[PERSPECTIVES] Antimalarial Drug Resistance: A Threat to Malaria Elimination
Increasing antimalarial drug resistance once again threatens effective antimalarial drug treatment, malaria control, and elimination. Artemisinin combination therapies (ACTs) are first-line treatment for uncomplicated falciparum malaria in all endemic countries, yet partial resistance to artemisinins has emerged in the Greater Mekong Subregion. Concomitant emergence of partner drug resistance is now causing high ACT treatment failure rates in several areas. Genetic markers for artemisinin resistance and several of the partner drugs have been established, greatly facilitating surveillance. Single point mutations in the gene...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Menard, D., Dondorp, A. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria Epigenetics
Organisms with identical genome sequences can show substantial differences in their phenotypes owing to epigenetic changes that result in different use of their genes. Epigenetic regulation of gene expression plays a key role in the control of several fundamental processes in the biology of malaria parasites, including antigenic variation and sexual differentiation. Some of the histone modifications and chromatin-modifying enzymes that control the epigenetic states of malaria genes have been characterized, and their functions are beginning to be unraveled. The fundamental principles of epigenetic regulation of gene express...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Cortes, A., Deitsch, K. W. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Huntingtons Disease: Mechanisms of Pathogenesis and Therapeutic Strategies
Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Finally, we outline some of the therapeutic strategies that are currently being pursued to slow down the disease. (S...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Jimenez-Sanchez, M., Licitra, F., Underwood, B. R., Rubinsztein, D. C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules
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. (Sourc...
Source: Cold Spring Harbor perspectives in medicine - July 5, 2017 Category: Research Authors: Rauch, J. N., Olson, S. H., Gestwicki, J. E. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Role of Nuclear Receptors in Exercise-Induced Muscle Adaptations
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 therapeuti...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: Kupr, B., Schnyder, S., Handschin, C. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution
Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations—subclones—that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preser...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: Bakhoum, S. F., Landau, D. A. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Nuclear Receptor-Binding SET Domain Family Histone Lysine Methyltransferases in Cancer
The nuclear receptor–binding SET Domain (NSD) family of histone H3 lysine 36 methyltransferases is comprised of NSD1, NSD2 (MMSET/WHSC1), and NSD3 (WHSC1L1). These enzymes recognize and catalyze methylation of histone lysine marks to regulate chromatin integrity and gene expression. The growing number of reports demonstrating that alterations or translocations of these genes fundamentally affect cell growth and differentiation leading to developmental defects illustrates the importance of this family. In addition, overexpression, gain of function somatic mutations, and translocations of NSDs are associated with human...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: Bennett, R. L., Swaroop, A., Troche, C., Licht, J. D. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria during Pregnancy
One hundred and twenty-five million women in malaria-endemic areas become pregnant each year (see Dellicour et al. PLoS Med 7: e1000221 [2010]) and require protection from infection to avoid disease and death for themselves and their offspring. Chloroquine prophylaxis was once a safe approach to prevention but has been abandoned because of drug-resistant parasites, and intermittent presumptive treatment with sulfadoxine–pyrimethamine, which is currently used to protect pregnant women throughout Africa, is rapidly losing its benefits for the same reason. No other drugs have yet been shown to be safe, tolerable, and ef...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: Fried, M., Duffy, P. E. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria Parasite Liver Infection and Exoerythrocytic Biology
In their infection cycle, malaria parasites undergo replication and population expansions within the vertebrate host and the mosquito vector. Host infection initiates with sporozoite invasion of hepatocytes, followed by a dramatic parasite amplification event during liver stage parasite growth and replication within hepatocytes. Each liver stage forms up to 90,000 exoerythrocytic merozoites, which are in turn capable of initiating a blood stage infection. Liver stages not only exploit host hepatocyte resources for nutritional needs but also endeavor to prevent hepatocyte cell death and detection by the host’s immune ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: Vaughan, A. M., Kappe, S. H. I. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetics of {beta}-Amyloid Precursor Protein in Alzheimer's Disease
