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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...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
Eui-Cheol Shin, Sook-Hyang Jeong
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...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
Thomas Prod'homme, Scott S Zamvil
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...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
Graham Campbell, Don Mahad
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 projection axons...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
Sarah G Hymowitz, Shiva Malek
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 RAS mutant cancers with small molecule kinase inhibitors...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
Joseph J Sabatino, Scott S Zamvil, Stephen L Hauser
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 disease activity in relapsing MS as well as lessening of disability progression in primary progressive MS...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Michael A Wheeler, Francisco J Quintana
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...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Hans Lassmann
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesions in the gray and white matter and to diffuse neurodegeneration in the entire brain. In this review, the spectrum of MS lesions and their relation to the inflammatory process is described. Pathology suggests that inflammation drives tissue injury at all stages of the disease. Focal inflammatory infiltrates in the meninges and the perivascular spaces appear to produce soluble factors, which induce demyelination or neurodegeneration either directly or indirectly through microglia activation...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Christopher C Hemond, Rohit Bakshi
Since its technical development in the early 1980s, magnetic resonance imaging (MRI) has quickly been adopted as an essential tool in supporting the diagnosis, longitudinal monitoring, evaluation of therapeutic response, and scientific investigations in multiple sclerosis (MS). The clinical usage of MRI has increased in parallel with technical innovations in the technique itself; the widespread adoption of clinically routine MRI at 1.5T has allowed sensitive qualitative and quantitative assessments of macroscopic central nervous system (CNS) inflammatory demyelinating lesions and tissue atrophy...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Marc N Wein, Henry M Kronenberg
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...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Sylvia Klineova, Fred D Lublin
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...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Elizabeth M Terrell, Deborah K Morrison
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, which ultimately results in ERK activation and the downstream phosphorylation of cellular targets that will specify a particular biological response...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Belinda J Kaskow, Clare Baecher-Allan
Multiple sclerosis (MS) has long been considered a CD4 T-cell disease, primarily because of the findings that the strongest genetic risk for MS is the major histocompatibility complex (MHC) class II locus, and that T cells play a central role in directing the immune response. The importance that the T helper (Th)1 cytokine, interferon γ (IFN-γ), and the Th17 cytokine, interleukin (IL)-17, play in MS pathogenesis is indicated by recent clinical trial data by the enhanced presence of Th1/Th17 cells in central nervous system (CNS) tissue, cerebrospinal fluid (CSF), and blood, and by research on animal models of MS, such as experimental autoimmune encephalomyelitis (EAE)...
January 22, 2018: Cold Spring Harbor Perspectives in Medicine
Claire H Pernar, Ericka M Ebot, Kathryn M Wilson, Lorelei A Mucci
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...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
Ian Ahearn, Mo Zhou, Mark R Philips
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.
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
Lucy C Young, Pablo Rodriguez-Viciana
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...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
Alexandra Kitz, Emily Singer, David Hafler
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...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
J Ricardo Rivero, Ian M Thompson, Michael A Liss, Dharam Kaushik
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.
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
Derek Cheng, David Tuveson
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...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
Gail P Risbridger, Roxanne Toivanen, Renea A Taylor
Prostate cancer remains a lethal disease. Preclinical cancer models that accurately represent the tumors of the patients they are intended to help are necessary to test potential therapeutic approaches and to better translate research discoveries. However, research in the prostate cancer field is hampered by the limited number of human cell lines and xenograft models, most of which do not recapitulate the human disease seen in the clinic today. This work reviews the recent advances in human patient-derived xenograft, organoid, and other explant models to address this need...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
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