[PERSPECTIVES] Regulation of Bone Metabolism by Sex Steroids
Osteoporosis is a significant public health problem, and a major cause of the disease is estrogen deficiency following menopause in women. In addition, considerable evidence now shows that estrogen is also a major regulator of bone metabolism in men. Since the original description of the effects of estrogen deficiency on bone by Fuller Albright more than 70 years ago, there has been enormous progress in understanding the mechanisms of estrogen and testosterone action on bone using human and mouse models. Although we understand more about the effects of estrogen on bone as compared with testosterone, both sex steroids do pl...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Khosla, S., Monroe, D. G. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Theoretical and Biological Evaluation of the Link between Low Exercise Capacity and Disease Risk
Large-scale epidemiological studies show that low exercise capacity is the highest risk factor for all-cause morbidity and mortality relative to other conditions including diabetes, hypertension, and obesity. This led us to formulate the energy transfer hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As a test of this hypothesis, we predicted that two-way selective breeding of genetically heterogeneous rats for low and high intrinsic treadmill running capacity (a surrogate for energy transfer) would also produce rats that differ fo...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Koch, L. G., Britton, S. L. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] The Interleukin (IL)-23/T helper (Th)17 Axis in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
T helper (Th)17 cells are responsible for host defense against fungi and certain extracellular bacteria but have also been reported to play a role in a variety of autoimmune diseases. Th17 cells respond to environmental cues, are very plastic, and might also be involved in tissue homeostasis and regeneration. The imprinting of pathogenic properties in Th17 cells in autoimmunity seems highly dependent on interleukin (IL)-23. Since Th17 cells were first described in experimental autoimmune encephalomyelitis, they have been suggested to also promote tissue damage in multiple sclerosis (MS). Indeed, some studies linked Th17 ce...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Hiltensperger, M., Korn, T. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] The "Achilles' Heel" of Cancer and Its Implications for the Development of Novel Immunotherapeutic Strategies
Over the last century, scientists have embraced the idea of mobilizing antitumor immune responses in patients with cancer. In the last decade, we have seen the rebirth of cancer immunotherapy and its validation in a series of high profile clinical trials following the discovery of several immune-regulatory receptors. Recent studies point toward the tumor mutational load and resulting neoantigen burden as being crucial to tumor cell recognition by the immune system, highlighting a potentially targetable Achilles' heel in cancer. In this review, we explore the key mechanisms that underpin the recognition of cancerous cells b...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Joshi, K., Chain, B. M., Peggs, K. S., Quezada, S. A. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Craniofacial Tissue Engineering
The craniofacial complex is composed of fundamental components such as blood vessels and nerves, and also a variety of specialized tissues such as craniofacial bones, cartilages, muscles, ligaments, and the highly specialized and unique organs, the teeth. Together, these structures provide many functions including speech, mastication, and aesthetics of the craniofacial complex. Craniofacial defects not only influence the structure and function of the jaws and face, but may also result in deleterious psychosocial issues, emphasizing the need for rapid and effective, precise, and aesthetic reconstruction of craniofacial tiss...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Zhang, W., Yelick, P. C. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Modern Vector Control
The rapid spread of mosquito resistance to currently available insecticides, and the current lack of an efficacious malaria vaccine are among many challenges that affect large-scale efforts for malaria control. As goals of malaria elimination and eradication are put forth, new vector-control paradigms and tools and/or further optimization of current vector-control products are required to meet public health demands. Vector control remains the most effective measure to prevent malaria transmission and present gains against malaria mortality and morbidity may be maintained as long as vector-intervention strategies are sustai...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Lobo, N. F., Achee, N. L., Greico, J., Collins, F. H. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria Pathogenesis
In the mosquito–human life cycle, the six species of malaria parasites infecting humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 106 organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Milner, D. A. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Therapeutic Strategies for Restoring Tau Homeostasis
Normal tau homeostasis is achieved when the synthesis, processing, and degradation of the protein is balanced. Together, the pathways that regulate tau homeostasis ensure that the protein is at the proper levels and that its posttranslational modifications and subcellular localization are appropriately controlled. These pathways include the enzymes responsible for posttranslational modifications, those systems that regulate mRNA splicing, and the molecular chaperones that control tau turnover and its binding to microtubules. In tauopathies, this delicate balance is disturbed. Tau becomes abnormally modified by posttranslat...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Young, Z. T., Mok, S. A., Gestwicki, J. E. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission
More than 30 proteins form amyloid in humans, most of them outside of the brain. Deposition of amyloid in extracerebral tissues is very common and seems inevitable for an aging person. Most deposits are localized, small, and probably without consequence, but in some instances, they are associated with diseases such as type 2 diabetes. Other extracerebral amyloidoses are systemic, with life-threatening effects on the heart, kidneys, and other organs. Here, we review how amyloid may spread through seeding and whether transmission of amyloid diseases may occur between humans. We also discuss whether cross-seeding is important...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Westermark, G. T., Fändrich, M., Lundmark, K., Westermark, P. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of MicroRNAs in the Cardiac Response to Exercise
Noncoding microRNAs (miRNAs) have emerged as central regulators of cardiac biology, modulating cardiac development and the response to pathological stress in disease. Although less well developed, emerging evidence suggests miRNAs are likely also important in the heart’s response to the physiological stress of exercise. Given the well-recognized cardiovascular benefits of exercise, elucidating the contribution of miRNAs to this response has the potential not only to reveal novel aspects of cardiovascular biology but also to identify new targets for therapeutic intervention that may complement those discovered through...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Liu, X., Platt, C., Rosenzweig, A. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Evolution of Premalignant Disease
We describe the hurdles of prognosticating cancer risk in premalignant disease by making reference to the underlying continuous and multivariate natures of genotypes and phenotypes and the particular challenge inherent in defining a cell lineage as "cancerized." (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Curtius, K., Wright, N. A., Graham, T. A. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[TECHNIQUE] Honing Cell and Tissue Culture Conditions for Bone and Cartilage Tissue Engineering
An avenue of tremendous interest and need in health care encompasses the regeneration of bone and cartilage. Over the years, numerous tissue engineering strategies have contributed substantial progress toward the realization of clinically relevant therapies. Cell and tissue culture protocols, however, show many variations that make experimental results among different publications challenging to compare. This collection surveys prevalent cell sources, soluble factors, culture medium formulations, environmental factors, and genetic modification approaches in the literature. The intent of consolidating this information is to...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Lam, J., Lee, E. J., Clark, E. C., Mikos, A. G. Tags: Tissue Engineering and Regenerative Medicine TECHNIQUE Source Type: research

[PERSPECTIVES] Anopheline Reproductive Biology: Impacts on Vectorial Capacity and Potential Avenues for Malaria Control
Vectorial capacity is a mathematical approximation of the efficiency of vector-borne disease transmission, measured as the number of new infections disseminated per case per day by an insect vector. Multiple elements of mosquito biology govern their vectorial capacity, including survival, population densities, feeding preferences, and vector competence. Intriguingly, biological pathways essential to mosquito reproductive fitness directly or indirectly influence a number of these elements. Here, we explore this complex interaction, focusing on how the interplay between mating and blood feeding in female Anopheles not only s...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Mitchell, S. N., Catteruccia, F. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Determinants of Malaria Transmission at the Population Level
Transmission of malaria from man to mosquito defines the human infectious reservoir of malaria. At the population level this is influenced by a variety of human, parasite, and mosquito vector factors some or all of which may vary depending on the epidemiological setting. Here, we review our current state of knowledge related to human infectiousness to mosquitoes and how current malaria control strategies might be adapted to focus on reducing this. While much progress has been made in malaria control, we argue that an improved understanding of human infectivity will allow more effective use of current control tools and make...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Bousema, T., Drakeley, C. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Fused in Sarcoma Neuropathology in Neurodegenerative Disease
Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms. (Source...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Mackenzie, I. R. A., Neumann, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Structural and Chemical Biology of Presenilin Complexes
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the , , site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several confor...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Johnson, D. S., Li, Y.-M., Pettersson, M., St George-Hyslop, P. H. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations
Exercise stimulates the release of proteins with autocrine, paracrine, or endocrine functions produced in skeletal muscle, termed myokines. Based on the current state of knowledge, the major physiological function of myokines is to protect the functionality and to enhance the exercise capacity of skeletal muscle. Myokines control adaptive processes in skeletal muscle by acting as paracrine regulators of fuel oxidation, hypertrophy, angiogenesis, inflammatory processes, and regulation of the extracellular matrix. Endocrine functions attributed to myokines are involved in body weight regulation, low-grade inflammation, insul...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Hoffmann, C., Weigert, C. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Experimental Models of Inherited PrP Prion Diseases