Alzheimer’s disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Aβ is generated by proteolytic processing of the β-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of APP, leading to elevated APP expression, increased Aβ deposition, and characteristic AD neuropathology. Sequencing of APP in familial early-onset AD identified missense mutations that cause AD, while a recently discovered ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: TCW, J., Goate, A. M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Structural Biology of PrP Prions
Prion diseases are characterized by the deposition of amyloids, misfolded conformers of the prion protein. The misfolded conformation is self-replicating, by a mechanism solely enciphered in the conformation of the protein. Because of low solubility and heterogeneous aggregate sizes, the detailed atomic structure of the infectious isoform is still unknown. Progress has, however, been made, and has allowed insights into the structural and disease-related mechanisms of prions. Many structural models have been proposed, and a number of them support a consensus trimeric β-helical model, significantly more complex than sim...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2017 Category: Research Authors: Stubbs, G., Stöhr, J. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] DNA Hypomethylating Drugs in Cancer Therapy
Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in cl...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Sato, T., Issa, J.-P. J., Kropf, P. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation
The H3 lysine 36 histone methyltransferase SETD2 is mutated across a range of human cancers. Although other enzymes can mediate mono- and dimethylation, SETD2 is the exclusive trimethylase. SETD2 associates with the phosphorylated carboxy-terminal domain of RNA polymerase and modifies histones at actively transcribed genes. The functions associated with SETD2 are mediated through multiple effector proteins that bind trimethylated H3K36. These effectors directly mediate multiple chromatin-regulated processes, including RNA splicing, DNA damage repair, and DNA methylation. Although alterations in each of these processes have...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Fahey, C. C., Davis, I. J. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges
MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2–p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2–p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at leas...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Wang, S., Zhao, Y., Aguilar, A., Bernard, D., Yang, C.-Y. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres
Telomeres, the nucleoprotein complex at the ends of eukaryotic chromosomes, perform an essential cellular role in part by preventing the chromosomal end from initiating a DNA-damage response. This function of telomeres can be compromised as telomeres erode either as a consequence of cell division in culture or as a normal part of cellular ageing in proliferative tissues. Telomere dysfunction in this context leads to DNA-damage signaling and activation of the tumor-suppressor protein p53, which then can prompt either cellular senescence or apoptosis. By culling cells with dysfunctional telomeres, p53 plays a critical role i...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Roake, C. M., Artandi, S. E. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Plasmodium Sporozoite Biology
Plasmodium sporozoite transmission is a critical population bottleneck in parasite life-cycle progression and, hence, a target for prophylactic drugs and vaccines. The recent progress of a candidate antisporozoite subunit vaccine formulation to licensure highlights the importance of sporozoite transmission intervention in the malaria control portfolio. Sporozoites colonize mosquito salivary glands, migrate through the skin, penetrate blood vessels, breach the liver sinusoid, and invade hepatocytes. Understanding the molecular and cellular mechanisms that mediate the remarkable sporozoite journey in the invertebrate vector ...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Frischknecht, F., Matuschewski, K. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Prion-Like Protein Aggregates and Type 2 Diabetes
Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronic insulin resistance and β-cell dysfunction and loss, leading to impaired insulin release and hyperglycemia. Although the mechanism responsible for β-cell dysfunction and death is not completely understood, recent findings suggest that the accumulation of misfolded aggregates of the islet amyloid polypeptide (IAPP) in the islets of Langerhans may play an important role in pancreatic damage. Misfolding and aggregation of diverse proteins and their accumulation as amyloid in different organs is the hallmark feature in a group of ch...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Mukherjee, A., Soto, C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Binding Sites for Amyloid-{beta} Oligomers and Synaptic Toxicity
In Alzheimer’s disease (AD), insoluble and fibrillary amyloid-β (Aβ) peptide accumulates in plaques. However, soluble Aβ oligomers are most potent in creating synaptic dysfunction and loss. Therefore, receptors for Aβ oligomers are hypothesized to be the first step in a neuronal cascade leading to dementia. A number of cell-surface proteins have been described as Aβ binding proteins, and one or more are likely to mediate Aβ oligomer toxicity in AD. Cellular prion protein (PrPC) is a high-affinity Aβ oligomer binding site, and a range of data delineates a signaling pathway leading fr...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2017 Category: Research Authors: Smith, L. M., Strittmatter, S. M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Structural Evolution and Dynamics of the p53 Proteins
