Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is ...an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.
Summary
Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical ...features. FDH is transmitted as an X‐linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low‐level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice‐site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.
What's already known about this topic?
Mutations in PORCN cause focal dermal hypoplasia (FDH).
In male children, hemizygous PORCN mutations are lethal in utero.
To date, only around 300 patients with mutations in PORCN have been reported.
What does this study add?
In four women affected by FDH, PORCN mutations were found to be present in affected cutaneous tissue but not in peripheral blood.
Negative mutation analysis of blood samples does not exclude the diagnosis of FDH, as a mosaic constellation due to postzygotic mutations has been repeatedly observed in female patients with FDH as shown in this study.
Linked Comment: Traupe. Br J Dermatol 2019; 180:461–462.
Plain language summary available online
Abstract
Earth's core is an iron‐rich alloy containing several weight percent of light element(s), possibly including silicon. Therefore, the high pressure‐temperature equations of state of ...iron‐silicon alloys can provide understanding of the properties of Earth's core. We performed X‐ray diffraction experiments using laser‐heated diamond anvil cells to achieve simultaneous high pressures and temperatures, up to ~200 GPa for Fe–9 wt % Si alloy and ~145 GPa for stoichiometric FeSi. We determined equations of state of the D0
3
, hcp + B2, and hcp phases of Fe–9Si, and the B20 and B2 phases of FeSi. We also calculated equations of state of Fe, Fe
11
Si, Fe
5
Si, Fe
3
Si, and FeSi using ab initio methods, finding that iron and silicon atoms have similar volumes at high pressures. By comparing our experimentally determined equations of state to the observed core density deficit, we find that the maximum amount of silicon in the outer core is ~11 wt %, while the maximum amount in the inner core is 6–8 wt %, for a purely Fe‐Si‐Ni core. Bulk sound speeds predicted from our equations of state also match those of the inner and outer core for similar ranges of compositions. We find a compositional contrast between the inner and outer core of 3.5–5.6 wt % silicon, depending on the seismological model used. Theoretical and experimental equations of state agree at high pressures. We find a good match to the observed density, density profile, and sound speed of the Earth's core, suggesting that silicon is a viable candidate for the dominant light element.
Key Points
We determined equations of state of Fe–9Si and FeSi to 200 and 145 GPa
Outer core contains up to ~11–12 wt % Si based on density and sound speed
Inner core contains up to ~6–8 wt % Si based on density and sound speed
Iron-Rich Silicates in the Earth's D″ Layer Mao, Wendy L.; Meng, Yue; Shen, Guoyin ...
Proceedings of the National Academy of Sciences - PNAS,
07/2005, Letnik:
102, Številka:
28
Journal Article
Recenzirano
Odprti dostop
High-pressure experiments and theoretical calculations demonstrate that an iron-rich ferromagnesian silicate phase can be synthesized at the pressure-temperature conditions near the core-mantle ...boundary. The iron-rich phase is up to 20% denser than any known silicate at the core-mantle boundary. The high mean atomic number of the silicate greatly reduces the seismic velocity and provides an explanation to the low-velocity and ultra-low-velocity zones. Formation of this previously undescribed phase from reaction between the silicate mantle and the iron core may be responsible for the unusual geophysical and geochemical signatures observed at the base of the lower mantle.
The Fifth Edition of Luellmann's Color Atlas of Pharmacology has been extensively revised to include all recent advances and new drugs, and the illustrations have been optimized and updated. Each ...two-page spread presents concise text on the left complemented by detailed full-color illustrations on the right to help users quickly digest important facts and concepts. Color-coded sections provide readers with a helpful framework with which to approach the latest developments in pharmacology. * Part 1, General Pharmacology, explains basic aspects, such as drug absorption, distribution, and elimination, along with the molecular mechanisms of drug actions * Part 2, Systems Pharmacology, presents the different groups of drugs, emphasizing their functional and therapeutic aspects * Part 3, Therapy of Selected Diseases, provides all the relevant information regarding the pharmacological treatment of a large number of conditions Key features: * User-friendly format ideal for study and review, self-assessment, and quick reference * Completely revised and updated, with 174 color plates * New glossary of important and interesting pharmacological terms * Updated detailed drug indexes containing current information on drugs listed by both generic and brand names The Fifth Edition of Color Atlas of Pharmacology is an essential study guide and reference for every student, nurse, and practicing physician needing to keep up to date with recent advances in the field.
Mosaicism in women with focal dermal hypoplasia Heinz, L.; Bourrat, E.; Vabres, P. ...
