[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

[PERSPECTIVES] Appropriate Targets for Antibacterial Drugs
Successful small-molecule antibacterial agents must meet a variety of criteria. Foremost is the need for selectivity and safety: It is easy to kill bacteria with chemicals, but difficult to do it without harming the patient. Other requirements are possession of a useful antibacterial spectrum, no cross-resistance with existing therapeutics, low propensity for rapid resistance selection, and pharmacological properties that allow effective systemic dosing. Choosing molecular targets for new antibiotics does seem a good basis for achieving these criteria, but this could be misleading. Although the presence of the target is ne...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: Silver, L. L. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity
Solid tumors consist of cancer cells and stromal cells, including resident and transiting immune cells—all ensconced in an extracellular matrix (ECM)—nourished by blood vessels and drained by lymphatic vessels. The microenvironment constituents are abnormal and heterogeneous in morphology, phenotype, and physiology. Such irregularities include an inefficient tumor vascular network comprised of leaky and compressed vessels, which impair blood flow and oxygen delivery. Low oxygenation in certain tumor regions—or focal hypoxia—is a mediator of cancer progression, metastasis, immunosuppression, and trea...
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: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance
The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide deriv...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: Zeng, D., Debabov, D., Hartsell, T. L., Cano, R. J., Adams, S., Schuyler, J. A., McMillan, R., Pace, J. L. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Cohesin Mutations in Cancer
Cohesin is a large ring-shaped protein complex, conserved from yeast to human, which participates in most DNA transactions that take place in the nucleus. It mediates sister chromatid cohesion, which is essential for chromosome segregation and homologous recombination (HR)-mediated DNA repair. Together with architectural proteins and transcriptional regulators, such as CTCF and Mediator, respectively, it contributes to genome organization at different scales and thereby affects transcription, DNA replication, and locus rearrangement. Although cohesin is essential for cell viability, partial loss of function can affect thes...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: De Koninck, M., Losada, A. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Inherited p53 Mutation in the Brazilian Population
A common criticism of studying rare diseases is the often-limited relevance of the findings to human health. Here, we review ~15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis. We have come to learn that the p.R337H mutation exists at a very high frequency in Southern and Southeastern Brazil, occurring in one of 375 individuals within a total population of ~100 million. Moreover, it has been determined that carriers of this founder mutation display vari...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: Achatz, M. I., Zambetti, G. P. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] The Evolution of the Ribosomal Protein-MDM2-p53 Pathway
The progression of our understanding of ribosomal proteins as static building blocks of the ribosome to highly integrated sensors of p53 surveillance and function has achieved a tremendous rate of growth over the past several decades. As the workhorse of the cell, ribosomes are responsible for translating the genetic code into the functional units that drive cell growth and proliferation. The seminal identification of ribosomal protein binding to MDM2, the negative regulator of p53, has evolved into a paradigm for ribosomal protein–MDM2–p53 signaling that extends into processes as diverse as energy metabolism t...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: Deisenroth, C., Franklin, D. A., Zhang, Y. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Prion Strain Diversity
Prion diseases affect a wide range of mammal species and are caused by a misfolded self-propagating isoform (PrPSc) of the normal prion protein (PrPC). Distinct strains of prions exist and are operationally defined by differences in a heritable phenotype under controlled experimental transmission conditions. Prion strains can differ in incubation period, clinical signs of disease, tissue tropism, and host range. The mechanism by which a protein-only pathogen can encode strain diversity is only beginning to be understood. The prevailing hypothesis is that prion strain diversity is encoded by strain-specific conformations of...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2016 Category: Research Authors: Bartz, J. C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Lincosamides, Streptogramins, Phenicols, and Pleuromutilins: Mode of Action and Mechanisms of Resistance
Lincosamides, streptogramins, phenicols, and pleuromutilins (LSPPs) represent four structurally different classes of antimicrobial agents that inhibit bacterial protein synthesis by binding to particular sites on the 50S ribosomal subunit of the ribosomes. Members of all four classes are used for different purposes in human and veterinary medicine in various countries worldwide. Bacteria have developed ways and means to escape the inhibitory effects of LSPP antimicrobial agents by enzymatic inactivation, active export, or modification of the target sites of the agents. This review provides a comprehensive overview of the m...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Schwarz, S., Shen, J., Kadlec, K., Wang, Y., Brenner Michael, G., Fessler, A. T., Vester, B. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Mechanism of Action and Resistance to Daptomycin in Staphylococcus aureus and Enterococci
Lipopeptides are natural product antibiotics that consist of a peptide core with a lipid tail with a diverse array of target organisms and mechanisms of action. Daptomycin (DAP) is an example of these compounds with specific activity against Gram-positive organisms. DAP has become increasingly important to combat infections caused by Gram-positive bacteria because of the presence of multidrug resistance in these organisms, particularly in methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). However, emergence of resistance to DAP during therapy is a well-described phenomenon that t...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Miller, W. R., Bayer, A. S., Arias, C. A. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Nonhistone Lysine Methylation in the Regulation of Cancer Pathways
