The Effects of the Alkaloid Tambjamine J on Mice Implanted with Sarcoma 180 Tumor Cells

The tambjamines are a small group of bipyrrolic alkaloids that, collectively, display a significant range of biological activities including antitumor, antimicrobial and immunosuppressive properties. The key objective of the present study was to undertake preclinical assessments of tambjamine J (T-J) so as to determine its in vivo antitumor effects. To that end, sarcoma 180 cells were transplanted in mice and the impacts of the title compound then evaluated using a range of protocols including hematological, biochemical, histopathological, genotoxic and clastogenic assays. As a result it was established that this alkaloid has a significant therapeutic window and effectively reduces tumor growth (by 40 % and 79 % at doses of 10 and 20 mg/kg/day, respectively). In this regard it displays similar antitumor activity to the anticancer agent cyclophosphamide and alters animal weight in an analogous manner.     

Funktionalisierte Kern-Schale-Partikel als Träger zur Enzymimmobilisierung und deren Anwendung

Mono- and bifunctional hybrid core-shell particles were used for enzyme immobilization. Ideal conditions for enzyme immobilization were evaluated based on monofunctional poly(2-dimethylamino)ethyl methacrylate-modified particles. Then, the obtained results were transferred to a bifunctional Janus particle system, which should simultaneously enable enzyme immobilization, switchable separation, and reuse of the enzyme. Finally, application of the system was exemplarily demonstrated by multiple discoloration of textile industry process water with laccase and a cost estimation is presented.     

Behavior of partially hydrolyzed polyacrylamide/polyethyleneimine reinforced with coal fly ash for preformed particle hydrogels

High water production and low oil recovery are attributable to reservoir heterogeneity, making extraction economically inefficient. To improve oil production, it is important to solve permeability issues, to allow a more uniform and efficient sweep. In recent years, several studies of preformed particle gel (PPG) have been performed reduce reservoir heterogeneity and enhance oil recovery. In this work, the effect of coal fly ash (CFA) on hydrolyzed polyacrylamide (PHPA) crosslinked with polyethyleneimine PPG were evaluated regarding thermal, rheological, and structural properties. The rheological results showed an increase in elastic behavior with the presence of CFA. Thermal analysis revealed degradation resistance of 271% with only 1.0% CFA. The swelling test proved that the presence of CFA supports the absorption of a brine solution. The results suggest a significant increase in properties assessed with small CFA contents due to a strong interaction between CFA and three-dimensional polymer networks.     

High-temperature phase and microstructure evolution of polymer-derived SiZrCN and SiZrBCN ceramic nanocomposites

A zirconium and a zirconium/boron containing single-source precursor were synthesized via chemical modification of a commercially available polysilazane (Durazane 1800) with tetrakis (dimethylamido) zirconium (IV) (TDMAZ) as well as with both TDMAZ and borane dimethyl sulfide complex, respectively. The polymer-to-ceramic transformation of the precursors into SiZrCN and SiZrBCN ceramics as well as the thermal evolution of their phase composition and microstructure was studied. The pyrolysis of the precursors led to the formation of amorphous SiZrCN and SiZrBCN ceramics. Interestingly, the as prepared SiZrBCN ceramic was single-phasic and fully featureless; whereas SiZrCN exhibited the presence of nano-sized ZrO₂ particles; however, only very localized in close proximity to internal surfaces. Heat treatment at higher temperatures induced crystallization processes in both prepared ceramics. Thus, at temperatures beyond 1500°C, cubic ZrC_xN_y, β-Si₃N₄ as well as β-SiC were generated. It was shown that the incorporation of B into SiZrCN suppressed the crystallization of ZrC_xN_y and, in addition, impeded the reaction of SiN_x with C, resulting in an improved thermal stability of SiZrBCN compared to SiZrCN ceramic. Moreover boron was shown to be mainly located in the sp²-hybridized “free” carbon present in SiZrBCN, forming a turbostratic BCN phase which has been unequivocally detected by means of high-resolution transmission electron microscopy (HRTEM) and energy-dispersive X-ray spectroscopy (EDS).     

