[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

[PERSPECTIVES] Multiple Sclerosis Pathology
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 activa...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Lassmann, H. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] TDP-43 Prions
The most common neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, are all protein-misfolding diseases and are characterized by the presence of disease-specific protein aggregates in affected neuronal cells. Recent studies have shown that, like tau and α-synuclein, TAR-DNA binding protein of 43 kDa (TDP-43) can form aggregates in vitro in a seed-dependent, self-templating, prion-like manner. Insoluble TDP-43 prepared from the brains of patients has been classified into several strains, which can be transferred from cell to cell in vitro, suggesting the involve...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Nonaka, T., Hasegawa, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Cell Biology and Pathophysiology of {alpha}-Synuclein
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson’s disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated. In this perspective, we review the structural characteristics of α-synuclei...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Burre, J., Sharma, M., Südhof, T. C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[RETROSPECTIVE] From Ras to Rap and Back, a Journey of 35 Years
Our laboratory has studied Ras and Ras-like proteins since the discovery of the Ras oncogene 35 years ago. In this review, I will give an account of what we have done in these 35 years and indicate the main papers that have guided our research. Our efforts started with the early analysis of mutant Ras in human tumors followed by deciphering of the role of Ras in signal transduction pathways. In an attempt to interfere in Ras signaling we turned to Rap proteins. These proteins are the closest relatives of Ras and were initially identified as Ras antagonists. However, our studies revealed that the Rap signaling network prima...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Bos, J. L. Tags: Ras and Cancer in the 21st Century RETROSPECTIVE Source Type: research

[PERSPECTIVES] Control of Muscle Metabolism by the Mediator Complex
Exercise represents an energetic challenge to whole-body homeostasis. In skeletal muscle, exercise activates a variety of signaling pathways that culminate in the nucleus to regulate genes involved in metabolism and contractility; however, much remains to be learned about the transcriptional effectors of exercise. Mediator is a multiprotein complex that links signal-dependent transcription factors and other transcriptional regulators with the basal transcriptional machinery, thereby serving as a transcriptional "hub." In this article, we discuss recent studies highlighting the role of Mediator subunits in metabol...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Amoasii, L., Olson, E. N., Bassel-Duby, R. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+ Handling
The contractile function of skeletal muscle declines during intense or prolonged physical exercise, that is, fatigue develops. Skeletal muscle fibers fatigue acutely during highly intense exercise when they have to rely on anaerobic metabolism. Early stages of fatigue involve impaired myofibrillar function, whereas decreased Ca2+ release from the sarcoplasmic reticulum (SR) becomes more important in later stages. SR Ca2+ release can also become reduced with more prolonged, lower intensity exercise, and it is then related to glycogen depletion. Increased reactive oxygen/nitrogen species can cause long-lasting impairments in...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Cheng, A. J., Place, N., Westerblad, H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[TECHNIQUES] Observing Clonal Dynamics across Spatiotemporal Axes: A Prelude to Quantitative Fitness Models for Cancer
The ability to accurately model evolutionary dynamics in cancer would allow for prediction of progression and response to therapy. As a prelude to quantitative understanding of evolutionary dynamics, researchers must gather observations of in vivo tumor evolution. High-throughput genome sequencing now provides the means to profile the mutational content of evolving tumor clones from patient biopsies. Together with the development of models of tumor evolution, reconstructing evolutionary histories of individual tumors generates hypotheses about the dynamics of evolution that produced the observed clones. In this review, we ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: McPherson, A. W., Chan, F. C., Shah, S. P. Tags: Cancer Evolution TECHNIQUES Source Type: research

[PERSPECTIVES] Microglial Phenotypes and Functions in Multiple Sclerosis
Microglia are the resident immune cells that constantly survey the central nervous system. They can adapt to their environment and respond to injury or insult by altering their morphology, phenotype, and functions. It has long been debated whether microglial activation is detrimental or beneficial in multiple sclerosis (MS). Recently, the two opposing yet connected roles of microglial activation have been described with the aid of novel microglial markers, RNA profiling, and in vivo models. In this review, microglial phenotypes and functions in the context of MS will be discussed with evidence from both human pathological ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: OLoughlin, E., Madore, C., Lassmann, H., Butovsky, O. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Historical Perspective and Future Direction of Blood Vessel Developments
Over the past 40 years, remarkable advances have been made in our understanding of successful blood vessel regeneration, starting with the failures of early tissue-engineered vascular grafts designed using isolated components or molecules, such as collagen gels. The vascular tissue engineers are today better educated and have steered ongoing research developments toward clinical developments of more complete vascular grafts that replicate the multitude of specialized arterial aspects required for function. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Dimitrievska, S., Niklason, L. E. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[TECHNIQUES] Three-Dimensional Bioprinting Strategies for Tissue Engineering
Over the past decades, many approaches have been developed to fabricate biomimetic extracellular matrices of desired properties for engineering functional tissues. However, the inability of these techniques to precisely control the spatial architecture has posed a significant challenge in producing complex tissues. 3D bioprinting technology has emerged as a potential solution by bringing unprecedented freedom and versatility in depositing biological materials and cells in a well-controlled manner in the 3D volumes, therefore achieving precision engineering of functional tissues. In this article, we review the application o...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Zhang, Y. S., Oklu, R., Dokmeci, M. R., Khademhosseini, A. Tags: Tissue Engineering and Regenerative Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Prion-Like Characteristics of Polyglutamine-Containing Proteins
Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by the conversion of prion protein (PrP) into a self-replicating conformation that spreads via templated conversion of natively folded PrP molecules within or between cells. Recent studies provide compelling evidence that prion-like behavior is a general property of most protein aggregates associated with neurodegenerative diseases. Many of these disorders are associated with spontaneous protein aggregation, but genetic mutations can increase the aggregation propensity of specific proteins, including expansion of polyglutamine (polyQ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Pearce, M. M. P., Kopito, R. R. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Chronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation?
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. There is often a long latency period between an individual’s exposure to repetitive brain trauma and the clinical symptoms of CTE. The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebr...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Kriegel, J., Papadopoulos, Z., McKee, A. C. Tags: Prion Diseases PERSPECTIVES Source Type: research