Proteins are regulated by an incredible array of posttranslational modifications (PTMs). Methylation of lysine residues on histone proteins is a PTM with well-established roles in regulating chromatin and epigenetic processes. The recent discovery that hundreds and likely thousands of nonhistone proteins are also methylated at lysine has opened a tremendous new area of research. Major cellular pathways involved in cancer, such as growth signaling and the DNA damage response, are regulated by lysine methylation. Although the field has developed quickly in recent years many fundamental questions remain to be addressed. We re...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Carlson, S. M., Gozani, O. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] MLL3/MLL4/COMPASS Family on Epigenetic Regulation of Enhancer Function and Cancer
During development, precise spatiotemporal patterns of gene expression are coordinately controlled by cis-regulatory modules known as enhancers. Their crucial role in development helped spur numerous studies aiming to elucidate the functional properties of enhancers within their physiological and disease contexts. In recent years, the role of enhancer malfunction in tissue-specific tumorigenesis is increasingly investigated. Here, we direct our focus to two primary players in enhancer regulation and their role in cancer pathogenesis: MLL3 and MLL4, members of the COMPASS family of histone H3 lysine 4 (H3K4) methyltransfera...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Sze, C. C., Shilatifard, A. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Somatic TP53 Mutations in the Era of Genome Sequencing
Amid the complexity of genetic alterations in human cancer, TP53 mutation appears as an almost invariant component, representing by far the most frequent genetic alteration overall. Compared with previous targeted sequencing studies, recent integrated genomics studies offer a less biased view of TP53 mutation patterns, revealing that>20% of mutations occur outside the DNA-binding domain. Among the 12 mutations representing each at least 1% of all mutations, five occur at residues directly involved in specific DNA binding, four affect the tertiary fold of the DNA-binding domain, and three are nonsense mutations, two of t...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Hainaut, P., Pfeifer, G. P. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] p53 and the Carcinogenicity of Chronic Inflammation
Chronic inflammation is a major cancer predisposition factor. Constitutive activation of the inflammation-driving NF-B pathway commonly observed in cancer or developed in normal tissues because of persistent infections or endogenous tissue irritating factors, including products of secretion by senescent cells accumulating with age, markedly represses p53 functions. In its turn, p53 acts as a suppressor of inflammation helping to keep it within safe limits. The antagonistic relationship between p53 and NF-B is controlled by multiple mechanisms and reflects cardinal differences in organismal responses to intrinsic and extrin...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Gudkov, A. V., Komarova, E. A. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Clinical Versus Research Sequencing
Historically, sequencing has been the key technology to assess variation in the genetic code, and has been widely accepted in clinical diagnostics of genetic disease. The advent of next-generation sequencing (NGS) methods increased the size of the analyzed target by several orders of magnitude, while at the same time drastically reducing the cost of sequencing. Current research allows sequencing of germline and tumor whole genomes. However, with the arrival of cutting-edge technology to the clinical diagnostic field, strict regulatory oversight is required to use the advances of the latest research when applied to routine ...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2016 Category: Research Authors: Shevchenko, Y., Bale, S. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] HDACs and HDAC Inhibitors in Cancer Development and Therapy
Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Posttranslational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling, and nuclear architecture. Histone acetylation, a well-studied posttranslational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Li, Y., Seto, E. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Next-Generation Sequencing and the Return of Results
The impact of next-generation sequencing (NGS) on the issue of return of results is defying clear policy guidance and creating international confusion. Limiting ourselves to the return of results revealed by NGS (including incidental findings) in adults, children, family members of deceased individuals, and population studies, we describe and contrast emerging policy positions in Europe, Canada, and the United States. Until there are clear, scientific, and professional standards and practical policy, both researchers and clinicians cannot be faulted for being either hesitant or pressured to return NGS results. (Source: Col...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Knoppers, B. M., Nguyen, M. T., Senecal, K., Tasse, A. M., Zawati, M. H. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Additional Sex Combs-Like Proteins in Cancer
Additional sex combs-like (ASXL) proteins are mammalian homologs of Addition of sex combs (Asx), a protein that regulates the balance of trithorax and Polycomb function in Drosophila. All three ASXL family members (ASXL1, ASXL2, and ASXL3) are affected by somatic or de novo germline mutations in cancer or rare developmental syndromes, respectively. Although Asx is characterized as a catalytic partner for the deubiquitinase Calypso (or BAP1), there are domains of ASXL proteins that are distinct from Asx and the roles and redundancies of ASXL members are not yet well understood. Moreover, it is not yet fully clarified if com...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Micol, J.-B., Abdel-Wahab, O. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Paradox of p53: What, How, and Why?