The inherited prion protein (PrP) prion disorders, which include familial Creutzfeldt–Jakob disease, Gerstmann–Stra╠łussler–Scheinker disease, and fatal familial insomnia, constitute ~10%–15% of all PrP prion disease cases in humans. Attempts to generate animal models of these disorders using transgenic mice expressing mutant PrP have produced variable results. Although many lines of mice develop spontaneous signs of neurological illness with accompanying prion disease–specific neuropathological changes, others do not. Furthermore, demonstrating the presence of protease-resistant PrP species a...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Watts, J. C., Prusiner, S. B. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Current and Future Prospects for Preventing Malaria Transmission via the Use of Insecticides
Malaria vectors have developed resistance to all classes of insecticides that are used to target the adult mosquito to prevent parasite transmission. The number of resistant mosquito populations has increased dramatically in recent years, most likely as a result of the scale-up of vector control activities, and the intensity of this resistance is increasing rapidly and compromising the performance of vector control tools. Bednets and indoor residual spray formulations containing alternative active ingredients have shown promise in field trials but are still several years away from implementation. As existing insecticides b...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Ranson, H. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia
Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associ...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Krivtsov, A. V., Hoshii, T., Armstrong, S. A. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Self-Assembling Process and Applications in Tissue Engineering
Tissue engineering strives to create neotissues capable of restoring function. Scaffold-free technologies have emerged that can recapitulate native tissue function without the use of an exogenous scaffold. This review will survey, in particular, the self-assembling and self-organization processes as scaffold-free techniques. Characteristics and benefits of each process are described, and key examples of tissues created using these scaffold-free processes are examined to provide guidance for future tissue-engineering developments. We aim to explore the potential of self-assembly and self-organization scaffold-free approache...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Lee, J. K., Link, J. M., Hu, J. C. Y., Athanasiou, K. A. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Host Cell Tropism and Adaptation of Blood-Stage Malaria Parasites: Challenges for Malaria Elimination
Plasmodium falciparum and Plasmodium vivax account for most of the mortality and morbidity associated with malaria in humans. Research and control efforts have focused on infections caused by P. falciparum and P. vivax, but have neglected other malaria parasite species that infect humans. Additionally, many related malaria parasite species infect nonhuman primates (NHPs), and have the potential for transmission to humans. For malaria elimination, the varied and specific challenges of all of these Plasmodium species will need to be considered. Recent advances in molecular genetics and genomics have increased our knowledge o...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Lim, C., Dankwa, S., Paul, A. S., Duraisingh, M. T. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Biological Spectrum of Amyotrophic Lateral Sclerosis Prions
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, the...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Polymenidou, M., Cleveland, D. W. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Histopathology of Prostate Cancer
This review focuses on histopathological aspects of carcinoma of the prostate. A tissue diagnosis of adenocarcinoma is often essential for establishing a diagnosis of prostate cancer, and the foundation for a tissue diagnosis is currently light microscopic examination of hematoxylin and eosin (H&E)-stained tissue sections. Markers detected by immunohistochemistry on tissue sections can support a diagnosis of adenocarcinoma that is primary in the prostate gland or metastatic. Histological variants of carcinoma of the prostate are important for diagnostic recognition of cancer or as clinicopathologic entities that have p...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Humphrey, P. A. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[TECHNIQUES] Omics and Exercise: Global Approaches for Mapping Exercise Biological Networks
The application of global "-omics" technologies to exercise has introduced new opportunities to map the complexity and interconnectedness of biological networks underlying the tissue-specific responses and systemic health benefits of exercise. This review will introduce major research tracks and recent advancements in this emerging field, as well as critical gaps in understanding the orchestration of molecular exercise dynamics that will benefit from unbiased omics investigations. Furthermore, significant research hurdles that need to be overcome to effectively fill these gaps related to data collection, computat...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Hoffman, N. J. Tags: The Biology of Exercise TECHNIQUES Source Type: research

[PERSPECTIVES] Rate Coding and the Control of Muscle Force
