If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.     

Development of Covalent Chitosan-Polyethylenimine Derivatives as Gene Delivery Vehicle: Synthesis,Characterization, and Evaluation

There is an increasing interest in cationic polymers as important constituents of non-viral gene delivery vectors. In the present study, we developed a versatile synthetic route for the production of covalent polymeric conjugates consisting of water-soluble depolymerized chitosan (dCS; M_W 6–9 kDa) and low molecular weight polyethylenimine (PEI; 2.5 kDa linear, 1.8 kDa branched). dCS-PEI derivatives were evaluated based on their physicochemical properties, including purity, covalent bonding, solubility in aqueous media, ability for DNA condensation, and colloidal stability of the resulting polyplexes. They were complexed with non-integrating DNA vectors coding for reporter genes by simple admixing and assessed in vitro using liver-derived HuH-7 cells for their transfection efficiency and cytotoxicity. Using a rational screening cascade, a lead compound was selected (dCS-Suc-LPEI-14) displaying the best balance of biocompatibility, cytotoxicity, and transfection efficiency. Scale-up and in vivo evaluation in wild-type mice allowed for a direct comparison with a commercially available non-viral delivery vector (in vivo-jetPEI). Hepatic expression of the reporter gene luciferase resulted in liver-specific bioluminescence, upon intrabiliary infusion of the chitosan-based polyplexes, which exceeded the signal of the in vivo jetPEI reference formulation by a factor of 10. We conclude that the novel chitosan-derivative dCS-Suc-LPEI-14 shows promise and potential as an efficient polymeric conjugate for non-viral in vivo gene therapy.     

Luminescent Amphiphilic Aminoglycoside Probes to Study Transfection

We report the characterization of amphiphilic aminoglycoside conjugates containing luminophores with aggregation-induced emission properties as transfection reagents. These inherently luminescent transfection vectors are capable of binding plasmid DNA through electrostatic interactions; this binding results in an emission “on” signal due to restriction of intramolecular motion of the luminophore core. The luminescent cationic amphiphiles effectively transferred plasmid DNA into mammalian cells (HeLa, HEK 293T), as proven by expression of a red fluorescent protein marker. The morphologies of the aggregates were investigated by microscopy as well as ζ-potential and dynamic light-scattering measurements. The transfection efficiencies using luminescent cationic amphiphiles were similar to that of the gold-standard transfection reagent Lipofectamine® 2000.     

Effect of Grain Size on Mechanical Properties of Submicrometer 3Y-TZP: Fracture Strength and Hydrothermal Degradation

This paper considers fracture strength, fracture origins, and hydrothermal degradation of 3Y-TZP with grain sizes in the range of 110–480 nm. Biaxial fracture strength testing was used to show that the fracture strength increases with grain size and is governed by the concurrent change in fracture toughness. Hydrothermal degradation was studied by means of fractography, Raman microscopy and its effect on fracture strength. Up to 200 nm grain size, hydrothermal degradation of strength is limited. Larger grain sizes exhibit either premature failure or an increase in strength. A surface transformation zone was found to be responsible for both phenomena.     

Energieinformatik

Due to the increasing importance of producing and consuming energy more sustainably, Energy Informatics (EI) has evolved into a thriving research area within the CS/IS community. The article attempts to characterize this young and highly dynamic field of research by describing current EI research topics and methods and provides an outlook of how the field might evolve in the future. It is shown that two general research questions have received the most attention so far and are likely to dominate the EI research agenda in the coming years: How to leverage information and communication technology (ICT) to (1) improve energy efficiency, and (2) to integrate decentralized renewable energy sources into the power grid. Selected EI streams are reviewed, highlighting how the respective research questions are broken down into specific research projects and how EI researchers have made contributions based on their individual academic background.     

Modification of margarine fats by enzymatic interesterification: Evaluation of a solid-fat-content-based exponential model with two groups of oil blends

Lipozyme TL IM-catalyzed interesterification for the modification of margarine fats was carried out in a batch reactor at 70°C with a lipase dosage of 4%. Solid fat content (SFC) was used to monitor the reaction progress. Lipase-catalyzed interesterification, which led to changes in the SFC, was assumed to be a first-order reversible reaction. Accordingly, the change in SFC vs. reaction time was described by an exponential model. The model contained three parameters, each with a particular physical or chemical meaning: (i) the initial SFC (SFC₀), (ii) the change in SFC (ΔSFC) from the initial to the equilibrium state, and (iii) the reaction rate constant value (k). SFC_o and ΔSFC were related to only the types of blends and the blend ratios. The rate constant k was related to lipase activity on a given oil blend. Evaluation of the model was carried out with two groups of oil blends, i.e., palm stearin/coconut oil in weight ratios of 90∶10, 80∶20, and 70∶30, and soybean oil/fully hydrogenated soybean oil in weight ratios of 80∶20, 65∶35, and 50∶50. Correlation coefficients higher than 0.99 between the experimental and predicted values were observed for SFC at temperatures above 30°C. The model is useful for predicting changes in the SFC during lipase-catalyzed interesterification with a selected group of oil blends. It also can be used to control the process when particular SFC values are targeted.     

IISPH‐FLIP for incompressible fluids

We propose to use Implicit Incompressible Smoothed Particle Hydrodynamics (IISPH) for pressure projection and boundary handling in Fluid‐Implicit‐Particle (FLIP) solvers for the simulation of incompressible fluids. This novel combination addresses two issues of existing SPH and FLIP solvers, namely mass preservation in FLIP and efficiency and memory consumption in SPH. First, the SPH component enables the simulation of incompressible fluids with perfect mass preservation. Second, the FLIP component efficiently enriches the SPH component with detail that is comparable to a standard SPH simulation with the same number of particles, while improving the performance by a factor of 7 and significantly reducing the memory consumption. We demonstrate that the proposed IISPH‐FLIP solver can simulate incompressible fluids with a quantifiable, imperceptible density deviation below 0.1%. We show large‐scale scenarios with up to 160 million particles that have been processed on a single desktop PC using only 15GB of memory. One‐ and two‐way coupled solids are illustrated.     

The Failure of the Strong Pumping Lemma for Multiple Context-Free Languages

Seki et al. (Theor. Comput. Sci. 88(2):191–229, 1991) showed that every m-multiple context-free language L is weakly 2m-iterative in the sense that either L is finite or L contains a subset of the form \(\{ u_{0} w_{1}^{i} u_{1} \cdots w_{2m}^{i} u_{2m} \mid i \in \mathbb {N}\}\) , where w ₁?w _2n ≠ε. Whether every m-multiple context-free language L is 2m-iterative, that is to say, whether all but finitely many elements z of L can be written as z=u ₀ w ₁ u ₁?w _2m u _2m with w ₁?w _2m ≠ε and \(\{ u_{0} w_{1}^{i} u_{1} \cdots w_{2m}^{i} u_{2m} \mid i \in \mathbb {N}\} \subseteq L\) , has been open. We show that there is a 3-multiple context-free language that is not k-iterative for any k.