Histone Modifications and Cancer Audia, James E; Campbell, Robert M
Cold Spring Harbor perspectives in biology,
2016-Apr-01, 2016-04-00, 20160401, Letnik:
8, Številka:
4
Journal Article
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Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable ...maintenance of repressive chromatin. In this article, we review many of the key and newly identified histone modifications known to be deregulated in cancer and how this impacts function. The latter part of the article addresses the challenges and current status of the epigenetic drug development process as it applies to cancer therapeutics.
Transmission electron microscopy (TEM) of rapidly frozen biological specimens, or cryo-EM, would benefit from the development of a phase plate for in-focus phase contrast imaging. Several types of ...phase plates have been investigated, but rapid electrostatic charging of all such devices has hindered these efforts. Here, we demonstrate electron phase manipulation with a high-intensity continuous-wave laser beam, and use it as a phase plate for TEM. We demonstrate the laser phase plate by imaging an amorphous carbon film. The laser phase plate provides a stable and tunable phase shift without electrostatic charging or unwanted electron scattering. These results suggest the possibility for dose-efficient imaging of unstained biological macromolecules and cells.
•Uncertainty in market prices drives financial outcomes.•Monte Carlo simulation allows uncertainty to be quantified.•Biochar-only production offers a potentially profitable venture.•Biofuel-biochar ...coproduction requires RINs to achieve financial success.
A comparative techno-economic analysis of two different thermochemical biomass conversion pathways was conducted to examine the effects of fuel price and other variables on project financial performance. Monte Carlo simulation was used to quantify the effects of uncertainty and volatility of ten critical variables: biofuel, biochar and feedstock prices, discount rate, capital investment, labor cost, loan terms, feedstock drying, and biofuel and biochar conversion rates. Market prices for biofuel and biochar have the largest impact on net present value (NPV) of any variable considered, due in part to the high levels of uncertainty associated with future prices of both. Across the ranges of input values for these variables in simulation analysis, hearth-based pyrolysis biochar production had the highest likelihood of profitability with a mean NPV of $41.5 million and only 20% of outcomes resulting in a net loss, while 68% of outcomes for auger-based biochar-biofuel coproduction represented a financial loss, including a mean NPV of -$24.2 million. However, when additional revenue from Renewable Identification Numbers (RINs) credits generated by biofuel production is considered, financial outcomes of biochar-biofuel coproduction improve to 50% likelihood of experiencing a net loss. Findings of the very strong impact of market prices on financial outcomes, relative to other important technical and economic variables, can inform effective targeting of future renewable energy policy, as well as the design of future techno-economic analyses, which do not currently focus on the effect of market prices on profitability.
Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. ...These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved "first generation" of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area.
Global biomass burning generates 40 million to 250 million tons of charcoal every year, part of which is preserved for millennia in soils and sediments. We have quantified dissolution products of ...charcoal in a wide range of rivers worldwide and show that globally, a major portion of the annual charcoal production is lost from soils via dissolution and subsequent transport to the ocean. The global flux of soluble charcoal accounts to 26.5 ± 1.8 million tons per year, which is ~10% of the global riverine flux of dissolved organic carbon (DOC). We suggest that the mobilization of charcoal and DOC out of soils is mechanistically coupled. This study closes a major gap in the global charcoal budget and provides critical information in the context of geoengineering.
Abstract
Aims
To determine whether changing patterns of anticoagulant use in atrial fibrillation (AF) have impacted on stroke rates in England.
Methods and results
English national databases, ...2006–2016, were interrogated to assess stroke admissions and oral anticoagulant use. The number of patients with known AF increased linearly from 692 054 to 983 254 (prevalence 1.29% vs. 1.71%). Hospital episodes of AF-related stroke/100 000 AF patients increased from 80/week in 2006 to 98/week in 2011 and declined to 86/week in 2016 (2006–2011 difference 18.0, 95% confidence interval (CI) 17.9–18.1, 2011–2016 difference −12.0, 95% CI −12.1 to −11.9). Anticoagulant use amongst patients with CHA2DS2-VASc ≥2 increased from 48.0% to 78.6% and anti-platelet use declined from 42.9% to 16.1%; the greatest rate of change occurred in the second 5 year period (for anticoagulants 2006–2011 difference 4.8%, 95% CI 4.5–5.1%, 2011–2016 difference 25.8%, 95% CI 25.5–26.1%). After adjustment for AF prevalence, a 1% increase in anticoagulant use was associated with a 0.8% decrease in the weekly rate of AF-related stroke (incidence rate ratio 0.992, 95% CI 0.989–0.994). Had the use of anticoagulants remained at 2009 levels, 4068 (95% CI 4046–4089) more strokes would have been predicted in 2015/2016.
