The Fight against Cancer by Microgravity: The Multicellular Spheroid as a Metastasis Model

Cancer is a disease exhibiting uncontrollable cell growth and spreading to other parts of the organism. It is a heavy, worldwide burden for mankind with high morbidity and mortality. Therefore, groundbreaking research and innovations are necessary. Research in space under microgravity (µg) conditions is a novel approach with the potential to fight cancer and develop future cancer therapies. Space travel is accompanied by adverse effects on our health, and there is a need to counteract these health problems. On the cellular level, studies have shown that real (r-) and simulated (s-) µg impact survival, apoptosis, proliferation, migration, and adhesion as well as the cytoskeleton, the extracellular matrix, focal adhesion, and growth factors in cancer cells. Moreover, the µg-environment induces in vitro 3D tumor models (multicellular spheroids and organoids) with a high potential for preclinical drug targeting, cancer drug development, and studying the processes of cancer progression and metastasis on a molecular level. This review focuses on the effects of r- and s-µg on different types of cells deriving from thyroid, breast, lung, skin, and prostate cancer, as well as tumors of the gastrointestinal tract. In addition, we summarize the current knowledge of the impact of µg on cancerous stem cells. The information demonstrates that µg has become an important new technology for increasing current knowledge of cancer biology.     

纤维基材料的仿生学研究动向

纤维基技术的应用对仿生学的成功发展呈现出巨大的潜力,因为宇宙成物在生长过程、多毛结构和增强纤维方面具有许多相似性.约七年前,邓肯道夫纺织技术与工艺研究所协同众位生物学家一起开创了仿生学的研发,至今方兴未艾.     

Perception of plant species richness by people with different nationalities—an experimental study

This study investigates with the help of a manipulative experiment how people with different nationalities perceive meadow-like arrays of different species richness (1, 8, 16, 32, 64 species). Participants (n = 187) were all residents of the canton of Zurich and originated from 43 different countries. Overall valuation of the meadow-like arrays increased with species richness. However, while participants from high-income countries (measured by GDP per capita) clearly liked species-rich meadows most and species-poor ones least, participants from low-income countries did not have such clear preferences. Preferences were not related to the length of time a participant had already spent in Switzerland (on average seven years), but to perceived familiarity with a meadow-like array. Sex and education did not influence valuations. Environmental expertise fostered participants’ dislike of species-poor arrays, as did age.     

Concerted utility review of VVER-440 safety research needs (VERSAFE)

There are twelve operating VVER-440/213 reactors in the Czech Republic, Hungary and Slovakia. The plant owners have carried out extensive safety enhancement programmes, which have included measures to improve prevention, mitigation and control of design basis accidents. Recently, there have been a number of projects to study the Severe Accident Management aspects of these plants. The plant owners have also initiated Plant Life Management programmes. The objective of the VERSAFE Concerted Action is to create a network of the VVER-440/213 plant owners and operators, which aims at definition of the further research needs of severe accidents and plant ageing from the utilities’ viewpoint. The starting point is to formulate a general approach to severe accident management and plant life management and then proceed to define the needs for the additional information expected from the safety research. The role of national research institutes and organisations of the partner countries is of crucial importance in performing such research and, thus, creating and maintaining the expertise on the national level. The successful completion of the project will assist in establishing well-defined research projects that are oriented to the needs of the end-users and provide information that can be used to facilitate and support the negotiations of the EU applicant countries operating VVER-440 reactors.     

Synthesis and Characterization of Telmisartan-Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia

New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death-modulating effects of the telmisartan-derived lead 4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid ( 3 b ) was investigated. Inspired by the pharmacodynamics of HYL-6d and the selective PPARγ ligand VSP-51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2-COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60-100 % activation. Among the 2-CO₂CH₃ derivatives, only the ester of the lead ( 2 b ) slightly activated PPARγ. Sensitizing effects were further observed for this non-cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5-Br-substituted ester of the benzimidazoles ( 5 b ).     

Use of copper shavings to remove mercury from contaminated groundwater or wastewater by amalgamation

The efficacy of copper shavings (Cu(0)) for the removal of Hg2+ from aqueous solution by amalgamation is demonstrated. Two kinds of copper shavings were investigated: (a) chemically processed shavings (Fluka) and (b) recycled shavings from scrap metal. Batch sorption experiments yielded very high retardation coefficients of 28 850-82 830 for the concentration range studied (1-10 000 microg/L Hg2+ dissolved in distilled water or in a 0.01 M CaCl2 matrix solution). Sorption data were well-described bythe Freundlich isotherm equation. Kinetic batch sorption experiments showed that 96-98% of Hg2+ was removed within 2 h. Column experiments were performed with a mercury solution containing 1000 microg/L Hg in a 0.01 M CaCl2 matrix with a flow rate of 0.5 m/d. No mercury breakthrough (c/c(0) = 0.5) could be detected after more than 2300 percolated pore volumes, and the high retardation coefficients determined in the batch studies could be confirmed. Copper was released from the shavings due to the amalgamation process and to copper corrosion by oxygen, resulting in concentrations of mobilized copper of 0.2-0.6 mg/L. Due to their high efficiency in removing Hg2+ from aqueous solution, the use of copper shavings for the removal of mercury from contaminated water is suggested, employing a sequential system of mercury amalgamation followed by the removal of mobilized copper by an ion exchanger such as zeolites. Possible applications could be in environmental technologies such as wastewater treatment or permeable reactive barriers for in situ groundwater remediation.     

