Open Access

Background: Cancer heterogeneity poses a serious challenge concerning the toxicity and adverse effects of therapeutic inhibitors, especially when it comes to combinatorial therapies that involve multiple targeted inhibitors. In particular, in non-small cell lung cancer (NSCLC), a number of studies have reported synergistic effects of drug combinations in the preclinical models, while they were only partially successful in the clinical setup, suggesting those alternative clinical strategies (with genetic background and immune response) should be considered. Herein, we investigated the antitumor effect of cytokine-induced killer (CIK) cells in combination with ALK and PD-1 inhibitors in vitro on genetically variable NSCLC cell lines. Methods: We co-cultured the three genetically different NSCLC cell lines NCI-H2228 (EML4-ALK), A549 (KRAS mutation), and HCC-78 (ROS1 rearrangement) with and without nivolumab (PD-1 inhibitor) and crizotinib (ALK inhibitor). Additionally, we profiled the variability of surface expression multiple immune checkpoints, the concentration of absolute dead cells, intracellular granzyme B on CIK cells using flow cytometry as well as RT-qPCR. ELISA and Western blot were performed to verify the activation of CIK cells. Results: Our analysis showed that (a) nivolumab significantly weakened PD-1 surface expression on CIK cells without impacting other immune checkpoints or PD-1 mRNA expression, (b) this combination strategy showed an effective response on cell viability, IFN-g production, and intracellular release of granzyme B in CD3+ CD56+ CIK cells, but solely in NCI-H2228, (c) the intrinsic expression of Fas ligand (FasL) as a T-cell activation marker in CIK cells was upregulated by this additive effect, and (d) nivolumab induced Foxp3 expression in CD4+CD25+ subpopulation of CIK cells significantly increased. Taken together, we could show that CIK cells in combination with crizotinib and nivolumab can enhance the anti-tumor immune response through FasL activation, leading to increased IFN-g and granzyme B, but only in NCI-H2228 cells with EML4-ALK rearrangement. Therefore, we hypothesize that CIK therapy may be a potential alternative in NSCLC patients harboring EML4-ALK rearrangement, in addition, we support the idea that combination therapies offer significant potential when they are optimized on a patient-by-patient basis.

Typically, plastic packaging materials are produced using additives, like e.g. stabilisers, to introduce specific desired properties into the material or, in case of stabilisers, to prolong the shelf life of such packaging materials. However, those stabilisers are typically fossil-based and can pose risks to both environmental and human health. Therefore, the present study presents more sustainable alternatives based on regional renewable resources which show the relevant antioxidant, antimicrobial and UV absorbing properties to successfully serve as a plastic stabiliser. In the study, all plants are extracted and characterised with regard to not only antioxidant, antimicrobial and UV absorbing effects, but also with regard to additional relevant information like chemical constituents, molar mass distribution, absorbance in the visible range et cetera. The extraction process is furthermore optimised and, where applicable, reasonable opportunities for waste valorisation are explored and analysed. Furthermore, interactions between analysed plant extracts are described and model films based on Poly-Lactic Acid are prepared, incorporating analysed plant extracts. Based on those model films, formulation tests and migration analysis according to EU legislation is conducted. The well-known aromatic and medicinal plant thyme (Thymus vulgaris L.) includes phenolic terpenoids like thymol and carvacrol which have strong antioxidant, antimicrobial and UV absorbing effects. Analyses show that those effects can be used in both lipophilic and hydrophilic surroundings, that the variant Varico 3 is a more potent cultivar than other analysed thyme variants, and that a passive extraction setup can be used for extract preparation while distillation of the Essential Oils can be a more efficient approach. Macromolecular antioxidant polyphenols, particularly proanthocyanidins, have been found in the seed coats of the European horse chestnut (Aesculus hippocastanum L.) which are regularly discarded in phytopharmaceutical industry. In this study, such effects and compounds have been reported for the first time while a valorisation of waste materials has been analysed successfully. Furthermore, a passive extraction setup for waste materials and whole seeds has been developed. In extracts of snowdrops, precisely Galanthus elwesii HOOK.F., high concentrations of tocopherol have been found which promote a particularly high antioxidant capacity in lipophilic surroundings. Different coniferous woods (Abies div., Picea div.) which are in use as Christmas trees are extracted after separating the biomass in leafs and wood parts before being analysed regarding extraction optimisation and drought resistance of active substances. Antioxidant and UV absorbing proanthocyanidins are found even in dried biomasses, allowing the circular use of already used Christmas trees as bio-based stabilisers and the production of sustainable paper as a byproduct.

An aircraft plume model has been developed on the basis of two coupled trajectory box models. Two boxes, one for plume and one for background conditions, are coupled by means of a mixing parameterization based on turbulence theory. The model considers comprehensive gas phase chemistry for the tropopause region including acetone, ethane and their oxidation products. Heterogeneous halogen, N2O5 and HOx chemistry on various types of background and aircraft-induced aerosols (liquid and ice) is considered, using state-of-the-art solubility dependent uptake coefficients for liquid phase reactions. The microphysical scheme allows for coagulation, gas-diffusive particle growth and evaporation, so that the particle development from 1s after emission to several days can be simulated. Model results are shown, studying emissions into the upper troposphere as well as into the lowermost stratosphere for contrail and non-contrail conditions. We show the microphysical and chemical evolution of spreading plumes and use the concept of mean plume encounter time, tl, to define effective emission and perturbation indices (EEIs and EPIs) for the North Atlantic Flight Corridor (NAFC) showing EEI(NOy) and EPI(O3) for various background conditions, such as relative humidity, local time of emission, and seasonal variations. Our results show a high sensitivity of EEI and EPIs on the exact conditions under which emissions take place. The difference of EEIs with and without considering plume processes indicates that these processes cannot be neglected.

This report has been prepared by the SETAC Europe Scientific Task Group on Global And RegionaL Impact Categories (SETAC-Europe/STG-GARLIC) that is installed by the 2nd SETAC Europe working group on life cycle impact assessment (WIA-2). This document is background to a chapter written by the same authors under the title “Climate change, stratospheric ozone depletion, photo-oxidant formation, acidification and eutrophication” in Udo de Haes et al. (2002). The chapter summarises the work of the STG-GARLIC and aims to give a state-of-the-art review of the best available practice(s) regarding category indicators and lists of concomitant characterisation factors for climate change, stratospheric ozone depletion, photo-oxidant formation, acidification, and aquatic and terrestrial eutrophication. Backgrounds on each of the specific impact categories are given in another background report from Klöpffer and Potting (2001). This background report provides details on a selection of general issues relevant in relation to LCA and characterisation of impact in LCA. The document starts with a short introduction of the LCA methodology and impact assessment in LCA for non LCA-experts. LCA experts, on the other hand, will usually not be familiar in-depth with scientific and political backgrounds of the specific impact categories. A review of this is given. Also the discussion is provided about the issue of the position of the category indicator in the causality chain, and into the related issue of spatial differentiation. These two issues appeared to be one of the core items for SETAC-Europe/STG-GARLIC.