[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

[PERSPECTIVES] Preclinical Models of Prostate Cancer: Patient-Derived Xenografts, Organoids, and Other Explant Models
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. In contrast to other tumor streams, the prostate c...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Risbridger, G. P., Toivanen, R., Taylor, R. A. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance
Reciprocal signaling between prostate stroma and its epithelium are fundamental to organ development and homeostasis. Similarly, interactions between tumor cells and stromal constituents are central to key aspects of carcinogenesis and malignancy growth involving tumor cell invasion, dissemination, and growth in distant sites. The prostate stroma is complex with several distinct resident cell types, infiltrating nonresident cell types and an amalgam of structural matrix factors, matricellular proteins, metabolites, growth factors, and cytokines. Of importance, the stroma is dynamic with changes in composition as a cause or...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Levesque, C., Nelson, P. S. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Muscle-Adipose Tissue Cross Talk
Exercise training results in adaptations to both skeletal muscle and white adipose tissue (WAT) and protects against metabolic disorders including obesity and type 2 diabetes. Exercise-induced adaptations include an altered profile of secreted proteins, both myokines (from skeletal muscle) and adipokines (from adipose tissue). These secreted proteins may act in an endocrine manner to facilitate tissue-to-tissue communication and "cross talk," likely working together to improve overall metabolic health. Some studies suggest that contracting skeletal muscles release myokines that may function to alter the phenotype...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Stanford, K. I., Goodyear, L. J. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Exercise Metabolism: Fuels for the Fire
During exercise, the supply of adenosine triphosphate (ATP) is essential for the energy-dependent processes that underpin ongoing contractile activity. These pathways involve both substrate-level phosphorylation, without any need for oxygen, and oxidative phosphorylation that is critically dependent on oxygen delivery to contracting skeletal muscle by the respiratory and cardiovascular systems and on the supply of reducing equivalents from the degradation of carbohydrate, fat, and, to a limited extent, protein fuel stores. The relative contribution of these pathways is primarily determined by exercise intensity, but also m...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2018 Category: Research Authors: Hargreaves, M., Spriet, L. L. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[ERRATUM] Erratum: Metastases in Prostate Cancer
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: La Manna, F., Karkampouna, S., Zoni, E., De Menna, M., Hensel, J., Thalmann, G. N., Kruithof-de Julio, M. Tags: ERRATUM Source Type: research

[PERSPECTIVES] Efforts to Develop KRAS Inhibitors
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....
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Holderfield, M. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Biology of Bone: The Vasculature of the Skeletal System
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. Here we provide an overview of blood vessel ar...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Watson, E. C., Adams, R. H. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] The Bone Marrow Microenvironment in Health and Myeloid Malignancy
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. In this work, we review how different components of the BM nic...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Galan-Diez, M., Cuesta-Dominguez, A., Kousteni, S. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Prostate Organogenesis
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. The prostate goes through a number of different stages during organogenesis, w...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Francis, J. C., Swain, A. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Performance Fatigability: Mechanisms and Task Specificity
Performance fatigability is characterized as an acute decline in motor performance caused by an exercise-induced reduction in force or power of the involved muscles. Multiple mechanisms contribute to performance fatigability and originate from neural and muscular processes, with the task demands dictating the mechanisms. This review highlights that (1) inadequate activation of the motoneuron pool can contribute to performance fatigability, and (2) the demands of the task and the physiological characteristics of the population assessed, dictate fatigability and the involved mechanisms. Examples of task and population differ...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Hunter, S. K. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Health Benefits of Exercise
Overwhelming evidence exists that lifelong exercise is associated with a longer health span, delaying the onset of 40 chronic conditions/diseases. What is beginning to be learned is the molecular mechanisms by which exercise sustains and improves quality of life. The current review begins with two short considerations. The first short presentation concerns the effects of endurance exercise training on cardiovascular fitness, and how it relates to improved health outcomes. The second short section contemplates emerging molecular connections from endurance training to mental health. Finally, approximately half of the remaini...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Ruegsegger, G. N., Booth, F. W. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetics of Multiple Sclerosis: An Overview and New Directions
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. Here, we desc...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Patsopoulos, N. A. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] {alpha}-Synuclein: Multiple System Atrophy Prions
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed...
