MODULATION OF CALCIUM CHANNELS IN ARTERIAL SMOOTH-MUSCLE CELLS BY DIHYDROPYRIDINE ENANTIOMERS

The actions of the optical enantiomers of BAY K 8644 and Sandoz 202,791 were studied on barium inward currents recorded using the whole-cell configuration of the patch clamp technique from enzymatically isolated smooth muscle cells from the rabbit ear artery. The enantiomers were applied by bath perfusion or rapidly by a concentration jump technique, which enabled the study of drug action under equilibrium and nonequilibrium conditions. A larger effect of agonists was seen on peak inward current in 110 mM Ba when small rather than large depolarizations were applied. The midpoint voltage of the steady-state inactivation curve of IBa was -12.8 +/- 1.9 mV (n = 4) in the absence of drug, -16.4 +/- 2.5 mV (n = 4) in 1 microM (+)202,791, and -31.4 +/- 0.4 mV (n = 4) in 1 microM (-)202,791. The rate of onset of action of the agonist and antagonist enantiomers of BAY K 8644 and Sandoz 202,791 was studied by rapid application during 20-ms depolarizing steps from different holding potentials to +30 mV at 1 or 0.2 Hz. The drugs were applied as concentration jumps between two single pulses of a pulse train. The rates of onset of drug action on peak IBa during a 1-Hz pulse train were concentration dependent over the range of 100 nM-3 microM for both (+) and (-)202,791. The rate of onset of inhibition of peak current by antagonist enantiomers was not significantly influenced by the test pulse frequency. At a holding potential of -60 mV, the onset rate of the increase in peak IBa on application of 1 microM of agonist enantiomers (+)202,791 or (-)BAY K 8644 during a train of pulses occurred with mean time constants of 2.1 +/- 0.7 s (n = 7) and 2.3 +/- 0.2 s (n = 4), respectively. The onset of current increase on application of 1 microM (+)202,791 during a single voltage clamp step to 20 mV was faster, with a mean time constant of 380 +/- 80 ms (n = 3)

Methane emissions from the 2015 Aliso Canyon blowout in Los Angeles, CA.

Single-point failures of natural gas infrastructure can hamper methane emission control strategies designed to mitigate climate change. The 23 October 2015 blowout of a well connected to the Aliso Canyon underground storage facility in California resulted in a massive release of natural gas. Analysis of methane and ethane data from dozens of plume transects, collected during 13 research-aircraft flights between 7 November 2015 and 13 February 2016, shows atmospheric leak rates of up to 60 metric tons of methane and 4.5 metric tons of ethane per hour. At its peak, this blowout effectively doubled the methane emission rate of the entire Los Angeles basin and, in total, released 97,100 metric tons of methane to the atmosphere

Tivozanib in the treatment of renal cell carcinoma

Mehmet Hepgur, Sarmad Sadeghi, Tanya B Dorff, David I Quinn Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA Abstract: Renal cell carcinoma (RCC) is an aggressive malignancy compared to other urological malignancies and has been associated with poor responses to conventional cytotoxic chemotherapy. Interferon-a and interleukin-2 were previously utilized in a limited number of patients with good performance status due to toxicity and safety issues. Over the last decade, through advances in the understanding of the biology and pathology of RCC, the important role of vascular endothelial growth factor (VEGF) in RCC has been identified. Data from randomized trials have led to the approval of first-generation tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib; however, these agents inhibit a wide variety of kinase targets and are associated with a range of adverse effects. More recently, a new generation TKI, axitinib, has been approved by the US Food and Drug Administration. Tivozanib is a novel TKI, which is a potent inhibitor of VEGF-1, VEGF-2, VEGF-3, c-kit, and PDGR kinases, with a more restricted target spectrum. Phase II and III studies have demonstrated significant activity and a favorable safety profile as an initial targeted treatment for advanced RCC. This review examines the emerging data with tivozanib for the treatment of advanced RCC. Preclinical investigations as well as Phase I, II, and III data are examined; data on the comparative benefits of tivozanib are reviewed. Finally, we discuss the future potential of tivozanib in combination, biomarkers associated with tivozanib response, and acquisition of resistance and nonkidney cancer indications. Keywords: targeted therapy, renal cell cancer, tyrosine kinase inhibitor, tivozani

Mechanical and microstructural investigations of tungsten and doped tungsten materials produced via powder injection molding

The physical properties of tungsten such as the high melting point of 3420°C, the high strength and thermal conductivity, the low thermal expansion and low erosion rate make this material attractive as a plasma facing material. However, the manufacturing of such tungsten parts by mechanical machining such as milling and turning is extremely costly and time intensive because this material is very hard and brittle. Powder Injection Molding (PIM) as special process allows the mass production of components, the joining of different materials without brazing and the creation of composite and prototype materials, and is an ideal tool for scientific investigations. This contribution describes the characterization and analyses of prototype materials produced via PIM. The investigation of the pure tungsten and oxide or carbide doped tungsten materials comprises the microstructure examination, element allocation, texture analyses, and mechanical testing via four-point bend (4-PB). Furthermore, the different materials were characterized by high heat flux (HHF) tests applying transient thermal loads at different base temperatures to address thermal shock and thermal fatigue performance. Additionally, HHF investigations provide information about the thermo-mechanical behavior to extreme steady state thermal loading and measurements of the thermal conductivity as well as oxidation tests were done. Post mortem analyses are performed quantifying and qualifying the occurring damage with respect to reference tungsten grades by metallographic and microscopical means