The force exerted by a muscle during a voluntary contraction depends on the number of motor units recruited for the action and the rates at which they discharge action potentials (rate coding). Over most of the operating range of a muscle, the nervous system controls muscle force by varying both motor unit recruitment and rate coding. Except at relatively low forces, however, the control of muscle force depends primarily on rate coding, especially during fast contractions. This review provides five examples of how the modulation of rate coding influences the force exerted by muscle during voluntary actions. The five exampl...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Enoka, R. M., Duchateau, J. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Signaling Involved in Entry and Exit of Malaria Parasites from Host Erythrocytes
During the blood stage, Plasmodium spp. merozoites invade host red blood cells (RBCs), multiply, exit, and reinvade uninfected RBCs in a continuing cycle that is responsible for all the clinical symptoms associated with malaria. Entry into (invasion) and exit from (egress) RBCs are highly regulated processes that are mediated by an array of parasite proteins with specific functional roles. Many of these parasite proteins are stored in specialized apical secretory vesicles, and their timely release is critical for successful invasion and egress. For example, the discharge of parasite protein ligands to the apical surface of...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Singh, S., Chitnis, C. E. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[TECHNIQUES] Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells
The intestine shows extraordinary regenerative potential that might be harnessed to alleviate numerous morbid and lethal human diseases. The intestinal stem cells regenerate the epithelium every 5 days throughout an individual’s lifetime. Understanding stem-cell signaling affords power to influence the niche environment for growing intestine. The manifold approaches to tissue engineering may be organized by variations of three basic components required for the transplantation and growth of stem/progenitor cells: (1) cell delivery materials or scaffolds; (2) donor cells including adult stem cells, induced pluripotent ...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Trecartin, A., Grikscheit, T. Tags: Tissue Engineering and Regenerative Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Malaria Transmission and Prospects for Malaria Eradication: The Role of the Environment
Environmental factors affect the transmission intensity, seasonality, and geographical distribution of malaria, and together with the vector, the human, and the parasite compose the malaria system. Strategies that alter the environment are among the oldest interventions for malaria control, but currently are not the most prominent despite historical evidence of their effectiveness. The importance of environmental factors, the role they play considering the current goals of malaria eradication, the different strategies that can be adopted, and the current challenges for their implementation are discussed. As malaria elimina...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Castro, M. C. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] The Prion-Like Behavior of Assembled Tau in Transgenic Mice
Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer’s disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system. In chronic traumatic encephalopathy, tauopathy appears to sprea...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Clavaguera, F., Tolnay, M., Goedert, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Antibody Therapeutics Targeting A{beta} and Tau
The astonishing findings that active and passive immunization against amyloid-β (Aβ) in mouse models of Alzheimer’s disease (AD) dramatically decreased amyloid burden led to a rapid initiation of human clinical trials with much enthusiasm. However, methodological issues and adverse effects relating to these clinical trials arose, challenging the effectiveness and safety of these reagents. Efforts are now underway to develop safer immunotherapeutic approaches toward Aβ and the treatment of individuals at risk for AD before or in the earliest stages of cognitive decline with new hopes. Furthermore, sever...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2017 Category: Research Authors: Gallardo, G., Holtzman, D. M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Androgen Signaling in Prostate Cancer
The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, progression to castration-resistant prostate cancer (CRPC) typically follows and is largely the result of restored androgen signaling. Efforts to understand the mechanisms behind CRPC have revealed new insights into dysregulated androgen signaling and intratumoral androgen synthesis, which has ultimately led to the development of several novel androgen receptor (AR)-directed therapies for ...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Dai, C., Heemers, H., Sharifi, N. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Exercise and the Skeletal Muscle Epigenome
An acute bout of exercise is sufficient to induce changes in skeletal muscle gene expression that are ultimately responsible for the adaptive responses to exercise. Although much research has described the intracellular signaling responses to exercise that are linked to transcriptional regulation, the epigenetic mechanisms involved are only just emerging. This review will provide an overview of epigenetic mechanisms and what is known in the context of exercise. Additionally, we will explore potential interactions between metabolism during exercise and epigenetic regulation, which serves as a framework for potential areas f...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: McGee, S. L., Walder, K. R. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Homeostasis Back and Forth: An Ecoevolutionary Perspective of Cancer