Pentathiepins: A Novel Class of Glutathione Peroxidase 1 Inhibitors that Induce Oxidative Stress,Loss of Mitochondrial Membrane Potential and Apoptosis in Human Cancer Cells

A novel class of glutathione peroxidase 1 (GPx1) inhibitors, namely tri- and tetracyclic pentathiepins, has been identified that is approximately 15 times more potent than the most active known GPx1 inhibitor, mercaptosuccinic acid. Enzyme kinetic studies with bovine erythrocyte GPx1 indicate that pentathiepins reversibly inhibit oxidation of the substrate glutathione (GSH). Moreover, no inhibition of superoxide dismutase, catalase, thioredoxin reductase or glutathione reductase was observed at concentrations that effectively inhibit GPx1. As well as potent enzyme inhibitory activity, the pentathiepins show strong anticancer activity in various human cancer cell lines, with IC₅₀ values in a low-micromolar range. A representative tetracyclic pentathiepin causes the formation of reactive oxygen species in these cells, the fragmentation of nuclear DNA and induces apoptosis via the intrinsic pathway. Moreover, this pentathiepin leads to a rapid and strong loss of mitochondrial membrane potential in treated cancer cells. On the other hand, evidence for the induction of ferroptosis as a form of cell death was negative. These new findings show that pentathiepins possess interesting biological activities beyond those originally ascribed to these compounds.     

Procurement decisions and information sharing under multi-tier disruption risk in a supply chain

We consider a manufacturer's procurement decision in a three-tier supply chain (SC) under disruption risk. The manufacturer sources components from a single first-tier supplier (FT). The FT, in turn, sources raw materials from a single second-tier supplier (ST). Suppliers in both tiers are unreliable, i.e. prone to disruption risk. Increasing SC visibility through information sharing is a potential disruption management strategy for the manufacturer. While the manufacturer can obtain disruption risk information for the FT, disruption risk information for the ST is not easily accessible to the manufacturer except through the FT, who may not be willing to share ST information. We study different mechanisms under which the manufacturer can obtain ST information, and its impact on manufacturer's and FT's decisions and potential profits. We show that information sharing makes the manufacturer's procurement decisions more conservative, i.e. carrying more inventories, but the FT's procurement decision is contingent on the ST's reliability; more proactive (conservative) when ST is unreliable (reliable), i.e. carrying less (more) inventories. We demonstrate that there are two ways to induce the FT to share its information, and numerically show that their effectiveness is contingent on multiple factors, including FT and ST reliabilities and information sharing costs.     

Optimal consumption decisions of family networks with similar felicity functions

Family networks have increased at an accelerated pace through social networking through social networking services, online platforms, and social media clubs. This paper develops a model of an economy populated by networks of families with similar preferences (the same functional form of the felicity or utility function) but family members differ in their deep parameters (compulsion for consumption and risk tolerance), which, in turn, leads to some kind o heterogeneity among the families. In this context, the problem of felicity (utility) maximization of the average family in the network is solved. The optimal path of consumption is obtained for the average family and graphical comparative static exercises are performed. Finally, the economic welfare of the typical family in a network is calculated and comparative static experiments are carried out. This approach improves the understanding of the consumption decision making of families interacting in social networking services.

     

Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence

Irreparable double-strand breaks (DSBs) in response to ionizing radiation (IR) trigger prolonged DNA damage response (DDR) and induce premature senescence. Profound chromatin reorganization with formation of senescence-associated heterochromatin foci (SAHF) is an essential epigenetic mechanism for controlling the senescence-associated secretory phenotype (SASP). To decipher molecular mechanisms provoking continuous DDR leading to premature senescence, radiation-induced DSBs (53BP1-foci) and dynamics of histone variant H2A.J incorporation were analyzed together with chromatin re-modeling in human fibroblasts after IR exposure. High-resolution imaging by transmission electron microscopy revealed that persisting 53BP1-foci developed into DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), consistently located at the periphery of SAHFs. Quantitative immunogold-analysis by electron microscopy revealed that H2A.J, steadily co-localizing with 53BP1, is increasingly incorporated into DNA-SCARS during senescence progression. Strikingly, shRNA-mediated H2A.J depletion in fibroblasts modified senescence-associated chromatin re-structuring and abolished SASP, thereby shutting down the production of inflammatory mediators. These findings provide mechanistic insights into biological phenomena of SASP and suggest that H2A.J inhibition could ablate SASP, without affecting the senescence-associated growth arrest.     

Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus’ immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.