Unlike the rather stereotypic image by which it was portrayed until not too many years ago, p53 is now increasingly emerging as a multifaceted transcription factor that can sometimes exert opposing effects on biological processes. This includes pro-survival activities that seem to contradict p53’s canonical proapoptotic features, as well as opposing effects on cell migration, metabolism, and differentiation. Such antagonistic bifunctionality (balancing both positive and negative signals) bestows p53 with an ideal attribute to govern homeostasis. The molecular mechanisms underpinning the paradoxical activities of p53 ...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Aylon, Y., Oren, M. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation
More than half of human tumors harbor an inactivated p53 tumor-suppressor gene. It is well accepted that mutant p53 shows an oncogenic gain-of-function (GOF) activity that facilitates the transformed phenotype of cancer cells. In addition, a growing body of evidence supports the notion that cancer stem cells comprise a seminal constituent in the initiation and progression of cancer development. Here, we elaborate on the mutant p53 oncogenic GOF leading toward the acquisition of a transformed phenotype, as well as placing mutant p53 as a major component in the establishment of cancer stem cell entity. Therefore, therapy tar...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Shetzer, Y., Molchadsky, A., Rotter, V. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Resistance to Macrolide Antibiotics in Public Health Pathogens
Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome’s interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosph...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Fyfe, C., Grossman, T. H., Kerstein, K., Sutcliffe, J. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Polymyxin: Alternative Mechanisms of Action and Resistance
Antibiotic resistance among pathogenic bacteria is an ever-increasing issue worldwide. Unfortunately, very little has been achieved in the pharmaceutical industry to combat this problem. This has led researchers and the medical field to revisit past drugs that were deemed too toxic for clinical use. In particular, the cyclic cationic peptides polymyxin B and colistin, which are specific for Gram-negative bacteria, have been used as "last resort" antimicrobials. Before the 1980s, these drugs were known for their renal and neural toxicities; however, new clinical practices and possibly improved manufacturing have m...
Source: Cold Spring Harbor perspectives in medicine - October 3, 2016 Category: Research Authors: Trimble, M. J., Mlynarčik, P., Kolař, M., Hancock, R. E. W. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Mechanisms of Nucleosome Dynamics In Vivo
Nucleosomes function to tightly package DNA into chromosomes, but the nucleosomal landscape becomes disrupted during active processes such as replication, transcription, and repair. The realization that many proteins responsible for chromatin regulation are frequently mutated in cancer has drawn attention to chromatin dynamics; however, the basic mechanisms whereby nucleosomes are disrupted and reassembled is incompletely understood. Here, I present an overview of chromatin dynamics as has been elucidated in model organisms, in which our understanding is most advanced. A basic understanding of chromatin dynamics during nor...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Henikoff, S. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Role of the Polycomb Repressive Complex 2 (PRC2) in Transcriptional Regulation and Cancer
The chromatin environment is modulated by a machinery of chromatin modifiers, required for the specification and maintenance of cell fate. Many mutations in the machinery have been linked to the development and progression of cancer. In this review, we give a brief introduction to Polycomb group (PcG) proteins, their assembly into Polycomb repressive complexes (PRCs) and the normal physiological roles of these complexes with a focus on the PRC2. We review the many findings of mutations in the PRC2 coding genes, both loss-of-function and gain-of-function, associated with human cancers and discuss potential molecular mechani...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Laugesen, A., Hojfeldt, J. W., Helin, K. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Clinical Outcomes of TP53 Mutations in Cancers
High-throughput sequencing of cancer genomes is increasingly becoming an essential tool of clinical oncology that facilitates target identification and targeted therapy within the context of precision medicine. The cumulative profiles of somatic mutations in cancer yielded by comprehensive molecular studies also constitute a fingerprint of historical exposures to exogenous and endogenous mutagens, providing insight into cancer evolution and etiology. Mutational signatures that were first established by inspection of the TP53 gene somatic landscape have now been confirmed and expanded by comprehensive sequencing studies. Fu...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Robles, A. I., Jen, J., Harris, C. C. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation
The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viability may require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p5...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Levine, A. J., Puzio-Kuter, A. M., Chan, C. S., Hainaut, P. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Bacterial Protein Synthesis as a Target for Antibiotic Inhibition
Protein synthesis occurs on macromolecular machines, called ribosomes. Bacterial ribosomes and the translational machinery represent one of the major targets for antibiotics in the cell. Therefore, structural and biochemical investigations into ribosome-targeting antibiotics provide not only insight into the mechanism of action and resistance of antibiotics, but also insight into the fundamental process of protein synthesis. This review summarizes the recent advances in our understanding of protein synthesis, particularly with respect to X-ray and cryoelectron microscopy (cryo-EM) structures of ribosome complexes, and high...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Arenz, S., Wilson, D. N. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance
Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis. Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA–enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity. Resistance has emerged with clinical use of these agents and is common in some bacterial pathogens. Mechanisms of resistance include mutational alterations in drug target aff...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Hooper, D. C., Jacoby, G. A. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] {alpha}-Synuclein: Experimental Pathology
α-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified α-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic α-synuclein fibrils and pathological α-synuclein from diseased brains can act as triggers to convert normal α-synuclein to an abnormal form via prion-like m...
