[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

[PERSPECTIVES] Genetics of Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disorder of motor neurons that overlaps clinically with frontotemporal dementia (FTD). Investigations of the 10% of ALS cases that are transmitted as dominant traits have revealed numerous gene mutations and variants that either cause these disorders or influence their clinical phenotype. The evolving understanding of the genetic architecture of ALS has illuminated broad themes in the molecular pathophysiology of both familial and sporadic ALS and FTD. These central themes encompass disturbances of protein homeostasis, alterations in the bi...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Ghasemi, M., Brown, R. H. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] {beta}-Amyloid Prions and the Pathobiology of Alzheimers Disease
Alzheimer’s disease (AD) is the most common neurodegenerative disease in humans and will pose a considerable challenge to healthcare systems in the coming years. Aggregation of the β-amyloid (Aβ) peptide within the brain is thought to be an initiating event in AD pathogenesis. Many recent studies in transgenic mice have provided evidence that Aβ aggregates become self-propagating during disease, leading to a cascade of protein aggregation in the brain, which may underlie the progressive nature of AD. The ability to self-propagate and the existence of distinct "strains" reveals that Aβ ag...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2018 Category: Research Authors: Watts, J. C., Prusiner, S. B. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras
RAS genes are mutated in 5%–40% of a spectrum of myeloid and lymphoid cancers with NRAS affected 2–3 times more often than KRAS. Genomic analysis indicates that RAS mutations generally occur as secondary events in leukemogenesis, but are integral to the disease phenotype. The tractable nature of the hematopoietic system has facilitated generating accurate mouse models of hematologic malignancies characterized by hyperactive Ras signaling. These strains provide robust platforms for addressing how oncogenic Ras expression perturbs proliferation, differentiation, and self-renewal programs in stem and progenitor ce...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Wandler, A., Shannon, K. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Bone Remodeling and the Microbiome
Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the microbiome. The gastrointestinal tract harbors the greatest numbers of these microorganisms, which regulate human nutrition, metabolism, and immune system function. Moreover, the intestinal microbiota contains pro- and anti-inflammatory products that modulate immune responses and may play a role in maintaining gut barrier function. Therefore, the community composition of the microbiota has profound effects on the immune status of the host and impacts the development and/or progressi...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Pacifici, R. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Preclinical and Coclinical Studies in Prostate Cancer
Men who develop metastatic castration-resistant prostate cancer (mCRPC) will invariably succumb to their disease. Thus there remains a pressing need for preclinical testing of new drugs and drug combinations for late-stage prostate cancer (PCa). Insights from the mCRPC genomic landscape have revealed that, in addition to sustained androgen receptor (AR) signaling, there are other actionable molecular alterations and distinct molecular subclasses of PCa; however, the rate at which this knowledge translates into patient care via current preclinical testing is painfully slow and inefficient. Here, we will highlight the issues...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Chen, M., Pandolfi, P. P. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Effects of Exercise on Vascular Function, Structure, and Health in Humans
Physical activity has profound impacts on the vasculature in humans. Acute exercise induces immediate changes in artery function, whereas repeated episodic bouts of exercise induce chronic functional adaptation and, ultimately, structural arterial remodeling. The nature of these changes in function and structure are dependent on the characteristics of the training load and may be modulated by other factors such as exercise-induced inflammation and oxidative stress. The clinical implications of these physiological adaptations are profound. Exercise impacts on the development of atherosclerosis and on the incidence of primar...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Green, D. J., Smith, K. J. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] On the Run for Hippocampal Plasticity
Accumulating research in rodents and humans indicates that exercise benefits brain function and may prevent or delay onset of neurodegenerative conditions. In particular, exercise modifies the structure and function of the hippocampus, a brain area important for learning and memory. This review addresses the central and peripheral mechanisms underlying the beneficial effects of exercise on the hippocampus. We focus on running-induced changes in adult hippocampal neurogenesis, neural circuitry, neurotrophins, synaptic plasticity, neurotransmitters, and vasculature. The role of peripheral factors in hippocampal plasticity is...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Cooper, C., Moon, H. Y., van Praag, H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Effector T Cells in Multiple Sclerosis
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 (IFN-), 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 exper...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Kaskow, B. J., Baecher-Allan, C. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[TECHNIQUE] Phylogenetic Quantification of Intratumor Heterogeneity
We describe how multiple samples can guide tree inference through accurate phasing of germline variants and copy-number profiles. We show their relevance in detecting clonal expansions and deriving summary statistics quantifying the overall degree of ITH, and discuss how the relationship of metastatic clades might give us insight into the dominant mode of cancer progression. We further outline how multisample studies might help us better understand selective processes acting on cancer genomes and help to detect neutral evolution and mutator phenotypes. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Watkins, T. B. K., Schwarz, R. F. Tags: Cancer Evolution TECHNIQUE Source Type: research