British journal of dermatology (1951),
March 2019, 2019-03-00, 20190301, Letnik:
180, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
This report from Germany and France describes four women with focal dermal hypoplasia (FDH), a genetic condition affecting the skin, skeleton, teeth and eyes. FDH is caused by a mutant ...(abnormal) gene called PORCN, found on the X chromosome. Male embryos with the mutant gene do not usually survive. Females are more complicated. Firstly, they have two X chromosomes, but for FDH to show up it only needs the mutant gene to be present on one of them. Secondly, soon after conception one of the two X chromosomes in each cell of the embryo is randomly deactivated. Cell lines (daughter cells) from cells where the normal X chromosome remains active develop normally; cell lines where the abnormal X chromosome remains active develop abnormally owing to the mutant gene. This phenomenon, where cell lines in an individual represent different genetic populations, is called mosaicism (and, incidentally, explains why tortoiseshell cats are always female). The FDH mutation also frequently happens spontaneously after fertilisation, in the earliest stages of development, but before X chromosome deactivation. The main message from this report is that one cannot exclude FDH simply by using standard genetic tests on blood alone. In affected women, in whom the clinical signs may be subtle and a blood test negative, because of mosaicism the abnormal gene may still be found in those skin cells where the X chromosome carrying it remains active. Importantly, the ovaries may also contain such cells, in which case the condition could be passed on to children.
Linked Article: Heinz et al. Br J Dermatol 2019; 180:657–661
Iron-Silicon Alloy in Earth's Core? Lin, Jung-Fu; Heinz, Dion L.; Campbell, Andrew J. ...
Science (American Association for the Advancement of Science),
01/2002, Letnik:
295, Številka:
5553
Journal Article
Recenzirano
We have investigated the phase relations in the iron-rich portion of the iron-silicon (Fe-Si) alloys at high pressures and temperatures. Our study indicates that Si alloyed with Fe can stabilize the ...body-centered cubic (bcc) phase up to at least 84 gigapascals (compared to ∼10 gigapascals for pure Fe) and 2400 kelvin. Earth's inner core may be composed of hexagonal close-packed (hcp) Fe with up to 4 weight percent Si, but it is also conceivable that the inner core could be a mixture of a Si-rich bcc phase and a Si-poor hcp phase.
Partial melting in the Fe–S system was investigated at high pressures because of its importance to understanding the formation, composition, and thermal structure of the Earth's core. Earlier studies ...at very high pressure (>25
GPa) took place before the discovery of Fe
3S, which compromised the interpretation of those results. Furthermore, they relied on textural criteria for melting that are difficult to apply at high pressure. In this study synchrotron X-ray diffraction was used to monitor coexisting metal and sulfide at high pressures and temperatures, during laser heating in a diamond anvil cell. The criterion for melting was the disappearance of one of the two coexisting phases, and reappearance upon quench. Temperatures of eutectic melting between Fe and Fe
3S were bracketed in this way up to 60
GPa, and a lower bound was established at 80
GPa. The accuracy of the melting point measured in these studies was improved through modelling of the axial temperature distribution through the thickness of the sample; this indicated a ∼6% correction to the spectroradiometrically determined temperature. The Fe–Fe
3S eutectic composition remains close to 15
wt% S up to 60
GPa.
Iron (Fe) and coexisting Fe3S were studied simultaneously using synchrotron X‐ray diffraction and a laser‐heated diamond anvil cell (DAC). The thermal equation of state (EOS) of Fe3S was investigated ...up to pressures of 80 GPa and temperatures of 2500 K. Fitting a third‐order Birch‐Murnaghan EOS to the room temperature data yielded bulk modulus K0 = 156(7) GPa (values in parentheses are standard deviation) and pressure derivative K′0 = 3.8(3) calibrated against NaCl in the B2 structure. The room temperature data were also calibrated against the EOS of hcp‐Fe for comparison and aid in the determination of the thermal pressure contribution of Fe3S. This fit yielded bulk modulus K0 = 113(9) GPa and pressure derivative K′0 = 5.2(6). The thermal pressure contribution of Fe3S was assumed to be of the form ΔPthermal = αKTΔT, where αKT is constant. The best fit to the data yielded αKT = 0.011(2) GPa K−1. Iron and Fe3S coexisted in the high‐pressure, high‐temperature experiments, and a density relationship between Fe and Fe3S was found to be linear and independent of temperature. Extrapolation of the data to the core‐mantle boundary (CMB), using an assumed temperature of 3500 K at the CMB, a 2% volume change associated with melting, and applying a small adjustment to account for the nickel content of the core indicates that 14.7(11) wt % sulfur is adequate to resolve the density deficit of the outer core.
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