Source: Cold Spring Harbor perspectives in medicine - September 1, 2016 Category: Research Authors: Hasegawa, M., Nonaka, T., Masuda-Suzukake, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Antibacterial Antifolates: From Development through Resistance to the Next Generation
The folate cycle is one of the key metabolic pathways used by bacteria to synthesize vital building blocks required for proliferation. Therapeutic agents targeting enzymes in this cycle, such as trimethoprim and sulfamethoxazole, are among some of the most important and continually used antibacterials to treat both Gram-positive and Gram-negative pathogens. As with all antibacterial agents, the emergence of resistance threatens the continued clinical use of these life-saving drugs. In this article, we describe and analyze resistance mechanisms that have been clinically observed and review newer generations of preclinical c...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Estrada, A., Wright, D. L., Anderson, A. C. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer
During the last decade, a host of epigenetic mechanisms were found to contribute to cancer and other human diseases. Several genomic studies have revealed that ~20% of malignancies have alterations of the subunits of polymorphic BRG-/BRM-associated factor (BAF) and Polybromo-associated BAF (PBAF) complexes, making them among the most frequently mutated complexes in cancer. Recurrent mutations arise in genes encoding several BAF/PBAF subunits, including ARID1A, ARID2, PBRM1, SMARCA4, and SMARCB1. These subunits share some degree of conservation with subunits from related adenosine triphosphate (ATP)-dependent chromatin remo...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Hodges, C., Kirkland, J. G., Crabtree, G. R. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Spatial Heterogeneity in the Tumor Microenvironment
Recent developments in studies of tumor heterogeneity have provoked new thoughts on cancer management. There is a desperate need to understand influence of the tumor microenvironment on cancer development and evolution. Applying principles and quantitative methods from ecology can suggest novel solutions to fulfil this need. We discuss spatial heterogeneity as a fundamental biological feature of the microenvironment, which has been largely ignored. Histological samples can provide spatial context of diverse cell types coexisting within the microenvironment. Advanced computer-vision techniques have been developed for spatia...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Yuan, Y. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End
The p53 pathway is perturbed in the majority of human cancers. Although this most frequently occurs through the direct mutation or deletion of p53 itself, there are a number of other alterations that can attenuate the pathway and contribute to tumorigenesis. For example, amplification of important negative regulators, MDM2 and MDM4, occurs in a number of cancers. In this work, we will review both the normal regulation of the p53 pathway and the different mechanisms of pathway inhibition in cancer, discuss these alterations in the context of the global genomic analyses that have been conducted across tumor types, and highli...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Wasylishen, A. R., Lozano, G. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] p53 Isoforms: Key Regulators of the Cell Fate Decision
It is poorly understood how a single protein, p53, can be responsive to so many stress signals and orchestrates very diverse cell responses to maintain/restore cell/tissue functions. The uncovering that TP53 gene physiologically expresses, in a tissue-dependent manner, several p53 splice variants (isoforms) provides an explanation to its pleiotropic biological activities. Here, we summarize a decade of research on p53 isoforms. The clinical studies and the diverse cellular and animal models of p53 isoforms (zebrafish, Drosophila, and mouse) lead us to realize that a p53-mediated cell response is, in fact, the sum of the in...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Joruiz, S. M., Bourdon, J.-C. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] {beta}-Lactams and {beta}-Lactamase Inhibitors: An Overview
β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the &bet...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Bush, K., Bradford, P. A. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Structure of Aggregated Amyloid-{beta}: Insights from Solid-State Nuclear Magnetic Resonance
Amyloid-β (Aβ) peptides aggregate to form polymorphic amyloid fibrils and a variety of intermediate assemblies, including oligomers and protofibrils, both in vitro and in human brain tissue. Since the beginning of the 21st century, considerable progress has been made to characterize the molecular structures of Aβ aggregates. Full molecular structural models based primarily on data from measurements using solid-state nuclear magnetic resonance (ssNMR) have been developed for several in vitro Aβ fibrils and one metastable protofibril. Partial structural characterization of other aggregation intermediates ...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2016 Category: Research Authors: Tycko, R. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PROSPECTIVE] The Epilepsy Spectrum: Targeting Future Research Challenges
