Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation

Breast cancer is the most frequent cancer in women worldwide and late diagnosis often adversely affects the prognosis of the disease. Radiotherapy is commonly used to treat breast cancer, reducing the risk of recurrence after surgery. However, the eradication of radioresistant cancer cells, including cancer stem cells, remains the main challenge of radiotherapy. Recently, lipid droplets (LDs) have been proposed as functional markers of cancer stem cells, also being involved in increased cell tumorigenicity. LD biogenesis is a multistep process requiring various enzymes, including Diacylglycerol acyltransferase 2 (DGAT2). In this context, we evaluated the effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays. Our results demonstrated that 72 h of PF-06424439 treatment reduced LD content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. In addition, the combined treatment negatively interfered with lipid metabolism-related genes, as well as with EMT gene expression, and modulated the expression of typical markers associated with the CSC-like phenotype. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness.     

Beyond Heparinization: Design of Highly Potent Thrombin Inhibitors Suitable for Surface Coupling

During extracorporeal circulation, when blood comes in contact with artificial surfaces, patients receive a standard treatment with anticoagulants to avoid blood coagulation. Dialysis patients in particular are systemically treated with heparin up to four times a week, causing a high burden for the body. For potential anticoagulant modification of external materials, such as dialysis equipment, a series of highly potent thrombin inhibitors was developed. All inhibitors share the general formula arylsulfonyl‐P3‐Pro‐4‐amidinobenzylamide, where P3 is glycyl or a trifunctional amino acid residue in L ‐configuration. Among this series, several derivatives inhibit thrombin with K_i values of less than 1 nM . Specificity measurements revealed that this inhibitor type is highly specific for thrombin with negligible activity against related trypsin‐like serine proteases. X‐ray analysis of the most potent analogue in complex with thrombin demonstrated that the N‐terminal arylsulfonyl group occupies the aryl binding site, whereas the P3 side chain is directed into the solvent and therefore is well suited for further coupling. Based on their in vitro profile, these inhibitors are suitable candidates for the development of hemocompatible materials with anticoagulant properties.     

Lastansätze bei Tragfähigkeitsnachweisen im Holzbau

Load formulations in ultimate limit state design of timber structures. With the issue of DIN 1052 the new safety concept has become state of the art even in design of timber structures. Especially the ultimate limit state design indicates a rather different procedure compared with the rules used up to now. The following contribution provides a working aid in order to make the design procedure for usual loads more transparent and clear.     

New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors?

The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling events termed unfolded protein response (UPR), activated as adaptative response to mitigate the ER stress condition. In this regard, calcium levels play a pivotal role in ER homeostasis and therefore in cell fate regulation since calcium signaling is implicated in a plethora of physiological processes, but also in disease conditions such as neurodegeneration, cancer and metabolic disorders. A large body of emerging evidence highlighted the functional role of TRP channels and their ability to promote cell survival or death depending on endoplasmic reticulum stress resolution, making them an attractive target. Thus, in this review we focused on the TRP channels’ correlation to UPR-mediated ER stress in disease pathogenesis, providing an overview of their implication in the activation of this cellular response.     

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc^−/−) and their wild type (Hdc^+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc^−/− and Hdc^+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc^+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.     

Solid‐state NMR and morphological studies of poly(ethylene‐co‐vinyl acetate)/poly(vinyl acetate) blends

To obtain a correlation among structure–morphology–mobility–compatibility properties of poly(ethylene‐co‐vinyl acetate) (EVA)/poly(vinyl acetate) (PVAc) blends, we have used scanning electron microscopy and solid‐state nuclear magnetic resonance in our investigations. The results are discussed in terms of blends, component dispersion, plasticization effect, and domain mobilities to acquire a response of the correlation between structural properties. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 2990–2996, 1999     

Electrokinetic removal of 2,6-dichlorophenol and diuron from kaolinite and humic acid-clay system

This paper presents the results of a study on the electrokinetic treatment of kaolinite and humic acid kaolinite complexes spiked with 2,6-dichlorophenol or 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron). In particular, the attention was paid to the interaction between solid surface and dissolved organics: the effects of contaminant sorption as well as the physicochemical reactions on the efficiency of electrokinetic remediation were investigated. Using a 3V/cm voltage gradient, approximately 90% of diuron was removed from kaolinite after one water pore volume was collected in the cathode reservoir, but much lower efficiency was obtained in the electrokinetic removal of this compound from humic acid-coated kaolinite. The results also showed that partial degradation of the contaminant occurred during electrokinetic treatment of kaolinite clay spiked with 2,6-dichlorophenol: the contamination in the clay could be remediated by the combination of electrokinetic extraction and electrochemical reactions.     

Über die Rolle der Flüssigkeits- und Gaseigenschaften in der Theorie mechanisch ähnlicher Strömungen

Zusammenfassung Die Arbeit befaßt sich mit der Frage, welche Materialeigenschaften ein strömendes Medium haben muß, damit mechanische Ähnlichkeit der Strömungsfelder möglich ist. Dabei ist zu unterscheiden, ob in Modell und Prototyp dasselbe Medium oder verschiedene Medien strömen. Ausgehend von den bekannten Forderungen, die in der Dimensionsanalysis an mechanisch ähnliche Strömungen gestellt werden, lassen sich notwendige und hinreichende Bedingungen für die Materialgleichungen des Mediums angeben. Strömungen dissoziierender Gase und Strömungen strahlender Gase werden als Beispiele behandelt, um die Anwendung der allgemeingültigen Überlegungen zu zeigen.

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On the role of fluid properties in the theory of mechanically similar flows

Summary The paper is concerned with the properties a fluid has to have to admit mechanical similarity of flow fields. Two cases are distinguished, wether or not the fluids in model and prototype are the same. Proceeding from the requirements that have to be met by mechanically similar flow fields, necessary and sufficient conditions are given for the constitutive equations of the fluids. The general concept is applied to the flow of dissociating gases and to the flow of thermally radiating gases.

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Zeichenerklärungen a _ik Exponent der Größeq _k im Ähnlichkeitsparameter _i - e innere Energie pro Masseneinheit - f Materialfunktion, vgl. Gl. (8) und (43) - L charakteristische Länge des Strömungsfeldes - n Anzahl der physikalischen Größen - p Druck - q _k k-te physikalische Größe - Q _k Materialkonstante mit der Dimension vonq _k , vgl. Gl. (43) - r Rang der Dimensionsmatrix - T absolute Temperatur - V Betrag der Strömungsgeschwindigkeit - _jk Exponent des Maßstabsfaktors _k in derj-ten Gleichung der Form (37) - _v , Volumen-Absorptionskoeffizient für nicht-graues bzw. graues Gas - _k Maßstabsfaktor für die Größeq _k , vgl. Gl. (12) - _k Quotient der MaterialkonstantenQ _k für Modell und Prototyp, vgl. Gl. (44) - 275-7 i-ter Ähnlichkeitsparameter - Dichte Indizea ref Referenzgrößen - red reduzierte (dimensionslose) Größen - - Modell Diese Arbeit wurde von der Fakultät für Maschinenwesen der Rheinisch-Westfälischen Technischen Hochschule Aachen als Habilitationsschrift genehmigt.