MErCuRIC1: A Phase I study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in RASMT and RASWT (with aberrant c-MET) metastatic colorectal cancer (mCRC) patients.

Background: RAS is mutated (RASMT) in ~55% of mCRC, and phase III studies have shown that patients harbouring RAS mutations do not benefit from anti-EGFR MoAbs. In addition, ~50% of RAS Wild Type (RASWT) will not benefit from the addition of an EGFR MoAb to standard chemotherapy. Hence, novel treatment strategies are urgently needed for RASMT and > 50% of RASWT mCRC patients. c-MET is overexpressed in ~50-60%, amplified in ~2-3% and mutated in ~3-5% of mCRC. Recent preclinical studies have shown that c-MET is an important mediator of resistance to MEK inhibitors (i) in RASMT mCRC, and that combined MEKi/METi resulted in synergistic reduction in tumour growth in RASMT xenograft models (1). A number of recent studies have highlighted the role of c-MET in mediating primary/secondary resistance to anti-EGFR MoAbs in mCRC, suggesting that patient with RASWT tumours with aberrant c-MET (RASWT/c-MET+) may benefit from anti-c-MET targeted therapies (2). These preclinical data supported the further clinical evaluation of combined MEKi/METi treatment in RASMT and RASWT CRC patients with aberrant c-MET signalling (overexpression, amplification or mutation; RASWT/c-MET+). Methods: MErCuRIC1 is a phase I combination study of METi crizotinib with MEKi PD-0325901. The dose escalation phase, utilizing a rolling six design, recruits 12-24 patients with advanced solid tumours and aims to assess safety/toxicity of combination, recommended phase II (RPII) dose, pharmacokinetics (PK) and pharmacodynamics (PD) (pERK1/2 in PBMC and tumour; soluble c-MET). In the dose expansion phase an additional 30-42 RASMT and RASWT/c-MET mCRC patients with biopsiable disease will be treated at the RPII dose to further evaluate safety, PK, PD and treatment response. In the dose expansion phase additional biopsy and blood samples will be obtained to define mechanisms of response/resistance to crizotinib/PD-0325901 therapy. Enrolment into the dose escalation phase began in December 2014 with cohort 1 still ongoing. EudraCT registry number: 2014-000463-40. (1) Van Schaeybroeck S et al. Cell Reports 2014;7(6):1940-55; (2) Bardelli A et al. Cancer Discov 2013;3(6):658-73. Clinical trial information: 2014-000463-40.

Biodegradation and Rhodococcus--masters of catabolic versatility.

The genus Rhodococcus is a very diverse group of bacteria that possesses the ability to degrade a large number of organic compounds, including some of the most difficult compounds with regard to recalcitrance and toxicity. They achieve this through their capacity to acquire a remarkable range of diverse catabolic genes and their robust cellular physiology. Rhodococcus appear to have adopted a strategy of hyperrecombination associated with a large genome. Notably, they harbour large linear plasmids that contribute to their catabolic diversity by acting as 'mass storage' for a large number of catabolic genes. In addition, there is increasing evidence that multiple pathways and gene homologues are present that further increase the catabolic versatility and efficiency of Rhodococcus.

High-resolution Keck I spectroscopy of Galactic halo post-asymptotic giant branch stars

Absolute and differential abundance analyses have been performed from high-resolution, high signal-to-noise ratio optical (Keck I) spectra for three evolved Galactic halo stars, namely PG 1704 + 222, HD 341617 and LSIV -0401. Their derived atmospheric parameters indicate that all three objects are undergoing a post-asymptotic giant branch (post-AGB) phase of evolution. A differential abundance analysis reveals HD 341617 as having a mild carbon deficiency of 0.74 dex, possibly due to the star having evolved off the AGB before the onset of the third dredge-up. Although such carbon underabundances are typical of hot post-AGB objects, the same trend is not observed in PG 1704 + 222, where the carbon abundance is found to be consistent with those derived for nitrogen and oxygen. Hence, a dredge-up scenario need not be invoked to explain the chemical composition of PG 1704 + 222. For LSIV -0401 no iron deficiency is apparent relative to magnesium and silicon, and hence a gas- dust separation event in the AGB progenitor need not be invoked for this star.

Plasma power measurement and hysteresis in the E-H transition of a rf inductively coupled plasma system

An experimental investigation of the argon plasma behavior near the E-H transition in an inductively coupled Gaseous Electronics Conference reference cell is reported. Electron density and temperature, ion density, argon metastable density, and optical emission measurements have been made as function of input power and gas pressure. When plotted versus plasma power, applied power corrected for coil and hardware losses, no hysteresis is observed in the measured plasma parameter dependence at the E-H mode transition. This suggests that hysteresis in the E-H mode transition is due to ignoring inherent power loss, primarily in the matching system.