There have been tremendous recent advances in our understanding of the biological underpinnings of epilepsy and associated comorbidities that justify its representation as a spectrum disorder. Advances in genetics, electrophysiology, and neuroimaging have greatly improved our ability to differentiate, diagnose, and treat individuals with epilepsy. However, we have made little overall progress in preventing epilepsy, and the number of patients who are cured remains small. Likewise, the comorbidities of epilepsy are often underdiagnosed or not adequately treated. In this article, we suggest a few areas in which additional re...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Holmes, G. L., Noebels, J. L. Tags: Epilepsy: The Biology of a Spectrum Disorder PROSPECTIVE Source Type: research

[PERSPECTIVES] Rifamycins, Alone and in Combination
Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive prosthetic joint and valve infections, in which biofilms are prominent. Rifabutin has use for AIDS patients in treating mycobacterial infections TB and Mycobacterium avium complex (MAC), having fewer drug–drug interactions that interfere with AIDS medications. Rifabutin is occasionally used in combination to eradicate Helicobacter pylori (peptic ulcer disease). Rifapentine has yet to fulfill its potential in reducing time of treatment for TB. Rifaxim...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Rothstein, D. M. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and Beyond
The MDMX protein was identified as a p53-interacting protein with a strong similarity to MDM2. Like Mdm2, Mdmx expression is essential for curbing p53 activity during embryonic development, indicating nonredundant functions of Mdmx and Mdm2. There is now a large body of evidence indicating that cancers frequently up-regulate MDMX expression as a means to dampen p53 tumor-suppressor function. Importantly, MDMX also shows p53-independent oncogenic functions. These data make MDMX an attractive therapeutic target for cancer therapy. Here, we summarize the mechanisms used by cancer cells to increase MDMX expression and promisin...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Marine, J.-C., Jochemsen, A. G. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Regulation of Cellular Metabolism and Hypoxia by p53
The p53 protein is essential for the implementation of the cellular response to challenging environmental conditions. Reacting to stochastic nutrient stress, p53 integrates the activity of key metabolite-sensing pathways to coordinate an appropriate cell response. During starvation, p53 activity augments cell survival pathways, inhibits unnecessary growth, and promotes efficient nutrient generation, utilization, and conservation. Similarly, during oxygen stress, p53 facilitates redirection of cellular metabolism toward energy generation through nonoxidative means, the suppression of reactive oxygen species (ROS) generation...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Humpton, T. J., Vousden, K. H. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC
This article will summarize the history of LpxC as a drug target and the parallel history of research on LpxC biology. Both academic and industrial researchers have used LpxC inhibitors as tool compounds, leading to increased understanding of the differing mechanisms for regulation of LPS synthesis in Escherichia coli and Pseudomonas aeruginosa. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Erwin, A. L. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] The Prion-Like Properties of Amyloid-{beta} Assemblies: Implications for Alzheimer's Disease
Since the discovery that prion diseases can be transmitted to experimental animals by inoculation with afflicted brain matter, researchers have speculated that the brains of patients suffering from other neurodegenerative diseases might also harbor causative agents with transmissible properties. Foremost among these disorders is Alzheimer’s disease (AD), the most common cause of dementia in the elderly. A growing body of research supports the concept that the pathogenesis of AD is initiated and sustained by the endogenous, seeded misfolding and aggregation of the protein fragment amyloid-β (Aβ). At the mole...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Walker, L. C., Schelle, J., Jucker, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Common Mechanisms Underlying Epileptogenesis and the Comorbidities of Epilepsy
The importance of comorbidities in determining the quality of life of individuals with epilepsy and their families has received increasing attention in the past decade. Along with it has come a recognition that in some individuals, certain comorbidities may have preexisted, and may have contributed to their developing epilepsy. Many mechanisms are capable of interconnecting different dysfunctions that manifest as distinct disorders, often diagnosed and managed by different specialists. We review the human data from the perspective of epidemiology as well as insights gathered from neurodiagnostic and endocrine studies. Anim...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2016 Category: Research Authors: Mazarati, A., Sankar, R. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research