The family of the p53 tumor suppressive transcription factors includes p73 and p63 in addition to p53 itself. Given the high degree of amino-acid-sequence homology and structural organization shared by the p53 family members, they display some common features (i.e., induction of cell death, cell-cycle arrest, senescence, and metabolic regulation in response to cellular stress) as well as several distinct properties. Here, we describe the structural evolution of the family members with recent advances on the molecular dynamic studies of p53 itself. A crucial role of the carboxy-terminal domain in regulating the properties o...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Chillemi, G., Kehrloesser, S., Bernassola, F., Desideri, A., Dötsch, V., Levine, A. J., Melino, G. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Order Matters: The Order of Somatic Mutations Influences Cancer Evolution
Cancers evolve as a consequence of multiple somatic lesions, with competition between subclones and sequential subclonal evolution. Some driver mutations arise either early or late in the evolution of different individual tumors, suggesting that the final malignant properties of a subclone reflect the sum of mutations acquired rather than the order in which they arose. However, very little is known about the cellular consequences of altering the order in which mutations are acquired. Recent studies of human myeloproliferative neoplasms show that the order in which individual mutations are acquired has a dramatic impact on ...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Kent, D. G., Green, A. R. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Coevolution of Leukemia and Host Immune Cells in Chronic Lymphocytic Leukemia
Cumulative studies on the dissection of changes in driver genetic lesions in cancer across the course of the disease have provided powerful insights into the adaptive mechanisms of tumors in response to the selective pressures of therapy and environmental changes. In particular, the advent of next-generation-sequencing (NGS)-based technologies and its implementation for the large-scale comprehensive analyses of cancers have greatly advanced our understanding of cancer as a complex dynamic system wherein genetically distinct subclones interact and compete during tumor evolution. Aside from genetic evolution arising from int...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Purroy, N., Wu, C. J. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer
A plethora of mutations in chromatin regulators in diverse human cancers is emerging, attesting to the pivotal role of chromatin dynamics in tumorigenesis. A recurrent theme is inactivation of the chromodomain helicase DNA-binding (CHD) family of proteins—ATP-dependent chromatin remodelers that govern the cellular machinery’s access to DNA, thereby controlling fundamental processes, including transcription, proliferation, and DNA damage repair. This review highlights what is currently known about how genetic and epigenetic perturbation of CHD proteins and the pathways that they regulate set the stage for cancer...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Mills, A. A. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Inherited TP53 Mutations and the Li-Fraumeni Syndrome
Li–Fraumeni syndrome (LFS) is a complex hereditary cancer predisposition disorder associated with early-onset cancers in diverse tissues of origin. Germline TP53 mutations are identified in 75% of patients with classic LFS. The lifetime likelihood of a TP53 mutation carrier developing cancer approaches 75% in males and almost 100% in females. Several genetic modifiers have been implicated to account for the phenotypic variability within and across LFS families; however, efforts to develop predictive algorithms of age of onset and type of cancers in individual patients have not yet found clinical use. Although it is n...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Guha, T., Malkin, D. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria Modeling in the Era of Eradication
Mathematical models provide the essential basis of rational research and development strategies in malaria, informing the choice of which technologies to target, which deployment strategies to consider, and which populations to focus on. The Internet and remote sensing technologies also enable assembly of ever more relevant field data. Together with supercomputing technology, this has made available timely descriptions of the geography of malaria transmission and disease across the world and made it possible for policy and planning to be informed by detailed simulations of the potential impact of intervention programs. The...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Smith, T. A., Chitnis, N., Penny, M., Tanner, M. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Developing Therapeutics for PrP Prion Diseases
The prototypical PrP prion diseases are invariably fatal, and the search for agents to treat them spans more than 30 years, with limited success. However, in the last few years, the application of high-throughput screening, medicinal chemistry, and pharmacokinetic optimization has led to important advances. The PrP prion inoculation paradigm provides a robust assay for testing therapeutic efficacy, and a dozen compounds have been reported that lead to meaningful extension in survival of prion-infected mice. Here, we review the history and recent progress in the field, focusing on studies validated in animal models. Based o...
Source: Cold Spring Harbor perspectives in medicine - April 3, 2017 Category: Research Authors: Giles, K., Olson, S. H., Prusiner, S. B. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] The Cellular Origin and Evolution of Breast Cancer
In this review, we will discuss how the cell of origin may modulate breast cancer intratumoral heterogeneity (ITH) as well as the role of ITH in the evolution of cancer. The clonal evolution and the cancer stem cell (CSC) models, as well as a model that integrates clonal evolution with a CSC hierarchy, have all been proposed to explain the development of ITH. The extent of ITH correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. A unique subtype of breast cancer, the claudin-low subtype that is highly resistant to chemotherapy and most closely resembles mammary epithelial stem ...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Zhang, M., Lee, A. V., Rosen, J. M. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability
Genetic or genomic mutation is a major cause of intellectual disability (ID). However, despite the generally anticipated strong genotype/phenotype correlation for ID, there are huge obstacles to gene identification, except perhaps where very distinct syndromic features are observed, because of the high degree of genetic heterogeneity and wide variability of phenotype for different mutations or even with the same mutation within a single gene. A recent review estimates in excess of 2500 genes for ID. Fortunately for researchers and diagnosticians alike, the recent advent of massively parallel sequencing technologies, or nex...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Harripaul, R., Noor, A., Ayub, M., Vincent, J. B. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] ATRX and DAXX: Mechanisms and Mutations
Recent genome sequencing efforts in a variety of cancers have revealed mutations and/or structural alterations in ATRX and DAXX, which together encode a complex that deposits histone variant H3.3 into repetitive heterochromatin. These regions include retrotransposons, pericentric heterochromatin, and telomeres, the latter of which show deregulation in ATRX/DAXX-mutant tumors. Interestingly, ATRX and DAXX mutations are often found in pediatric tumors, suggesting a particular developmental context in which these mutations drive disease. Here we review the functions of ATRX and DAXX in chromatin regulation as well as their po...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Dyer, M. A., Qadeer, Z. A., Valle-Garcia, D., Bernstein, E. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Exploitation of EP300 and CREBBP Lysine Acetyltransferases by Cancer
p300 and CREB-binding protein (CBP), two homologous lysine acetyltransferases in metazoans, have a myriad of cellular functions. They exert their influence mainly through their roles as transcriptional regulators but also via nontranscriptional effects inside and outside of the nucleus on processes such as DNA replication and metabolism. The versatility of p300/CBP as molecular tools has led to their exploitation by viral oncogenes for cellular transformation and by cancer cells to achieve and maintain an oncogenic phenotype. How cancer cells use p300/CBP in their favor varies depending on the cellular context and is evide...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Attar, N., Kurdistani, S. K. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Exploiting the p53 Pathway for Therapy
The excitement around the entry into the clinic of the first generation of p53-specific drugs has become muted as the hoped-for dramatic clinical responses have not yet been seen. However, these pioneer molecules have become exceptionally powerful tools in the analysis of the p53 pathway and, as a result, a whole spectrum of new interventions are being explored. These include entirely novel and innovative approaches to drug discovery, such as the use of exon-skipping antisense oligonucleotides and T-cell-receptor-based molecules. The extraordinary resources available to the p53 community in terms of reagents, models, and c...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Cheok, C. F., Lane, D. P. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is an aggressive neoplasm of B- or T-lymphoid progenitors and is the commonest childhood tumor. ALL comprises multiple subtypes characterized by distinct genetic alterations, with stereotyped patterns of aneuploidy present in many cases. Although alterations of TP53 are common in many tumors, they are infrequent in ALL, with the exception of two ALL subtypes associated with poor outcome: relapsed disease and ALL with hypodiploidy. TP53 alterations are present in almost all cases of ALL with low hypodiploidy and are associated with alterations of the lymphoid transcription factor IKZF2 and...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Comeaux, E. Q., Mullighan, C. G. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Biology of Malaria Transmission
