The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic ...translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev).
A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed.
AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005).
MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.
Electrochemical decarboxylation of aryloxyacetic acids followed by fluorination provides easy access to fluoromethyl aryl ethers. This electrochemical fluorodecarboxylation offers a sustainable ...approach with electric current as traceless oxidant. Using Et
3
N·5HF as fluoride source and as supporting electrolyte, this simple electrosynthesis affords various fluoromethoxyarenes in yields up to 85%.
Electrochemical decarboxylation of aryloxyacetic acids followed by fluorination provides easy access to fluoromethyl aryl ethers.
The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find ...that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.
Homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes develop ...normally, apoptosis, vascularization, and ossification are delayed, resulting in progressive lengthening of the growth plate to about eight times normal. After 3 weeks postnatal, aberrant apoptosis, vascularization, and ossification compensate to remodel the enlarged growth plate and ultimately produce an axial skeleton of normal appearance. Transplantation of wild-type bone marrow cells rescues vascularization and ossification in gelatinase B–null growth plates, indicating that these processes are mediated by gelatinase B–expressing cells of bone marrow origin, designated chondroclasts. Growth plates from gelatinase B–null mice in culture show a delayed release of an angiogenic activator, establishing a role for this proteinase in controlling angiogenesis.
The final chapter in the long-standing mystery of the gamma-ray bursts (GRBs) centres on the origin of the short-hard class of bursts, which are suspected on theoretical grounds to result from the ...coalescence of neutron-star or black-hole binary systems. Numerous searches for the afterglows of short-hard bursts have been made, galvanized by the revolution in our understanding of long-duration GRBs that followed the discovery in 1997 of their broadband (X-ray, optical and radio) afterglow emission. Here we present the discovery of the X-ray afterglow of a short-hard burst, GRB 050709, whose accurate position allows us to associate it unambiguously with a star-forming galaxy at redshift z = 0.160, and whose optical lightcurve definitively excludes a supernova association. Together with results from three other recent short-hard bursts, this suggests that short-hard bursts release much less energy than the long-duration GRBs. Models requiring young stellar populations, such as magnetars and collapsars, are ruled out, while coalescing degenerate binaries remain the most promising progenitor candidates.
Heme oxygenase-1 is critical for iron recycling during red blood cell turnover, whereas its impact on steady-state erythropoiesis and red blood cell lifespan is not known. We show here that in 8- to ...14-week old mice, heme oxygenase-1 deficiency adversely affects steady-state erythropoiesis in the bone marrow. This is manifested by a decrease in Ter-119(+)-erythroid cells, abnormal adhesion molecule expression on macrophages and erythroid cells, and a greatly diminished ability to form erythroblastic islands. Compared with wild-type animals, red blood cell size and hemoglobin content are decreased, while the number of circulating red blood cells is increased in heme oxygenase-1 deficient mice, overall leading to microcytic anemia. Heme oxygenase-1 deficiency increases oxidative stress in circulating red blood cells and greatly decreases the frequency of macrophages expressing the phosphatidylserine receptor Tim4 in bone marrow, spleen and liver. Heme oxygenase-1 deficiency increases spleen weight and Ter119(+)-erythroid cells in the spleen, although α4β1-integrin expression by these cells and splenic macrophages positive for vascular cell adhesion molecule 1 are both decreased. Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice compared with wild-type mice. Our findings suggest that while macrophages and relevant receptors required for red blood cell formation and removal are substantially depleted in heme oxygenase-1 deficient mice, the extent of anemia in these mice may be ameliorated by the prolonged lifespan of their oxidatively stressed erythrocytes.
A Reverse Shock in GRB 181201A Laskar, Tanmoy; Hendrik van Eerten; Schady, Patricia ...
arXiv.org,
12/2019
Paper, Journal Article
Odprti dostop
We present comprehensive multiwavelength radio to X-ray observations of GRB 181201A spanning from \(\approx150\) s to \(\approx163\) days after the burst, comprising the first joint ALMA-VLA-GMRT ...observations of a gamma-ray burst (GRB) afterglow. The radio and mm-band data reveal a distinct signature at \(\approx3.9\) days, which we interpret as reverse shock (RS) emission. Our observations present the first time that a single radio-frequency spectral energy distribution can be decomposed directly into RS and forward shock (FS) components. We perform detailed modeling of the full multiwavelength data set, using Markov Chain Monte Carlo sampling to construct the joint posterior density function of the underlying physical parameters describing the RS and FS synchrotron emission. We uncover and account for all degeneracies in the model parameters. The joint RS-FS modeling reveals a weakly magnetized (\(\sigma\approx3\times10^{-3}\)), mildly relativistic RS, from which we derive an initial bulk Lorentz factor of \(\Gamma_0\approx103\) for the GRB jet. Our results support the hypothesis that low-density environments are conducive to the observability of RS emission. We compare our observations to other events with strong RS detections, and find a likely observational bias selecting for longer lasting, non-relativistic reverse shocks. We present and begin to address new challenges in modeling posed by the present generation of comprehensive, multi-frequency data sets.
Here we present the results from a search within the Pan-STARRS1 Medium Deep Survey (PS1-MDS) for rapidly evolving and luminous transients. We identify 10 new transients with a time above ...half-maximum (t sub(1/2)) of less than 12 days and -16.5 > M > -20 mag. We find it difficult to reconcile the short timescale, high peak luminosity (L > 10 super(43) erg s super(-1)), and lack of UV line blanketing observed in many of these transients with an explosion powered mainly by the radioactive decay of super(56)Ni. Rather, we find that many are consistent with either (1) cooling envelope emission from the explosion of a star with a low-mass extended envelope that ejected very little (<0.03 M sub(middot in circle)) radioactive material, or (2) a shock breakout within a dense, optically thick, wind surrounding the progenitor star.
The catalytic partial oxidation (CPO) of methane with oxygen was studied at atmospheric pressure in a continuous-flow reactor containing a single Pt metal gauze. Experiments were performed at ...catalyst temperatures and residence times in the range of 950–1200
K and 0.02–0.2
ms, respectively. Heat-transport limitations are taken into account explicitly, by measuring the catalyst temperature directly by means of a surface thermocouple. The experimental results indicated that the conversions of methane and oxygen were determined by transport phenomena; however, the CO selectivity appeared to be influenced significantly by the kinetics of the catalytic reactions. Hydrogen was found only at temperatures above 1273
K. In order to be able to derive intrinsic kinetic information from the experimental data, a reactor model consisting of two rows of parallel flat plates in series was developed, taking into account the relevant transport phenomena. This flat-plate reactor model was validated by comparing the model results to 3D
fluent simulations of simultaneous heat and mass transfer in case of a simple surface reaction on the gauze catalyst. A series-parallel CPO reaction mechanism allowed simulation of the observed conversions and selectivities at different space-times. More detailed elementary-step reaction mechanisms can be developed, using both the experimental data and the flat-plate reactor model.
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