The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC

Dynamic Monitoring of Cellular Remodeling Induced by the Transforming Growth Factor-β1

The plasticity of differentiated adult cells could have a great therapeutic potential, but at the same time, it is characteristic of progression of serious pathological states such as cancer and fibrosis. In this study, we report on the application of a real-time noninvasive system for dynamic monitoring of cellular plasticity. Analysis of the cell impedance profile recorded as cell index using a real-time cell analyzer revealed its significant increase after the treatment of prostate epithelial cells with the transforming growth factor-β1. Changes in the cell index profile were paralleled with cytoskeleton rebuilding and induction of epithelial–mesenchymal transition and negatively correlated with cell proliferation. This novel application of such approach demonstrated a great potential of the impedance-based system for noninvasive and real-time monitoring of cellular fate

Solar wind current sheets and deHoffmann-Teller analysis. First results from Solar Orbiter's DC electric field measurements

Context: Solar Orbiter was launched on 10 February 2020 with the purpose of investigating solar and heliospheric physics using a payload of instruments designed for both remote and in situ studies. Similar to the recently launched Parker Solar Probe, and unlike earlier missions, Solar Orbiter carries instruments designed to measure low-frequency DC electric fields. Aims: In this paper, we assess the quality of the low-frequency DC electric field measured by the Radio and Plasma Waves instrument (RPW) on Solar Orbiter. In particular, we investigate the possibility of using Solar Orbiter’s DC electric and magnetic field data to estimate the solar wind speed. Methods: We used a deHoffmann-Teller (HT) analysis, based on measurements of the electric and magnetic fields, to find the velocity of solar wind current sheets, which minimises a single component of the electric field. By comparing the HT velocity to the proton velocity measured by the Proton and Alpha particle Sensor (PAS), we have developed a simple model for the effective antenna length, Leff of the E-field probes. We then used the HT method to estimate the speed of the solar wind. Results: Using the HT method, we find that the observed variations in Ey are often in excellent agreement with the variations in the magnetic field. The magnitude of Ey , however, is uncertain due to the fact that the Leff depends on the plasma environment. Here, we derive an empirical model relating Leff to the Debye length, which we can use to improve the estimate of Ey and, consequently, the estimated solar wind speed. Conclusions: The low-frequency electric field provided by RPW is of high quality. Using the deHoffmann-Teller analysis, Solar Orbiter’s magnetic and electric field measurements can be used to estimate the solar wind speed when plasma data are unavailable

Statistical analysis of mirror mode waves in sheath regions driven by interplanetary coronal mass ejection

We present a comprehensive statistical analysis of mirror mode waves and the properties of their plasma surroundings in sheath regions driven by interplanetary coronal mass ejection (ICME). We have constructed a semi-automated method to identify mirror modes from the magnetic field data. We analyze 91 ICME sheath regions from January 1997 to April 2015 using data from the Wind spacecraft. The results imply that similarly to planetary magnetosheaths, mirror modes are also common structures in ICME sheaths. However, they occur almost exclusively as dip-like structures and in mirror stable plasma. We observe mirror modes throughout the sheath, from the bow shock to the ICME leading edge, but their amplitudes are largest closest to the shock. We also find that the shock strength (measured by Alfven Mach number) is the most important parameter in controlling the occurrence of mirror modes. Our findings suggest that in ICME sheaths the dominant source of free energy for mirror mode generation is the shock compression. We also suggest that mirror modes that are found deeper in the sheath are remnants from earlier times of the sheath evolution, generated also in the vicinity of the shock.Peer reviewe

Lineage specific composition of cyclin D–CDK4/CDK6–p27 complexes reveals distinct functions of CDK4, CDK6 and individual D-type cyclins in differentiating cells of embryonic origin

Objectives: This article is to study the role of G1/S regulators in differentiation of pluripotent embryonic cells. Materials and methods: We established a P19 embryonal carcinoma cell-based experimental system, which profits from two similar differentiation protocols producing endodermal or neuroectodermal lineages. The levels, mutual interactions, activities, and localization of G1/S regulators were analysed with respect to growth and differentiation parameters of the cells. Results and Conclusions: We demonstrate that proliferation parameters of differentiating cells correlate with the activity and structure of cyclin A/E–CDK2 but not of cyclin D–CDK4/6–p27 complexes. In an exponentially growing P19 cell population, the cyclin D1–CDK4 complex is detected, which is replaced by cyclin D2/3–CDK4/6–p27 complex following density arrest. During endodermal differentiation kinase-inactive cyclin D2/D3–CDK4–p27 complexes are formed. Neural differentiation specifically induces cyclin D1 at the expense of cyclin D3 and results in predominant formation of cyclin D1/D2–CDK4–p27 complexes. Differentiation is accompanied by cytoplasmic accumulation of cyclin Ds and CDK4/6, which in neural cells are associated with neural outgrowths. Most phenomena found here can be reproduced in mouse embryonic stem cells. In summary, our data demonstrate (i) that individual cyclin D isoforms are utilized in cells lineage specifically, (ii) that fundamental difference in the function of CDK4 and CDK6 exists, and (iii) that cyclin D–CDK4/6 complexes function in the cytoplasm of differentiated cells. Our study unravels another level of complexity in G1/S transition-regulating machinery in early embryonic cells

Hypergravity effects on glide arc plasma

The behaviour of a special type of electric discharge – the gliding arc plasma – has been investigated in hypergravity (1g –18g) using the Large Diameter Centrifuge (LDC) at ESA/ESTEC. The discharge voltage and current together with the videosignal from a fast camera have been recorded during the experiment. The gliding of the arc is governed by hot gas buoyancy and by consequence, gravity. Increasing the centrifugal acceleration makes the glide arc movement substantially faster. Whereas at 1g the discharge was stationary, at 6g it glided with 7 Hz frequency and at 18g the gliding frequency was 11 Hz. We describe a simple model for the glide arc movement assuming low gas flow velocities, which is compared to our experimental results

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic o

Comparison of chromosomal aberrations frequency and polymorphism of GSTs genes in workers occupationally exposed to cytostatics or anaesthetics

Authors compared the incidence of chromosomal aberrations (CAs) of workers occupationally exposed to cytostatics (group EXP1) or anaesthetics (group EXP2) in relationship to polymorphism of GSTM1, GSTP1 and GSTT1 genes. The cytogenetic analysis for chromosomal aberrations frequency and for polymorphisms of genes the PCR and PCR-RFLP method were used. Statistically higher frequency of total CAs was detected in both exposed groups: group EXP1 1.90±1.34%; Mann-Whitney U-test, p=0.001; group EXP2 2.53±1.46%, p=0.0008) as compared to control (1.26±0.93%). In group EXP2 was detected statistically higher frequency of aberrations CSA-type as compared to CTA-type. In xenobiotic metabolizing genes for GST higher frequency of total CAs and constituent types chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) of genes GSTM1 and GSTT1 with null genotype was detected. Statistically significant difference was detected only in CSA-type of aberrations in GSTT1 gene. In gene GSTP1 was not detected any difference in frequency of aberrations in presence of the variant allele. Presented results point out importance of individual susceptibility in evaluation of genotoxic agents of anaesthetics or cytostatics

Erratum: The solar orbiter radio and plasma waves (RPW) instrument (Astronomy and Astrophysics (2020) 642 (A12) DOI: 10.1051/0004-6361/201936214)

The erratum concerns Fig. 9 entitled "Antenna radio-electrical properties" for which some of the parameters are not correct. The new figure with new parameters is provided in Fig. 1 of this corrigendum. Fig. 1. Corrected Antenna radio-electrical properties. (Figure Presented)