[PERSPECTIVES] The Genetics of C9orf72 Expansions
Repeat expansions in the promoter region of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and related disorders of the ALS/frontotemporal lobar degeneration (FTLD) spectrum. Remarkable clinical heterogeneity among patients with a repeat expansion has been observed, and genetic anticipation over different generations has been suggested. Genetic factors modifying the clinical phenotype have been proposed, including genetic variation in other known disease genes, the genomic context of the C9orf72 repeat, and expanded repeat size, which has been estimated between 45 and several thousand unit...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Gijselinck, I., Cruts, M., Van Broeckhoven, C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Disease Mechanisms of C9ORF72 Repeat Expansions
G4C2 repeat expansions within the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense G4C2 and antisense G2C4 repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased C9ORF72 mRNA and protein expression. Consequently, there is ample opportunity for the C9ORF72 mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in be...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Gendron, T. F., Petrucelli, L. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] The Evolution and Ecology of Resistance in Cancer Therapy
Despite continuous deployment of new treatment strategies and agents over many decades, most disseminated cancers remain fatal. Cancer cells, through their access to the vast information of human genome, have a remarkable capacity to deploy adaptive strategies for even the most effective treatments. We note there are two critical steps in the clinical manifestation of treatment resistance. The first, which is widely investigated, requires deployment of a mechanism of resistance that usually involves increased expression of molecular machinery necessary to eliminate the cytotoxic effect of treatment. However, the emergence ...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Gatenby, R., Brown, J. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] The Heart and Great Vessels
This article gives a general overview of this work as it pertains to the development of great vessels, myocardium, and heart valves. In each area, we focus on currently studied methods, limitations, and areas for future study. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Onwuka, E., King, N., Heuer, E., Breuer, C. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Targeting Ras with Macromolecules
Activating Ras mutations are associated with ~30% of all human cancers and the four Ras isoforms are highly attractive targets for anticancer drug discovery. However, Ras proteins are challenging targets for conventional drug discovery because they function through intracellular protein–protein interactions and their surfaces lack major pockets for small molecules to bind. Over the past few years, researchers have explored a variety of approaches and modalities, with the aim of specifically targeting oncogenic Ras mutants for anticancer treatment. This perspective will provide an overview of the efforts on developing...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Pei, D., Chen, K., Liao, H. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[TECHNIQUE] Anatomic and Molecular Imaging in Prostate Cancer
Prostate cancer is characterized by a complex set of heterogeneous disease states. This review aims to describe how imaging has been studied within each specific state. As physicians transition into an era of precision medicine, multiparametric magnetic resonance imaging (mpMRI) is proving to be a powerful tool leading the way for a paradigm shift in the diagnosis and management of localized prostate cancer. With further research and development, molecular imaging modalities will likely change the way we approach recurrent and metastatic disease. Given the range of possible oncological progression patterns, a thorough unde...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Miller, E. T., Salmasi, A., Reiter, R. E. Tags: Prostate Cancer TECHNIQUE Source Type: research

[PERSPECTIVES] Exosomes as Mediators of the Systemic Adaptations to Endurance Exercise
Habitual endurance exercise training is associated with multisystemic metabolic adaptations that lower the risk of inactivity-associated disorders such as obesity and type 2 diabetes mellitus (T2DM). Identification of complex systemic signaling networks responsible for these benefits are of great interest because of their therapeutic potential in metabolic diseases; however, specific signals that modulate the multisystemic benefits of exercise in multiple tissues and organs are only recently being discovered. Accumulated evidence suggests that muscle and other tissues have an endocrine function and release peptides and nuc...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Safdar, A., Tarnopolsky, M. A. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Effects of Exercise and Aging on Skeletal Muscle
A substantial loss of muscle mass and strength (sarcopenia), a decreased regenerative capacity, and a compromised physical performance are hallmarks of aging skeletal muscle. These changes are typically accompanied by impaired muscle metabolism, including mitochondrial dysfunction and insulin resistance. A challenge in the field of muscle aging is to dissociate the effects of chronological aging per se on muscle characteristics from the secondary influence of lifestyle and disease processes. Remarkably, physical activity and exercise are well-established countermeasures against muscle aging, and have been shown to attenuat...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Distefano, G., Goodpaster, B. H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research