1,816 research outputs found
A STATement on vemurafenib-resistant melanoma.
Despite recent advancements in the treatment of late-stage mutant BRAF (V600E/K) melanomas, a major hurdle continues to be acquired resistance to BRAF inhibitors such as vemurafenib. The mechanisms for resistance have proven to be heterogeneous, emphasizing the need to use broad therapeutic approaches. In this issue, the study Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas by Liu et al. proposes that signal transducer and activator of transcription 3 (STAT3)-paired box 3 (PAX3) signaling may be a mechanism that is used by melanomas to resist RAF inhibitors
The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox.
The novel Hsp90 inhibitor XL888 is undergoing clinical investigation for use in conjunction with the rapidly accelerated fibrosarcoma (RAF) kinase inhibitor vemurafenib to treat unresectable melanoma. The addition of XL888 to current regimens may serve an additional purpose by blocking the RAF inhibitor paradox. Such activity could reduce adverse events in patients and provide a biomarker for the successful inhibition of Hsp90 target proteins
Measuring ionizing radiation in the atmosphere with a new balloon-borne detector
Increasing interest in energetic particle effects on weather and climate has motivated development of a miniature scintillator-based detector intended for deployment on meteorological radiosondes or unmanned airborne vehicles. The detector was calibrated with laboratory gamma sources up to 1.3 MeV, and known gamma peaks from natural radioactivity of up to 2.6 MeV. The specifications of our device in combination with the performance of similar devices suggest that it will respond to up to 17 MeV gamma rays. Laboratory tests show the detector can measure muons at the surface, and it is also expected to respond to other ionizing radiation including, for example, protons, electrons (>100 keV) and energetic helium nuclei from cosmic rays or during space weather events. Its estimated counting error is ±10%. Recent tests, when the detector was integrated with a meteorological radiosonde system, and carried on a balloon to ~25 km altitude, identified the transition region between energetic particles near the surface, which are dominated by terrestrial gamma emissions, to higher-energy particles in the free troposphere
Aspirated capacitor measurements of air conductivity and ion mobility spectra
Measurements of ions in atmospheric air are used to investigate atmospheric
electricity and particulate pollution. Commonly studied ion parameters are (1)
air conductivity, related to the total ion number concentration, and (2) the
ion mobility spectrum, which varies with atmospheric composition. The physical
principles of air ion instrumentation are long-established. A recent
development is the computerised aspirated capacitor, which measures ions from
(a) the current of charged particles at a sensing electrode, and (b) the rate
of charge exchange with an electrode at a known initial potential, relaxing to
a lower potential. As the voltage decays, only ions of higher and higher
mobility are collected by the central electrode and contribute to the further
decay of the voltage. This enables extension of the classical theory to
calculate ion mobility spectra by inverting voltage decay time series. In
indoor air, ion mobility spectra determined from both the novel voltage decay
inversion, and an established voltage switching technique, were compared and
shown to be of similar shape. Air conductivities calculated by integration
were: 5.3 +- 2.5 fS/m and 2.7 +- 1.1 fS/m respectively, with conductivity
determined to be 3 fS/m by direct measurement at a constant voltage.
Applications of the new Relaxation Potential Inversion Method (RPIM) include
air ion mobility spectrum retrieval from historical data, and computation of
ion mobility spectra in planetary atmospheres.Comment: To be published in Review of Scientific Instrument
Field methods for rodent studies in Asia and the Indo-Pacific
Farm Management,
Surface Visualisation of Tissue Interfaces by Scanning Electron Microscopy. Methods for Exposure of the Basal Lamina and Associated Structures in Human Amnion
Tissue interfaces such as basal lamina have been traditionally investigated in transmission electron microscopy by sections cut vertical to the lamina, presenting information restricted to a single ultrathin plane. In order to overcome this limitation, a methodology for surface visualisation of the underside cell membranes of the amniotic epithelium, the upper and lower basal lamina surfaces, and their relationship to the stromal collagen has been devised. This involves alkaline, detergent or enzymatic loosening and/or removal of the epithelial monolayer prior to fixation, followed by dry fracture after critical point drying. In this way we have visualised large areas of all interfaces and the inter-relationships between these elements during the process of stromal collagen production by the amniotic epithelial cells
Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells.
Melanoma cells driven by mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) are highly resistant to chemotherapeutic treatments. Recent phase 1 results with PLX4032/RG7204/vemurafenib, which selectively inhibits B-RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling in mutant B-RAF cells, has given encouragement to this struggling field. Nearly all patients in the phase 1-3 studies saw at least some response and the overall response rates ranged from 48 and 81%. However, despite initial tumor shrinkage, most responders in the trial experienced tumor relapse over time. These findings indicate that both intrinsic and acquired resistance may affect the clinical efficacy of PLX4032. It is critical to optimize PLX4032 activity to improve response rates and understand why some patients with the B-RAF mutation do not respond. We have previously shown that the stemness factor, Forkhead box D3 (FOXD3), is upregulated following inhibition of B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that upregulation of FOXD3 following treatment with PLX4032 and PLX4720 (the non-clinical tool compound for PLX4032) confers resistance to cell death. Small interfering RNA-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032/4720 treatment in mutant B-RAF melanoma cell lines. Additionally, upregulation of FOXD3 after PLX4720 treatment was attenuated in non-adherent conditions and correlated with enhanced cell death. Ectopic expression of FOXD3 in non-adherent cells significantly reduced cell death in response to PLX4720 treatment. Together, these data indicate that upregulation of FOXD3 is an adaptive response to RAF inhibitors that promotes a state of drug resistance
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Brief communication: Earthquake–cloud coupling through the global atmospheric electric circuit
We illustrate how coupling could occur between surface air and clouds via the global electric circuit – through Atmospheric Lithosphere–Ionosphere Charge Exchange (ALICE) processes – in an attempt to develop a physical understanding of the possible relationships between
earthquakes and cloud
Stress and pore pressure histories in complex tectonic settings predicted with coupled geomechanical-fluid flow models
Most of the methods currently used for pore pressure prediction in sedimentary basins assume one dimensional compaction based on relationships between vertical effective stress and porosity. These methods may be inaccurate in complex tectonic regimes where stress tensors are variable. Modelling approaches for compaction adopted within the geotechnical field account for both the full three dimensional stress tensor and the stress history. In this paper a coupled geomechanical-fluid flow model is used, along with an advanced version of the Cam-Clay constitutive model, to investigate stress,pore pressure and porosity in a Gulf of Mexico style mini-basin bounded by salt subjected to lateral deformation. The modelled structure consists of two depocentres separated by a salt diapir. 20% of horizontal shortening synchronous to basin sedimentation is imposed. An additional model accounting solely for the overpressure generated due to 1D disequilibrium compaction is also defined. The predicted deformation regime in the two depocentres of the mini-basin is one of tectonic lateral compression, in which the horizontal effective stress is higher than the vertical effective stress. In contrast, sediments above the central salt diapir show lateral extension and tectonic vertical compaction due to the rise of the diapir. Compared to the 1D model, the horizontal shortening in the mini-basin increases the predicted present-day overpressure by 50%, from 20 MPa to 30 MPa. The porosities predicted by the mini-basin models are used to perform 1D, porosity-based pore pressure predictions. The 1D method underestimated overpressure by up to 6 MPa at 3400 m depth (26% of the total overpressure) in the well located at the basin depocentre and up to 3 MPa at 1900 m depth (34% of the total overpressure) in the well located above the salt diapir. The results show how 2D/3D methods are required to accurately predict overpressure in regions in which tectonic stresses are important
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