Source: Cold Spring Harbor perspectives in medicine - July 2, 2018 Category: Research Authors: Woerman, A. L., Watts, J. C., Aoyagi, A., Giles, K., Middleton, L. T., Prusiner, S. B. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Regulation of Energy Metabolism by Bone-Derived Hormones
Like many other organs, bone can act as an endocrine organ through the secretion of bone-specific hormones or "osteokines." At least two osteokines are implicated in the control of glucose and energy metabolism: osteocalcin (OCN) and lipocalin-2 (LCN2). OCN stimulates the production and secretion of insulin by the pancreatic β-cells, but also favors adaptation to exercise by stimulating glucose and fatty acid (FA) utilization by the muscle. Both of these OCN functions are mediated by the G-protein-coupled receptor GPRC6A. In contrast, LCN2 influences energy metabolism by activating appetite-suppressing signa...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Mera, P., Ferron, M., Mosialou, I. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] PI3K: A Crucial Piece in the RAS Signaling Puzzle
RAS proteins are key signaling switches essential for control of proliferation, differentiation, and survival of eukaryotic cells. RAS proteins are mutated in 30% of human cancers. In addition, mutations in upstream or downstream signaling components also contribute to oncogenic activation of the pathway. RAS proteins exert their functions through activation of several signaling pathways and dissecting the contributions of these effectors in normal cells and in cancer is an ongoing challenge. In this review, we summarize our current knowledge about how RAS regulates type I phosphatidylinositol 3-kinase (PI3K), one of the m...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Krygowska, A. A., Castellano, E. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] The Biology of Bone Metastasis
Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these e...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Esposito, M., Guise, T., Kang, Y. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Treatment of Advanced Prostate Cancer--A Review of Current Therapies and Future Promise
We describe putative predictive biomarkers, including androgen receptor splice variants, phosphatase and tensin homolog (PTEN) loss, homologous recombination repair defects, including BRCA2 loss, and mismatch repair defects. The development of next-generation sequencing techniques and the routine biopsy of metastatic disease have driven significant advances in our understanding of the genomics of cancer, and are now poised to transform our treatment of this disease. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Sumanasuriya, S., De Bono, J. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Adaptations to Endurance and Strength Training
The capacity for human exercise performance can be enhanced with prolonged exercise training, whether it is endurance- or strength-based. The ability to adapt through exercise training allows individuals to perform at the height of their sporting event and/or maintain peak physical condition throughout the life span. Our continued drive to understand how to prescribe exercise to maximize health and/or performance outcomes means that our knowledge of the adaptations that occur as a result of exercise continues to evolve. This review will focus on current and new insights into endurance and strength-training adaptations and ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Hughes, D. C., Ellefsen, S., Baar, K. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy
Skeletal muscle hypertrophy is a widely sought exercise adaptation to counteract the muscle atrophy of aging and disease, or to improve athletic performance. While this desired muscle enlargement is a well-known adaptation to resistance exercise training (RT), the mechanistic underpinnings are not fully understood. The purpose of this review is thus to provide the reader with a summary of recent advances in molecular mechanisms—based on the most current literature—that are thought to promote RT-induced muscle hypertrophy. We have therefore focused this discussion on the following areas of fertile investigation:...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Bamman, M. M., Roberts, B. M., Adams, G. R. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] The Gut Microbiome and Multiple Sclerosis
The microbiome can be defined as the sum of the microbial and host’s genome. Recent information regarding this complex organ suggests that in animal models of multiple sclerosis (MS), the composition of the gut microbiome can be altered, giving rise to both the effector and regulatory phases of central nervous system (CNS) demyelination. Experimental findings during the past decade in animal models of MS have provided clear evidence for the significant role of gut microbes in both the effector and regulatory phase of this condition. There is mounting evidence in preliminary human studies suggesting that a dysbiotic M...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Ochoa-Reparaz, J., Kirby, T. O., Kasper, L. H. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Mechanisms of Chronic Wasting Disease Prion Propagation