Understanding transmission biology at an individual level is a key component of intervention strategies that target the spread of malaria parasites from human to mosquito. Gametocytes are specialized sexual stages of the malaria parasite life cycle developed during evolution to achieve crucial steps in transmission. As sexual differentiation and transmission are tightly linked, a deeper understanding of molecular and cellular events defining this relationship is essential to combat malaria. Recent advances in the field are gradually revealing mechanisms underlying sexual commitment, gametocyte sequestration, and dynamics o...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Meibalan, E., Marti, M. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Insights from Therapeutic Studies for PrP Prion Disease
Although an effective therapy for prion disease has not yet been established, many advances have been made toward understanding its pathogenesis, which has facilitated research into therapeutics for the disease. Several compounds, including flupirtine, quinacrine, pentosan polysulfate, and doxycycline, have recently been used on a trial basis for patients with prion disease. Concomitantly, several lead antiprion compounds, including compound B (compB), IND series, and anle138b, have been discovered. However, clinical trials are still far from yielding significantly beneficial results, and the findings of lead compound stud...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2017 Category: Research Authors: Teruya, K., Doh-ura, K. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] DNMT3A in Leukemia
DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) pati...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Brunetti, L., Gundry, M. C., Goodell, M. A. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Natural Selection in Cancer Biology: From Molecular Snowflakes to Trait Hallmarks
Evolution by natural selection is the conceptual foundation for nearly every branch of biology and increasingly also for biomedicine and medical research. In cancer biology, evolution explains how populations of cells in tumors change over time. It is a fundamental question whether this evolutionary process is driven primarily by natural selection and adaptation or by other evolutionary processes such as founder effects and drift. In cancer biology, as in organismal evolutionary biology, there is controversy about this question and also about the use of adaptation through natural selection as a guiding framework for resear...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Fortunato, A., Boddy, A., Mallo, D., Aktipis, A., Maley, C. C., Pepper, J. W. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[TECHNIQUES] Lesion-Directed Therapies and Monitoring Tumor Evolution Using Liquid Biopsies
Precision oncology relies on targeted drugs, such as kinase inhibitors, that are presently administered based on molecular profiles obtained from surgical or bioptic tissue samples. The inherent ability of human tumors to molecularly evolve in response to drug pressures represents a daunting diagnostic challenge. Circulating free DNA (cfDNA) released from primary and metastatic lesions can be used to draw molecular maps that can be continuously updated to match each tumor’s evolution. We will present evidence that liquid biopsies can effectively interrogate how targeted therapies drive lesion-specific drug-resistance...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Russo, M., Bardelli, A. Tags: Cancer Evolution TECHNIQUES Source Type: research

[PERSPECTIVES] The Regulation of Cellular Functions by the p53 Protein: Cellular Senescence
Transformed cells have properties that allow them to survive and proliferate inappropriately. These characteristics often arise as a result of mutations caused by DNA damage. p53 suppresses transformation by removing the proliferative or survival capacity of cells with DNA damage or inappropriate cell-cycle progression. Cellular senescence, marked by morphological and gene expression changes, is a critical component of p53-mediated tumor suppression. In response to stress, p53 can facilitate an arrest and senescence program in cells exposed to stresses such as DNA damage and oncogene activation, preventing transformation. ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Tonnessen-Murray, C. A., Lozano, G., Jackson, J. G. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53
