The use of epidermal growth factor receptor ( EGFR ) inhibitors such as osimertinib has improved outcomes and quality of life for patients with EGFR -mutated non-small cell lung cancer (NSCLC). Osimertinib has become the preferred EGFR tyrosine kinase inhibitor (TKIs) for patients with these mutations after demonstrating superior efficacy compared to first generation EGFR TKIs, such as erlotinib and gefitinib. More recently osimertinib has also shown to be beneficial in patients with resectable NSCLC harboring EGFR mutations irrespective of whether they received adjuvant chemotherapy or not. The drug is now FDA approved in this setting. With osimertinib being used more commonly in earlier stage and front-line settings, we are more likely to see patients who develop resistance to this drug. The aim of this review is to provide a comprehensive review of the data with osimertinib in EGFR mutation positive NSCLC, potential resistance mechanisms and an overview of key ongoing clinical trials.

The world of medicinal therapies has been historically, and remains to be, dominated by the use of elegant organic molecular structures. Now, a novel medical treatment is emerging based on CeO2 nano-crystals that are discrete clusters of a few hundred atoms. This development is generating a great deal of exciting and promising research activity, as evidenced by this Special Issue of Biomolecules. In this paper, we provide both a steady-state and time-dependent mathematical description of a sequence of reactions: superoxide generation, superoxide dismutase, and hydrogen peroxide catalase and ceria regeneration. This sequence describes the reactive oxygen species (ROS); superoxide, O2–, molecular oxygen, O2, hydroxide ion OH– and hydrogen peroxide, H2O2, interacting with the Ce3+, and Ce4+ surface cations of nanoparticle ceria, CeO2. Particular emphasis is placed on the predicted time-dependent role of the Ce3+/Ce4+ ratio within the crystal. The net reaction is succinctly described as: H2O2 + 2O2– + 2H+ → 2H2O + 2O2. The chemical equations and mathematical treatment appears to align well with several critical in vivo observations such as; direct and specific superoxide dismutase (SOD), ROS control, catalytic regeneration, ceria self-regulation and self-limiting behavior. However, in contrast to experimental observations, the model predicts that the 4+ ceric ion state is the key SOD agent. Future work is suggested based on these calculations.

Nonlinear internal waves in shallow water have significant acoustic impacts and cause three-dimensional ducting effects, for example, energy trapping in a duct between curved wavefronts that propagates over long distances. A normal mode approach applied to a three-dimensional idealized parametric model [Lin, McMahon, Lynch, and Siegmann, J. Acoust. Soc. Am. 133(1), 37–49 (2013)] determines the dependence of such effects on parameters of the features. Specifically, an extension of mode number conservation leads to convenient analytical formulas for along-duct (angular) acoustic wavenumbers. The radial modes are classified into five types depending on geometric characteristics, resulting in five distinct formulas to obtain wavenumber approximations. Examples of their dependence on wavefront curvature and duct width, along with benchmark comparisons, demonstrate approximation accuracy over a broad range of physical values, even including situations where transitions in mode types occur with parameter changes. Horizontal-mode transmission loss contours found from approximate and numerically exact wavenumbers agree well in structure and location of intensity features. Cross-sectional plots show only small differences between pattern phases and amplitudes of the two calculations. The efficiency and accuracy of acoustic wavenumber and field approximations, in combination with the mode-type classifications, suggest their application to determining parameter sensitivity and also to other feature models.

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Parameter dependence of acoustic quantities in a nonlinear internal wave duct BJD, Matt Milone, YTL Ocean features with 3-D spatial variability in shallow water can significantly affect acoustic propagation. One example is a curved front modeled with a discontinuous sound speed change over a sloping shelf [Lin and Lynch, JASA-EL (2012)], which has an extension to a continuous sound-speed change. An approach using normal modes and perturbation approximations yields convenient formulas that show how acoustic quantities depend on environmental parameters [DeCourcy et al., ASA, Salt Lake City (2016)]. Another common 3-D example is nonlinear internal waves, with wave fronts that pairwise can produce acoustic ducting, radiating, and scattering effects often observed in field data. The previous approach is applied to this feature, using a well model with two sound-speed jumps for such a duct [Lin et al., (2013)]. Approximate formulas for acoustic wavenumbers and phase speeds are determined in order to estimate sensitivity to changes in environmental parameters. All mode types will be considered (whispering gallery, fully bouncing, and leaky), highlighting differences from those in the single-front example. [Work supported by ONR Grants N00014-14-1-0372 and N00014-11-1-0701.]