Prion disease epidemics, which have been unpredictable recurrences, are of significant concern for animal and human health. Examples include kuru, once the leading cause of death among the Fore people in Papua New Guinea and caused by mortuary feasting; bovine spongiform encephalopathy (BSE) and its subsequent transmission to humans in the form of variant Creutzfeldt–Jakob disease (vCJD), and repeated examples of large-scale prion disease epidemics in animals caused by contaminated vaccines. The etiology of chronic wasting disease (CWD), a relatively new and burgeoning prion epidemic in deer, elk, and moose (members ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Moreno, J. A., Telling, G. C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetics of Synucleinopathies
Parkinson’s disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA) constitute the three major neurodegenerative disorders referred to as synucleinopathies because both genetic and pathological results implicate the α-synuclein protein in their pathogenesis. PD and DLBD are recognized as closely related diseases with substantial clinical and pathological overlap. MSA, on the other hand, has a distinctive clinical presentation and neuropathological profile. In this review, we will summarize the evidence linking α-synuclein to these three disorders. Hundreds of patients with point ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2018 Category: Research Authors: Nussbaum, R. L. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetically Engineered Mouse Models of K-Ras-Driven Lung and Pancreatic Tumors: Validation of Therapeutic Targets
K-RAS signaling has been intensely studied for over 40 years. Yet, as of today, no drugs have been approved to treat K-RAS mutant cancers. Since the turn of the century, scientists have used genetically engineered mouse (GEM) models to reproduce K-RAS mutant cancers in a laboratory setting to elucidate those molecular events responsible for the onset and progression of these tumors and to identify suitable therapies. In this review, we outline a brief description of available GEM models for two tumor types known to be driven by K-RAS mutations: lung adenocarcinoma and pancreatic ductal adenocarcinoma. In addition, we summa...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Drosten, M., Guerra, C., Barbacid, M. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Biology of Fibroblast Growth Factor 23: From Physiology to Pathology
Fibroblast growth factor (FGF)23 is a phosphaturic hormone produced by osteocytes and osteoblasts that binds to FGF receptors in the presence of the transmembrane protein αKlotho. FGF23 mainly targets the renal proximal tubule to inhibit calcitriol production and the expression of the sodium/phosphate cotransporters NaPi2a and NaPi2c, thus inhibiting renal phosphate reabsorption. FGF23 also acts on the parathyroid glands to inhibit parathyroid hormone synthesis and secretion. FGF23 regulation involves many systemic and local factors, among them calcitriol, phosphate, and parathyroid hormone. Increased FGF23 is primar...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Courbebaisse, M., Lanske, B. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Anatomy and Histology of the Human and Murine Prostate
The human and murine prostate glands have similar functional roles in the generation of seminal fluid to assist in reproduction. There are significant differences in the anatomy and histology of murine and human prostate and knowledge of the normal anatomy and histology of the murine prostate is essential to interpreting changes in genetically engineered mouse models. In this review, the normal anatomy and histology of both human and mouse prostate will be described. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Ittmann, M. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Bioenergetics of Exercise
Animals possess a remarkable ability to perform physical activity over a wide range of workloads and durations, reflecting both the inherent efficiency and large reserve capacity of energy transfer systems. Deciphering how different organ/physiological systems respond to the acute and chronic demands of exercise depends on a foundational understanding of the redox and bioenergetic principles that underlie the flow of electrons in living systems and its coupling to ATP synthesis. The purpose of this review is to set the stage to cover (1) the thermodynamic driving forces responsible for generating and maintaining the energy...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Neufer, P. D. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Physiological Redundancy and the Integrative Responses to Exercise
The biological responses to acute and chronic exercise are marked by a high level of physiological redundancy that operates at various levels of integration, including the molecular, cellular, organ-system, and whole-body scale. During acute exercise, this redundancy protects whole-body homeostasis in the face of 10-fold or more increases in whole-body metabolic rate. In some cases, there are "trade-offs" between optimizing the performance of a given organ or system versus whole-body performance. Physiological redundancy also plays a key role in the adaptive responses to exercise training and high levels of habit...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Joyner, M. J., Dempsey, J. A. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[TECHNIQUE] Magnetic Resonance Imaging in Multiple Sclerosis
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. However, conventional MRI l...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Hemond, C. C., Bakshi, R. Tags: Multiple Sclerosis TECHNIQUE Source Type: research

[PERSPECTIVES] Big Bang Tumor Growth and Clonal Evolution
The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be ...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Sun, R., Hu, Z., Curtis, C. Tags: Cancer Evolution PERSPECTIVES Source Type: research