Mass Spectrometric Assays Reveal Discrepancies in Inhibition Profiles for the SARS-CoV-2 Papain-Like Protease

The two SARS-CoV-2 proteases, i. e. the main protease (M^pro) and the papain-like protease (PL^pro), which hydrolyze the viral polypeptide chain giving functional non-structural proteins, are essential for viral replication and are medicinal chemistry targets. We report a high-throughput mass spectrometry (MS)-based assay which directly monitors PL^pro catalysis in vitro. The assay was applied to investigate the effect of reported small-molecule PL^pro inhibitors and selected M^pro inhibitors on PL^pro catalysis. The results reveal that some, but not all, PL^pro inhibitor potencies differ substantially from those obtained using fluorescence-based assays. Some substrate-competing M^pro inhibitors, notably PF-07321332 (nirmatrelvir) which is in clinical development, do not inhibit PL^pro. Less selective M^pro inhibitors, e. g. auranofin, inhibit PL^pro, highlighting the potential for dual PL^pro/M^pro inhibition. MS-based PL^pro assays, which are orthogonal to widely employed fluorescence-based assays, are of utility in validating inhibitor potencies, especially for inhibitors operating by non-covalent mechanisms.     

(Z,Z)-4,7-tridecadien-(S)-2-yl acetate: sex pheromone of Douglas-fir cone gall midge,Contarinia oregonensis

Our objectives were to identify and field test the sex pheromone of female Douglas-fir cone gall midge, Contarinia oregonensis (Diptera: Cecidomyiidae). Coupled gas chromatographic–electroantennographic detection (GC-EAD) analyses of pheromone extract revealed a single compound (A) that elicited responses from male antennae. Hydrogenation of pheromone extract, followed by renewed GC-EAD analysis, revealed a new EAD-active compound with chromatographic characteristics identical to those of tridecan-2-yl acetate on five fused silica columns (DB-5, DB-210, DB-23, SP-1000, and Cyclodex-B). Syntheses, chromatography, and retention index calculations of all possible tridecen-2-yl acetates suggested that the candidate pheromone A was a tridecadien-2-yl acetate with nonconjugated double bonds. Synthetic candidate pheromone component (Z,Z)-4,7-tridecadien-2-yl acetate (Z4Z7) cochromatographed with A on all analytical columns and elicited comparable antennal activity. In GC-EAD analyses that separated the enantiomers (Z,Z)-4,7-tridecadien-(S)-2-yl acetate (2S-Z4Z7) and (Z,Z)-4,7-tridecadien-(R)-2-yl acetate (2R-Z4Z7) with baseline resolution, only 2S-Z4Z7 as a component in a racemic standard or in pheromone extract elicited antennal responses. In Douglas-fir seed orchards, sticky traps baited with 2S-Z4Z7 captured male C. oregonensis, whereas 2R-Z4Z7 was behaviorally benign. Comparable catches of males in traps baited with racemic Z4Z7 (50 g) or virgin female C. oregonensis suggested that synthetic pheromone baits could be developed for monitoring C. oregonensis populations in commercial Douglas-fir seed orchards.     

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.     

MicroRNA-16 Restores Sensitivity to Tyrosine Kinase Inhibitors and Outperforms MEK Inhibitors in KRAS-Mutated Non-Small Cell Lung Cancer

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the KRAS oncogene define a subclass that cannot benefit from tyrosine kinase inhibitors (TKIs). The tumor suppressor miR-16 is downregulated in many human cancers, including NSCLC. The main objectives of this study were to evaluate miR-16 treatment to restore the TKI sensitivity and compare its efficacy to MEK inhibitors in KRAS-mutated NSCLC. Methods: We performed in vitro and in vivo studies to investigate whether miR-16 could be exploited to overcome TKI resistance in KRAS-mutated NSCLC. We had three goals: first, to identify the KRAS downstream effectors targeted by mir-16, second, to study the effects of miR-16 restoration on TKI resistance in KRAS-mutated NSCLC both in vitro and in vivo, and finally, to compare miR-16 and the MEK inhibitor selumetinib in reducing KRAS-mutated NSCLC growth in vitro and in vivo. Results: We demonstrated that miR-16 directly targets the three KRAS downstream effectors MAPK3, MAP2K1, and CRAF in NSCLC, restoring the sensitivity to erlotinib in KRAS-mutated NSCLC both in vitro and in vivo. We also provided evidence that the miR-16–erlotinib regimen is more effective than the selumetinib–erlotinib combination in KRAS-mutated NSCLC. Conclusions: Our findings support the biological preclinical rationale for using miR-16 in combination with erlotinib in the treatment of NSCLC with KRAS-activating mutations.