The endoplasmic reticulum (ER) has recently emerged as a promising target for anticancer agents. Cytotoxic compounds that target the ER often exhibit selectivity for cancer cells over non-cancer ...cells. Furthermore, the induction of ER stress often leads to immunogenic cell death, providing another factor that contributes to the clinical efficacy of drugs that target this organelle. Among potential ER stress-inducing agents, metal complexes, which possess redox activity and modular structures, have arisen as promising candidates. In the last two decades, dozens of metal complexes have been reported that kill cancer cells via ER stress induction, and many of these complexes exhibit nanomolar activity in vitro as well as powerful tumor inhibition in vivo. In this review, we summarize the current state of investigations on the ER stress-inducing properties of metal complexes. This review starts with a description of the ER, its function, and its role in cancer progression and treatment. Following this discussion, a guide to experimental methods that can be used by researchers to detect ER stress is provided. The majority of this review summarizes previous studies on metal-based anticancer agents that cause ER stress. Finally, a discussion on the perspectives and significance of using metal complexes as ER stress-inducing agents for the treatment of cancer is provided, along with a summary of structural trends that contribute to this type of biological activity.
New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase–signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many ...different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.
Black hole outflows King, A. R
Monthly notices of the Royal Astronomical Society,
March 2010, Letnik:
402, Številka:
3
Journal Article
Recenzirano
Odprti dostop
I show that Eddington accretion episodes in active galactic nuclei (AGN) are likely to produce winds with velocities v∼ 0.1c and ionization parameters up to ξ∼ 104 (cgs), implying the presence of ...resonance lines of helium- and hydrogen-like iron. These properties are direct consequences of momentum and mass conservation, respectively, and agree with recent X-ray observations of fast outflows from AGN. Because the wind is significantly subluminal, it can persist long after the AGN is observed to have become sub-Eddington. The wind creates a strong cooling shock as it interacts with the interstellar medium of the host galaxy, and this cooling region may be observable in an inverse Compton continuum and lower excitation emission lines associated with lower velocities. The shell of matter swept up by the (‘momentum-driven’) shocked wind must propagate beyond the black hole's sphere of influence on a time-scale of ≲3 × 105 yr. Outside this radius, the shell stalls unless the black hole mass has reached the value Mσ implied by the M–σ relation. If the wind shock did not cool, as suggested here, the resulting (‘energy-driven’) outflow would imply a far smaller supermassive black hole mass than actually observed. In galaxies with large bulges the black hole may grow somewhat beyond this value, suggesting that the observed M–σ relation may curve upwards at large M. Minor accretion events with small gas fractions can produce galaxy-wide outflows with velocities significantly exceeding σ, including fossil outflows in galaxies where there is little current AGN activity. Some rare cases may reveal the energy-driven outflows which sweep gas out of the galaxy and establish the black hole–bulge mass relation. However, these require the quasar to be at the Eddington luminosity.
Experiments were conducted to enable the simultaneous measurement of electrochemical impedance and collection of hydrogen gas during the corrosion of pure magnesium in NaCl solutions. These results ...were then assessed along with the attendant specimen mass loss, providing three unique measures of magnesium corrosion for the same specimen. It was determined that analysis of impedance data, while accounting for a physically justified inductive response at low frequencies, enabled the determination of the polarization resistance, RP at the zero frequency limit. The determination of RP, as evaluated herein from electrochemical testing, provided excellent correlation to the mass loss and volume of hydrogen collected. This finding is elaborated in a broader discussion that critically addresses previous studies which have utilized the impedance behavior of magnesium and which claim electrochemical tests may underestimate Mg corrosion when attempting to use a charge transfer resistance at intermediate frequencies.
I suggest that the beaming factor in bright ultraluminous X-ray sources (ULXs) varies as , where is the Eddington ratio for accretion. This is required by the observed universal Lsoft∝T−4 relation ...between soft-excess luminosity and temperature, and is reasonable on general physical grounds. The beam scaling means that all observable properties of bright ULXs depend essentially only on the Eddington ratio , and that these systems vary mainly because the beaming is sensitive to the Eddington ratio. This suggests that bright ULXs are stellar-mass systems accreting at Eddington ratios of the order of 10–30, with beaming factors b≳ 0.1. Lower luminosity ULXs follow bolometric (not soft-excess) L∼T4 correlations and probably represent sub-Eddington accretion on to black holes with masses ∼10M⊙. High-mass X-ray binaries containing black holes or neutron stars and undergoing rapid thermal- or nuclear-time-scale mass transfer are excellent candidates for explaining both types. If the scaling for bright ULXs can be extrapolated to the Eddington ratios found in SS433, some objects currently identified as active galactic nuclei at modest redshifts might actually be ULXs (‘pseudo-blazars’). This may explain cases where the active source does not coincide with the centre of the host galaxy.
Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. ...2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.
Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new ...pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP)--in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics). Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools.
Biologists employ phylogenetic comparative methods to study adaptive evolution. However, none of the popular methods model selection directly. We explain and develop a method based on the ...Ornstein‐Uhlenbeck (OU) process, first proposed by Hansen. Ornstein‐Uhlenbeck models incorporate both selection and drift and are thus qualitatively different from, and more general than, pure drift models based on Brownian motion. Most importantly, OU models possess selective optima that formalize the notion of adaptive zone. In this article, we develop the method for one quantitative character, discuss interpretations of its parameters, and provide code implementing the method. Our approach allows us to translate hypotheses regarding adaptation in different selective regimes into explicit models, to test the models against data using maximum‐likelihood‐based model selection techniques, and to infer details of the evolutionary process. We illustrate the method using two worked examples. Relative to existing approaches, the direct modeling approach we demonstrate allows one to explore more detailed hypotheses and to utilize more of the information content of comparative data sets than existing methods. Moreover, the use of a model selection framework to simultaneously compare a variety of hypotheses advances our ability to assess alternative evolutionary explanations.
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