TP53 missense mutations produce a mutant p53 protein that cannot activate the p53 tumor suppressive transcriptional response, which is the primary selective pressure for TP53 mutation. Specific codons of TP53, termed hotspot mutants, are mutated at elevated frequency. Hotspot forms of mutant p53 possess oncogenic properties in addition to being deficient in tumor suppression. Such p53 mutants accumulate to high levels in the cells they inhabit, causing transcriptional alterations that produce pro-oncogenic activities, such as increased pro-growth signaling, invasiveness, and metastases. These forms of mutant p53 very likel...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Pfister, N. T., Prives, C. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Fosfomycin: Mechanism and Resistance
Fosfomycin, a natural product antibiotic, has been in use for>20 years in Spain, Germany, France, Japan, Brazil, and South Africa for urinary tract infections (UTIs) and other indications and was registered in the United States for the oral treatment of uncomplicated UTIs because of Enterococcus faecalis and Escherichia coli in 1996. It has a broad spectrum, is bactericidal, has very low toxicity, and acts as a time-dependent inhibitor of the MurA enzyme, which catalyzes the first committed step of peptidoglycan synthesis. Whereas resistance to fosfomycin arises rapidly in vitro through loss of active transport mechanis...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Silver, L. L. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] The Whys and Wherefores of Antibiotic Resistance
The development and rapid dissemination of antibiotic-resistant bacterial pathogens has tarnished the dream of a world without infectious diseases. However, our understanding of these processes, paired with sequence information from terrestrial bacterial populations, indicates that there is no shortage of novel natural products that could be developed into new medicines. Regardless, their therapeutic success in the clinic will depend on the introduction of mandatory controls and use restrictions. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Strachan, C. R., Davies, J. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[TECHNIQUES] Cellular Models for the Study of Prions
It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of prions, including the ability to create transmissible cellular pathology in vivo. We have developed cellular bioassays that report on the various features of prion activity using genetic engineering and quantitative fluorescence-based detection systems. We have exploited these biosensors to measure the binding and uptake of tau seeds into cells in culture and to quantify seeding activity in brain samples. These cell models have also been used to propagate ta...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2017 Category: Research Authors: Holmes, B. B., Diamond, M. I. Tags: Prion Diseases TECHNIQUES Source Type: research

[PERSPECTIVES] The Role of Aneuploidy in Cancer Evolution
Chromosomal aberrations during cell division represent one of the first recognized features of human cancer cells, and modern detection methods have revealed the pervasiveness of aneuploidy in cancer. The ongoing karyotypic changes brought about by chromosomal instability (CIN) contribute to tumor heterogeneity, drug resistance, and treatment failure. Whole-chromosome and segmental aneuploidies resulting from CIN have been proposed to allow "macroevolutionary" leaps that may contribute to profound phenotypic change. In this review, we will outline evidence indicating that aneuploidy and CIN contribute to cancer e...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Sansregret, L., Swanton, C. Tags: PERSPECTIVES Source Type: research

[PERSPECTIVES] Pleuromutilins: Potent Drugs for Resistant Bugs--Mode of Action and Resistance
Pleuromutilins are antibiotics that selectively inhibit bacterial translation and are semisynthetic derivatives of the naturally occurring tricyclic diterpenoid pleuromutilin, which received its name from the pleuromutilin-producing fungus Pleurotus mutilus. Tiamulin and valnemulin are two established derivatives in veterinary medicine for oral and intramuscular administration. As these early pleuromutilin drugs were developed at a time when companies focused on major antibacterial classes, such as the β-lactams, and resistance was not regarded as an issue, interest in antibiotic research including pleuromutilins was ...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Paukner, S., Riedl, R. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Histone Lysine Demethylase Inhibitors