The role of genetic mutations in cancer is indisputable: They are a key source of tumor heterogeneity and drive its evolution to malignancy. But, the success of these new mutant cells relies on their ability to disrupt the homeostasis that characterizes healthy tissues. Mutated clones unable to break free from intrinsic and extrinsic homeostatic controls will fail to establish a tumor. Here, we will discuss, through the lens of mathematical and computational modeling, why an evolutionary view of cancer needs to be complemented by an ecological perspective to understand why cancer cells invade and subsequently transform the...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Basanta, D., Anderson, A. R. A. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Biologic Scaffolds
Biologic scaffold materials composed of allogeneic or xenogeneic extracellular matrix are commonly used for the repair and functional reconstruction of injured and missing tissues. These naturally occurring bioscaffolds are manufactured by the removal of the cellular content from source tissues while preserving the structural and functional molecular units of the remaining extracellular matrix (ECM). The mechanisms by which these bioscaffolds facilitate constructive remodeling and favorable clinical outcomes include release or creation of effector molecules that recruit endogenous stem/progenitor cells to the site of scaff...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Costa, A., Naranjo, J. D., Londono, R., Badylak, S. F. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Vaccines to Accelerate Malaria Elimination and Eventual Eradication
Remarkable progress has been made in coordinated malaria control efforts with substantial reductions in malaria-associated deaths and morbidity achieved through mass administration of drugs and vector control measures including distribution of long-lasting insecticide-impregnated bednets and indoor residual spraying. However, emerging resistance poses a significant threat to the sustainability of these interventions. In this light, the malaria research community has been charged with the development of a highly efficacious vaccine to complement existing malaria elimination measures. As the past 40 years of investment in th...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Healer, J., Cowman, A. F., Kaslow, D. C., Birkett, A. J. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] The Biology of Plasmodium vivax
Plasmodium vivax is the second most prevalent cause of malaria worldwide and the leading cause of malaria outside of Africa. Although infections are seldom fatal clinical disease can be debilitating and imposes significant health and economic impacts on affected populations. Estimates of transmission and prevalence intensity can be problematic because many episodes of vivax originate from hypnozoite stages in the liver that have remained dormant from previous infections by an unknown mechanism. Lack of treatment options to clear hypnozoites and the ability to infect mosquitoes before disease symptoms present represent majo...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Adams, J. H., Mueller, I. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies
Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ~70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodeg...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Guo, L., Shorter, J. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] The Transcellular Propagation and Intracellular Trafficking of {alpha}-Synuclein
Parkinson’s disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals. Here, we discuss the transcellular propagation and intracellular...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2017 Category: Research Authors: Tofaris, G. K., Goedert, M., Spillantini, M. G. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Autophagy-Dependent Beneficial Effects of Exercise
Exercise has long been recognized as a powerful physiological stimulus for a wide variety of metabolic adaptations with implications for health and performance. The metabolic effects of exercise occur during and after each exercise bout and manifest as cumulative adaptive responses to successive exercise bouts. Studies on the beneficial effects of exercise have traditionally focused on the biosynthesis of metabolic proteins and organelles. However, the recycling of cellular components by autophagy has recently emerged as an important process involved in the adaptive responses to exercise. This review covers the regulation ...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Halling, J. F., Pilegaard, H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Biology and Genetics of PrP Prion Strains
Prion diseases are a group of fatal neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrPC) into a pathogenic conformation (PrPSc). PrPSc is capable of folding into multiple self-replicating prion strains that produce phenotypically distinct neurological disorders. Evidence suggests that the structural heterogeneity of PrPSc is the molecular basis of strain-specific prion properties. The self-templating of PrPSc typically ensures that prion strains breed true upon passage. However, prion strains also have the capacity to conformationally transform to maximize their rate of replication in a...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Ghaemmaghami, S. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Principles of Reconstructing the Subclonal Architecture of Cancers
We describe the principles that underlie subclonal reconstruction through single nucleotide variants (SNVs) or copy number alterations (CNAs) from bulk or single-cell sequencing. These principles include estimating the fraction of tumor cells for SNVs and CNAs, performing clustering of SNVs from single- and multisample cases, and single-cell sequencing. The application of subclonal reconstruction methods is providing key insights into tumor evolution, identifying subclonal driver mutations, patterns of parallel evolution and differences in mutational signatures between cellular populations, and characterizing the mechanism...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Dentro, S. C., Wedge, D. C., Van Loo, P. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution
