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Cold Spring Harbor Perspectives in Medicine

Johannes L Bos
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...
August 4, 2017: Cold Spring Harbor Perspectives in Medicine
Paula Mera, Mathieu Ferron, Ioanna Mosialou
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...
August 4, 2017: Cold Spring Harbor Perspectives in Medicine
Anica Wandler, Kevin Shannon
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 cell populations, for testing potential therapies, and for investigating mechanisms of drug response and resistance...
August 4, 2017: Cold Spring Harbor Perspectives in Medicine
Dehua Pei, Kuangyu Chen, Hui Liao
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...
August 4, 2017: Cold Spring Harbor Perspectives in Medicine
Marie Courbebaisse, Beate Lanske
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...
August 4, 2017: Cold Spring Harbor Perspectives in Medicine
Matthias Drosten, Carmen Guerra, Mariano Barbacid
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...
August 4, 2017: Cold Spring Harbor Perspectives in Medicine
Ruping Sun, Zheng Hu, Christina Curtis
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...
July 14, 2017: Cold Spring Harbor Perspectives in Medicine
Thomas B K Watkins, Roland F Schwarz
As sequencing efforts continue to reveal the extent of the intratumor heterogeneity (ITH) present in human cancers, the importance of evolutionary studies attempting to trace its etiology has increased. Sequencing multiple samples or tumor regions from the same patient has become affordable and is an effective way of tracing these evolutionary pathways, understanding selection, and detecting clonal expansions in ways impractical with single samples alone. In this article, we discuss and show the benefits of such multisample studies...
July 14, 2017: Cold Spring Harbor Perspectives in Medicine
Robert Gatenby, Joel Brown
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...
July 14, 2017: Cold Spring Harbor Perspectives in Medicine
Sundeep Khosla, David G Monroe
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 play important roles, perhaps in a somewhat compartment-specific (i...
July 14, 2017: Cold Spring Harbor Perspectives in Medicine
Eric T Miller, Amirali Salmasi, Robert E Reiter
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...
July 14, 2017: Cold Spring Harbor Perspectives in Medicine
Andrew W McPherson, Fong Chun Chan, Sohrab P Shah
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...
June 19, 2017: Cold Spring Harbor Perspectives in Medicine
Kroopa Joshi, Benjamin M Chain, Karl S Peggs, Sergio A Quezada
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...
June 19, 2017: Cold Spring Harbor Perspectives in Medicine
Subramanian Venkatesan, Charles Swanton, Barry S Taylor, Joseph F Costello
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 the drug target...
August 1, 2017: Cold Spring Harbor Perspectives in Medicine
Robert L Bowman, Ross L Levine
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...
August 1, 2017: Cold Spring Harbor Perspectives in Medicine
Leslie I Grad, Guy A Rouleau, John Ravits, Neil R Cashman
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...
August 1, 2017: Cold Spring Harbor Perspectives in Medicine
Sina Ghaemmaghami
Prion diseases are a group of fatal neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrP(C)) into a pathogenic conformation (PrP(Sc)). PrP(Sc) is capable of folding into multiple self-replicating prion strains that produce phenotypically distinct neurological disorders. Evidence suggests that the structural heterogeneity of PrP(Sc) is the molecular basis of strain-specific prion properties. The self-templating of PrP(Sc) typically ensures that prion strains breed true upon passage...
August 1, 2017: Cold Spring Harbor Perspectives in Medicine
Yali Xu, Christopher R Vakoc
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 transcription of cancer-promoting genes...
July 5, 2017: Cold Spring Harbor Perspectives in Medicine
Jennifer N Rauch, Steven H Olson, Jason E Gestwicki
Tau aggregation is linked to multiple neurodegenerative disorders that are collectively termed tauopathies. Small molecules are powerful probes of the aggregation process, helping to reveal the key steps and serving as diagnostics and reporters. Moreover, some of these small molecules may have potential as therapeutics. This review details how small molecules and chemical biology have helped to elucidate the mechanisms of tau aggregation and how they are being used to detect and prevent tau aggregation. In addition, we comment on how new insights into tau prions are changing the approach to small molecule discovery...
July 5, 2017: Cold Spring Harbor Perspectives in Medicine
Barbara Kupr, Svenia Schnyder, Christoph Handschin
Skeletal muscle is not only one of the largest, but also one of the most dynamic organs. For example, plasticity elicited by endurance or resistance exercise entails complex transcriptional programs that are still poorly understood. Various signaling pathways are engaged in the contracting muscle fiber and collectively culminate in the modulation of the activity of numerous transcription factors (TFs) and coregulators. Because exercise confers many benefits for the prevention and treatment of a wide variety of pathologies, pharmacological activation of signaling pathways and TFs is an attractive avenue to elicit therapeutic effects...
June 1, 2017: Cold Spring Harbor Perspectives in Medicine
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