Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.     

Syndecan-1 (CD138), Carcinomas and EMT

Cell surface proteoglycans are known to be important regulators of many aspects of cell behavior. The principal family of transmembrane proteoglycans is the syndecans, of which there are four in mammals. Syndecan-1 is mostly restricted to epithelia, and bears heparan sulfate chains that are capable of interacting with a large array of polypeptides, including extracellular matrix components and potent mediators of proliferation, adhesion and migration. For this reason, it has been studied extensively with respect to carcinomas and tumor progression. Frequently, but not always, syndecan-1 levels decrease as tumor grade, stage and invasiveness and dedifferentiation increase. This parallels experiments that show depletion of syndecan-1 can be accompanied by loss of cadherin-mediated adhesion. However, in some tumors, levels of syndecan-1 increase, but the characterization of its distribution is relevant. There can be loss of membrane staining, but acquisition of cytoplasmic and/or nuclear staining that is abnormal. Moreover, the appearance of syndecan-1 in the tumor stroma, either associated with its cellular component or the collagenous matrix, is nearly always a sign of poor prognosis. Given its relevance to myeloma progression, syndecan-1-directed antibody—toxin conjugates are being tested in clinical and preclinical trials, and may have future relevance to some carcinomas.     

New Insights into the Pathogenesis of Systemic Mastocytosis

Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.     

Influence of α′‐/α‐crystal polymorphism on properties of poly(l‐lactic acid)

Poly(l ‐lactic acid) (PLLA) is a biodegradable and biocompatible thermoplastic polyester produced from renewable sources, widely used for biomedical devices, in food packaging and in agriculture. It is a semicrystalline polymer, and as such its properties are strongly affected by the developed semicrystalline morphology. As a function of the crystallization temperature, PLLA can form different crystal modifications, namely α′‐crystals below about 120 °C and α‐crystals at higher temperatures. The α′ modification is therefore of special importance as it may be the preferred polymorph developing at processing‐relevant conditions. It is a metastable modification which typically transforms into the more stable α‐crystals on annealing at elevated temperature. The structure, kinetics of formation and thermodynamics of α′‐ and α‐crystals of PLLA are reviewed in this contribution, together with the effect of α′‐/α‐crystal polymorphism on the properties of PLLA. © 2018 Society of Chemical Industry     

Nanotechnology‐based wastewater treatment

Water contamination is a global challenge impacting both the environment and human health with significant economic and social costs. The growing scarcity of usable water resources requires effective treatment of wastewater. In this context, developing cheaper, safer and more efficient wastewater treatment technologies are the need of the hour. One promising approach that several studies have reported success has been the usage of nanomaterials in water and waste water management. The rapid progress of research in nanomaterial sciences has shown their growing potential; however, there has not been a great amount of information available on their implementation. This review focuses on developments in nanotechnology that hold strong potential for wastewater treatment. The review covers key techniques in nanomaterial‐based water treatments including adsorption, filtration and photocatalysis with recent examples showing how to improve their properties and efficiencies according to the need.     

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2^Mal, has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue GluCAB-1^Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) effect with a supportive role played by glucose metabolism. [⁶⁴Cu]Cu-GluCAB-2^Mal (99 % RCP) exhibited high serum stability with immediate binding to serum proteins. In vivo experiments for comparison between tumor targeting of [⁶⁴Cu]Cu-GluCAB-2^Mal and previous-generation [⁶⁴Cu]Cu-GluCAB-1^Mal encompassed microPET/CT imaging and biodistribution analysis in an allograft E0771 breast cancer mouse model. Tumor uptake of [⁶⁴Cu]Cu-GluCAB-2^Mal was clearly evident with twice as much accumulation as compared to its predecessor and a tumor/muscle ratio of up to 5 after 24 h. Further comparison indicated a decrease in liver accumulation for [⁶⁴Cu]Cu-Glu-CAB-2^Mal.     

Effects of upholstery materials on the burning behavior of real‐scale residential upholstered furniture mock‐ups

Fire spread and growth on real‐scale four cushion mock‐ups of residential upholstered furniture (RUF) were investigated with the goal of identifying whether changes in five classes of materials (barrier, flexible polyurethane foam, polyester fiber wrap, upholstery fabric, and sewing thread), referred to as factors, resulted in statistically significant changes in burning behavior. A fractional factorial experimental design plus practical considerations yielded a test matrix with 20 material combinations. Experiments were repeated a minimum of two times. Measurements included fire spread rates derived from video recordings and heat release rates (HRRs). A total of 13 experimental parameters (3 based on the videos and 10 on the HRR results), referred to as responses, characterized the measurements. Statistical analyses based on Main Effects Plots (main effects) and Block Plots (main effects and factor interactions) were used. The results showed that three of the factors resulted in statistically significant effects on varying numbers of the 13 responses. The Barrier and Fabric factors had the strongest main effects with roughly comparable magnitudes. Foam was statistically significant for fewer of the responses and its overall strength was weaker than for Barrier and Fabric. No statistically significant main effects were identified for Wrap or Thread. Multiple two‐term interactions between factors were identified as being statistically significant. The Barrier*Fabric interaction resulted in the highest number of and strongest statistically significant effects. The existence of two‐term interactions means that it will be necessary to consider their effects in approaches designed to predict the burning behavior of RUF.     

Preparation and Evaluation of a Self-Nanoemulsifying Drug Delivery System Loaded with Heparin Phospholipid Complex

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the absorption of heparin after oral administration, in which heparin was compounded with phospholipids to achieve better fat solubility in the form of heparin-phospholipid (HEP-Pc) complex. HEP-Pc complex was prepared using the solvent evaporation method, which increased the solubility of heparin in n-octanol. The successful preparation of HEP-Pc complex was confirmed by differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, NMR, and SEM. A heparin lipid microemulsion (HEP-LM) was prepared by high-pressure homogenization and characterized. HEP-LM can enhance the absorption of heparin after oral administration, significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) in mice, and reduce fibrinogen (FIB) content. All these outcomes indicate that HEP-LM has great potential as an oral heparin formulation.