Despite the great progress in our understanding of the molecular basis of human cancer, the heterogeneity of individual tumors and the evolutionary pressures imposed by therapy have hampered our ability to effectively eradicate and control this disease. How, therefore, do cancers evolve under the selective pressures of cancer therapy? Recent studies have linked both primary (or de novo) and acquired treatment resistance to intratumor heterogeneity and clonal evolution. Resistance to targeted therapies often includes mutation of the drug target itself and aberrations of pathways upstream of, downstream from, or parallel to ...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Venkatesan, S., Swanton, C., Taylor, B. S., Costello, J. F. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] TET2 in Normal and Malignant Hematopoiesis
The ten-eleven translocation (TET) family of enzymes were originally cloned from the translocation breakpoint of t(10;11) in infant acute myeloid leukemia (AML) with subsequent genomic analyses revealing somatic mutations and suppressed expression of TET family members across a range of malignancies, particularly enriched in hematological neoplasms. The TET family of enzymes is responsible for the hydroxylation of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), followed by active and passive mechanisms leading to DNA demethylation. Given the complexity and importance of DNA methylation events in cellular proli...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Bowman, R. L., Levine, R. L. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Immune Responses in Malaria
Evidence accumulated through the years clearly indicates that antiparasite immune responses can efficiently control malaria parasite infection at all development stages, and under certain circumstances they can prevent parasite infection. Translating these findings into vaccines or immunotherapeutic interventions has been difficult in part because of the extraordinary biological complexity of this parasite, which has several developmental stages expressing unique sets of stage-specific genes and multiple antigens, most of which are antigenically diverse. Nevertheless, in the last 30 years major advances have resulted in ch...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Long, C. A., Zavala, F. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria Genomics in the Era of Eradication
The first reference genome assembly for the Plasmodium falciparum malaria parasite was completed over a decade ago, and the impact of this and other genomic resources on malaria research has been significant. Genomic resources for other malaria parasites are being established, even as P. falciparum continues to be the focus of development of new genomic methods and applications. Here we review the impact and applications of genomic data on malaria research, and discuss future needs and directions as genomic data generation becomes less expensive and more decentralized. Specifically, we focus on how population genomic strat...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Neafsey, D. E., Volkman, S. K. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology. Because the same phenotypes can have multiple cause...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2017 Category: Research Authors: Grad, L. I., Rouleau, G. A., Ravits, J., Cashman, N. R. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Tumor Microenvironment and Differential Responses to Therapy
Cancer evolution plays a key role in both the development of tumors and their response to therapy. Like all evolutionary processes, tumor evolution is shaped by the environment. In tumors, this consists of a complex mixture of nontransformed cell types and extracellular matrix. Chemotherapy or radiotherapy imposes further strong selective pressures on cancer cells during cancer treatment. Here, we review how different components of the tumor microenvironment can modulate the response to chemo- and radiotherapy. We further describe how therapeutic strategies directly alter the composition, or function, of the tumor microenv...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Hirata, E., Sahai, E. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Targeting Cancer Cells with BET Bromodomain Inhibitors
Cancer cells are often hypersensitive to the targeting of transcriptional regulators, which may reflect the deregulated gene expression programs that underlie malignant transformation. One of the most prominent transcriptional vulnerabilities in human cancer to emerge in recent years is the bromodomain and extraterminal (BET) family of proteins, which are coactivators that link acetylated transcription factors and histones to the activation of RNA polymerase II. Despite unclear mechanisms underlying the gene specificity of BET protein function, small molecules targeting these regulators preferentially suppress the transcri...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Xu, Y., Vakoc, C. R. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Long Noncoding RNAs: At the Intersection of Cancer and Chromatin Biology
Although only 2% of the genome encodes protein, RNA is transcribed from the majority of the genetic sequence, suggesting a massive degree of cellular functionality is programmed in the noncoding genome. The mammalian genome contains tens of thousands of long noncoding RNAs (lncRNAs), many of which occur at disease-associated loci or are specifically expressed in cancer. Although the vast majority of lncRNAs have no known function, recurring molecular mechanisms for lncRNAs are now being observed in chromatin regulation and cancer pathways and emerging technologies are now providing tools to interrogate lncRNA molecular int...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Schmitt, A. M., Chang, H. Y. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research