Conclusion
Between 2006 and 2016, AF prevalence and anticoagulant use in England increased. From 2011, hospitalized AF-related stroke rates declined and were significantly associated with increased anticoagulant uptake.
A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Academy of Pediatrics, American Heart Association, American Society of Echocardiography, Heart Rhythm ...Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography Rating Panel Robert M. Campbell, MD, FACC, FAHA, FAAP, FHRS, Chairlow * Pamela S. Douglas, MD, MACC, FAHA, FASE, Moderatorlow * Louis I. Bezold, MD, FACC, FAAP, FASEdagger William B. Blanchard, MD, FACC, FAHA, FAAPlow * Jeffrey R. Boris, MD, FACClow * Bryan Cannon, MDdouble dagger Gregory J. Ensing, MD, FACC, FASE§ Craig E. Fleishman, MD, FACC, FASE|| Mark A. Fogel, MD, FACC, FAHA, FAAP¶ B. Kelly Han, MD, FACC# Shabnam Jain, MD, MPH, FAAPlow * Mark B. Lewin, MD|| Richard Lockwood, MDlow *low * G. Paul Matherne, MD, MBA, FACC, FAHAdaggerdagger David Nykanen, MD, FACCdouble daggerdouble dagger Catherine L. Webb, MD, FACC, FAHA, FASEdaggerdagger Robert Wiskind, MD, FAAPlow *American College of Cardiology representative.American Academy of Pediatrics representative.Heart Rhythm Society representative.American Society of Echocardiography representative.Society of Pediatric Echocardiography representative.Society for Cardiovascular Magnetic Resonance representative.Society of Cardiovascular Computed Tomography representative.Health Plan representative.American Heart Association representative.Society for Cardiovascular Angiography and Interventions representative.
Purpose
This review summarizes the experience with the vertical expandable prosthetic titanium rib (VEPTR) device, which enables five new procedures to treat complex spine and chest wall ...abnormalities in pediatric patients, which cause thoracic insufficiency syndrome, the inability of the thorax to support normal respiration or lung growth.
Methods
The literature on VEPTR was reviewed and discussed by the author, the inventor of the VEPTR.
Results
The central VEPTR treatment principle is to correct volume depletion deformity of the thorax, and maintain the correction until skeletal maturity, at which time procedures such as spinal fusion can be considered. For individual cases of complex deformity, VEPTR strategies can differ remarkably. The goal of VEPTR surgery is to pursue the surgical strategy that provides the largest, most symmetrical, most functional thorax that can grow as normally as possible. Assessment of these results is difficult, since natural history of VEPTR-treated diseases are not clearly known and no current imaging test can measure thoracic insufficiency syndrome, but dynamic lung MRI have promise for the future in better defining this potentially lethal condition.
Conclusion
VEPTR and its principles of use have become an important first step toward improving the quality of life and longevity of children with thoracic insufficiency syndrome, but much work remains to advance both its design and its use.
Abstract
The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics ...Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.
The secular dynamics of a nonrelativistic charged particle in an electromagnetic wave can be described by the ponderomotive potential. Although ponderomotive electron-laser interactions at ...relativistic velocities are important for emerging technologies from laser-based particle accelerators to laser-enhanced electron microscopy, the effects of special relativity on the interaction have only been studied theoretically. Here, we use a transmission electron microscope to measure the position-dependent phase shift imparted to a relativistic electron wave function when it traverses a standing laser wave. The kinetic energy of the electrons is varied between 80 and 300 keV, and the laser standing wave has a continuous-wave intensity of 175 GW/cm^{2}. In contrast to the nonrelativistic case, we demonstrate that the phase shift depends on both the electron velocity and the wave polarization, confirming the predictions of a quasiclassical theory of the interaction. Remarkably, if the electron's speed is greater than 1/sqrt2 of the speed of light, the phase shift at the electric field nodes of the wave can exceed that at the antinodes. In this case there exists a polarization such that the phase shifts at the nodes and antinodes are equal, and the electron does not experience Kapitza-Dirac diffraction. Our results thus provide new capabilities for coherent electron beam manipulation.
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