The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure–activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors. This review will briefly outline the connection between demethylases and...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Jambhekar, A., Anastas, J. N., Shi, Y. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Oncogenic Mechanisms of Histone H3 Mutations
Recurrent missense mutations in histone H3 were recently reported in pediatric gliomas and soft tissue tumors. Strikingly, these mutations only affected a minority of the total cellular H3 proteins and occurred at or near lysine residues at positions 27 and 36 on the amino-terminal tail of H3 that are subject to well-characterized posttranslational modifications. Here we review recent progress in elucidating the mechanisms by which these mutations perturb the chromatin landscape in cells through their effects on chromatin-modifying machinery, particularly through inhibition of specific histone lysine methyltransferases. On...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Weinberg, D. N., Allis, C. D., Lu, C. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] TP53 Mutations in Breast and Ovarian Cancer
Breast and ovarian cancers are the second and fifth leading causes of cancer deaths among women. Both breast and ovarian cancers are highly heterogeneous and are presented with diverse morphology, natural history, and response to therapy. In recent years, international efforts have led to extensive molecular characterization of both breast and ovarian tumors and identified biologically and clinically relevant subtypes of the diseases based on these molecular features. The role of TP53 in tumor initiation and progression is context dependent, and abrogation of the TP53 pathway seems to be essential for the development of ba...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Silwal-Pandit, L., Langerod, A., Borresen-Dale, A.-L. Tags: PERSPECTIVES Source Type: research

[PERSPECTIVES] The Transactivation Domains of the p53 Protein
The p53 tumor suppressor is a transcriptional activator, with discrete domains that participate in sequence-specific DNA binding, tetramerization, and transcriptional activation. Mutagenesis and reporter studies have delineated two distinct activation domains (TADs) and specific hydrophobic residues within these TADs that are critical for their function. Knockin mice expressing p53 mutants with alterations in either or both of the two TADs have revealed that TAD1 is critical for responses to acute DNA damage, whereas both TAD1 and TAD2 participate in tumor suppression. Biochemical and structural studies have identified fac...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Raj, N., Attardi, L. D. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] {beta}-Lactamases: A Focus on Current Challenges
β-Lactamases, the enzymes that hydrolyze β-lactam antibiotics, remain the greatest threat to the usage of these agents. In this review, the mechanism of hydrolysis is discussed for both those enzymes that use serine at the active site and those that require divalent zinc ions for hydrolysis. The β-lactamases now include>2000 unique, naturally occurring amino acid sequences. Some of the clinically most important of these are the class A penicillinases, the extended-spectrum β-lactamases (ESBLs), the AmpC cephalosporinases, and the carbapenem-hydrolyzing enzymes in both the serine and metalloenzyme gro...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Bonomo, R. A. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Sporadic and Infectious Human Prion Diseases
Human prion diseases are rare neurodegenerative diseases that have become the subject of public and scientific interest because of concerns about interspecies transmission and the unusual biological properties of the causal agents: prions. These diseases are unique in that they occur in sporadic, hereditary, and infectious forms that are characterized by an extended incubation period between exposure to infection and the development of clinical illness. Silent infection can be present in peripheral tissues during the incubation period, which poses a challenge to public health, especially because prions are relatively resis...
Source: Cold Spring Harbor perspectives in medicine - January 3, 2017 Category: Research Authors: Will, R. G., Ironside, J. W. Tags: PERSPECTIVES Source Type: research

[CORRIGENDUM] Corrigendum: Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: Martin, J. D., Fukumura, D., Duda, D. G., Boucher, Y., Jain, R. K. Tags: CORRIGENDUM Source Type: research