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

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

Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma.

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver