nutrients or vitamins as chemopreventive agents. The modulation of inflammation is one of the most promising targets for chemoprevention of prostate cancer. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Rivero, J. R., Thompson, I. M., Liss, M. A., Kaushik, D. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Neurodegeneration in Progressive Multiple Sclerosis
The neuron is the target of inflammatory demyelinating processes in multiple sclerosis (MS). In progressive MS, however, there is a gathering body of evidence indicating molecular changes within neuronal cell bodies. All of these molecular changes to intrinsic neurons converge on mitochondria, and the most reproduced change relates to mitochondrial respiratory chain complex deficiency. This compromise in the capacity to generate ATP in the neuronal cell body is coupled with an increased demand for energy by the demyelinated axon, which is particularly relevant to the long tracts such as corticospinal tracts with long proje...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2018 Category: Research Authors: Campbell, G., Mahad, D. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Classification and Genomic Diversity of Enterically Transmitted Hepatitis Viruses
Hepatitis A virus (HAV) and hepatitis E virus (HEV) are significant human pathogens and are responsible for a substantial proportion of cases of severe acute hepatitis worldwide. Genetically, both viruses are heterogeneous and are classified into several genotypes that differ in their geographical distribution and risk group association. There is, however, little evidence that variants of HAV or HEV differ antigenically or in their propensity to cause severe disease. Genetically more divergent but primarily hepatotropic variants of both HAV and HEV have been found in several mammalian species, those of HAV being classified...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Smith, D. B., Simmonds, P. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Kras and Tumor Immunity: Friend or Foe?
With the recent breakthroughs in immunotherapy as curative treatments in certain tumor types, there has been renewed interest in the relationship between immunity and tumor growth. Although we are gaining a greater understanding of the complex interplay of immune modulating components in the tumor microenvironment, the specific role that tumor cells play in shaping the immune milieu is still not well characterized. In this review, we focus on how mutant Kras tumor cells contribute to tumor immunity, with a specific focus on processes induced directly or indirectly by the oncogene. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Cullis, J., Das, S., Bar-Sagi, D. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A
Hepatitis A virus (HAV) is transmitted by the fecal–oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Shin, E.-C., Jeong, S.-H. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer
RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority for cancer research. Despite more than three decades of intense effort, no effective RAS inhibitors have yet to reach the cancer patient. With bitter lessons learned from past failures and with new ideas and strategies, there is renewed hope that undruggable RAS may finally be conquered. With the KRAS isoform muta...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Waters, A. M., Der, C. J. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Neural Regulation of Bone and Bone Marrow
Bones provide both skeletal scaffolding and space for hematopoiesis in its marrow. Previous work has shown that these functions were tightly regulated by the nervous system. The central and peripheral nervous systems tightly regulate compact bone remodeling, its metabolism, and hematopoietic homeostasis in the bone marrow (BM). Accumulating evidence indicates that the nervous system, which fine-tunes inflammatory responses and alterations in neural functions, may regulate autoimmune diseases. Neural signals also influence the progression of hematological malignancies such as acute and chronic myeloid leukemias. Here, we re...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Maryanovich, M., Takeishi, S., Frenette, P. S. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Prostate Cancer Disparities by Race and Ethnicity: From Nucleotide to Neighborhood
Prostate cancer (CaP) incidence, morbidity, and mortality rates vary substantially by race and ethnicity, with African American men experiencing among the highest CaP rates in the world. The causes of these disparities are multifactorial and complex, and likely involve differences in access to screening and treatment, exposure to CaP risk factors, variation in genomic susceptibility, and other biological factors. To date, the proportion of CaP that can be explained by environmental exposures is small and differences in the role factors play by race or ethnicity is poorly understood. In the absence of additional data, it is...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Rebbeck, T. R. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Prostate Cancer Germline Variations and Implications for Screening and Treatment
Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves common low-penetrance susceptibility alleles causing individually small but cumulatively significant risk and rarer genetic variants causing greater risk represent the current most accepted model. Through genome-wide association studies, more than 100 single-nucleotide polymorphisms (SNPs) associated with PCa risk have been identified. Consistent reports have identified germline mutations in the genes BRCA1...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Dias, A., Kote-Jarai, Z., Mikropoulos, C., Eeles, R. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Basis of Exercise-Induced Skeletal Muscle Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future Challenges
We provide an overview of groundbreaking studies that laid the foundation for our current understanding of exercise-induced mitochondrial biogenesis and its contribution to human skeletal muscle fitness. We highlight the mechanisms by which skeletal muscle responds to the acute perturbations in cellular energy homeostasis evoked by a single bout of endurance-based exercise and the adaptations resulting from the repeated demands of exercise training that ultimately promote mitochondrial biogenesis through hormetic feedback loops. Despite intense research efforts to elucidate the cellular mechanisms underpinning mitochondria...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Perry, C. G. R., Hawley, J. A. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Clinical Course of Multiple Sclerosis
The 1996 originally established multiple sclerosis (MS) subtypes, based solely on clinical impression and consensus, were revised in 2013 to review potential imaging and biological correlates and to reflect recently identified clinical aspects of MS. As a result, potential new disease phenotypes, radiologically isolated syndrome, and clinically isolated syndrome were considered along with the addition of two new descriptor subtypes: activity and progression applied to relapsing remitting and progressive MS phenotypes. In this way, the description of an individual patient’s disease course is refined and provides tempo...
Source: Cold Spring Harbor perspectives in medicine - September 4, 2018 Category: Research Authors: Klineova, S., Lublin, F. D. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers
KRAS is the most commonly mutated oncogene in human cancer. Most KRAS-mutant cancers depend on sustained expression and signaling of KRAS, thus making it a high-priority therapeutic target. Unfortunately, development of direct small molecule inhibitors of KRAS function has been challenging. An alternative therapeutic strategy for KRAS-mutant malignancies involves targeting codependent vulnerabilities or synthetic lethal partners that are preferentially essential in the setting of oncogenic KRAS. KRAS activates numerous effector pathways that mediate proliferation and survival signals. Moreover, cancer cells must cope with ...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Aguirre, A. J., Hahn, W. C. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] The K-Ras, N-Ras, and H-Ras Isoforms: Unique Conformational Preferences and Implications for Targeting Oncogenic Mutants
Ras controls a multitude of cellular signaling processes, including cell proliferation, differentiation, and apoptosis. Deregulation of Ras cycling often promotes tumorigenesis and various other developmental disorders, termed RASopothies. Although the structure of Ras has been known for many decades, it is still one of the most highly sought-after drug targets today, and is often referred to as "undruggable." At the center of this paradoxical protein is a lack of understanding of fundamental differences in the G domains between the highly similar Ras isoforms and common oncogenic mutations, despite the immense w...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Parker, J. A., Mattos, C. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Multiple Myeloma and Bone: The Fatal Interaction
Multiple myeloma (MM) is the second-most-common hematologic malignancy and the most frequent cancer to involve bone. MM bone disease (MMBD) has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact survival of MM patients. MMBD results from excessive osteoclastic bone resorption and persistent suppressed osteoblastic bone formation, causing lytic lesions that do not heal, even when patients are in complete and prolonged remission. This review discusses the cellular and molecular mechanisms that regulate the unc...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Marino, S., Roodman, G. D. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Regulation of Bone Remodeling by Parathyroid Hormone
Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net loss of bone mass, despite accelerating bone formation by osteoblasts. Intermittent treatment with PTH analogs represents the only Food and Drug Administration (FDA)-approved bone anabolic osteoporosis treatment strategy. Functional PTH receptors are present on cells of the osteoblast lineage, ranging from early skeletal stem cells to matrix-embedded osteocytes. In addition, bone remodeling by osteoclasts liberates latent growth factors present within bone m...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Wein, M. N., Kronenberg, H. M. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research