Patient-Derived Organoids as a Model for Cancer Drug Discovery

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.     

High-temperature stabilization of polypropylene using hindered phenol–thioester stabilizer combinations,Part 1: Optimization and efficacy via nondust blends

The thermal degradation of unstabilized polypropylene has been investigated under long-term processing (twin extruder) and thermal aging at 150°C, with additive concentration studies on combinations of an established hindered phenolic antioxidant (pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate) [S1010] and two popular thioesters (distearyl-3,3′-thiodipropionate [DSTDP] and didodecyl-3,3′-thiodipropionate [DLTDP]) using melt flow rate, carbonyl index and powder diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) (FTIR), and differential scanning calorimetry (DSC) (oxidation induction time [OIT]) and ultimate embrittlement time (Fracture) on injection-molded test pieces. It was found that 20:80 phenol:thioester ratios provided the best long-term thermal stability (LTTS); however, this was the reverse for processing stabilization (80:20), underlining the antioxidant nature of the two stabilizers (long term vs. melt). Melt preblending of the stabilizers (to form a no-dust blend) gave rise to improved LTTS. DRIFTS FTIR indicated that there was an improvement in preblending the additives, which removed any volatile impurities. Increased additive dispersion and localized potential efficacy in the stabilization cycle is important, as well as possible improved addition of the additives to the extruder rather than fine powder. The data are discussed in relation to the long-term stabilization of polypropylene in high-temperature applications such as under the bonnet of automobiles where minimizing stabilizer losses and maximizing synergy are important.     

Cyclooxygenase Inhibition Alters Proliferative,Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro

Prostaglandin E₂ (PGE₂) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE₂ receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE₂ and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE₂ in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE₂. In T98G cells exogenous PGE₂ increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE₂ signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.     

Towards an integrated neonatal brain and cardiac examination capability at 7 T: electromagnetic field simulations and early phantom experiments using an 8-channel dipole array

Objective

Neonatal brain and cardiac imaging would benefit from the increased signal-to-noise ratio levels at 7 T compared to lower field. Optimal performance might be achieved using purpose designed RF coil arrays. In this study, we introduce an 8-channel dipole array and investigate, using simulations, its RF performances for neonatal applications at 7 T.

Methods

The 8-channel dipole array was designed and evaluated for neonatal brain/cardiac configurations in terms of SAR efficiency (ratio between transmit-field and maximum specific-absorption-rate level) using adjusted dielectric properties for neonate. A birdcage coil operating in circularly polarized mode was simulated for comparison. Validation of the simulation model was performed on phantom for the coil array.

Results

The 8-channel dipole array demonstrated up to 46% higher SAR efficiency levels compared to the birdcage coil in neonatal configurations, as the specific-absorption-rate levels were alleviated. An averaged normalized root-mean-square-error of 6.7% was found between measured and simulated transmit field maps on phantom.

Conclusion

The 8-channel dipole array design integrated for neonatal brain and cardiac MR was successfully demonstrated, in simulation with coverage of the baby and increased SAR efficiency levels compared to the birdcage. We conclude that the 8Tx-dipole array promises safe operating procedures for MR imaging of neonatal brain and heart at 7 T.

     

Electrochemical Quantification of Neurotransmitters in Single Live Cell Vesicles Shows Exocytosis is Predominantly Partial

Exocytosis plays an essential role in the communication between cells in the nervous system. Understanding the regulation of neurotransmitter release during exocytosis and the amount of neurotransmitter content that is stored in vesicles is of importance, as it provides fundamental insights to understand how the brain works and how neurons elicit a certain behavior. In this minireview, we summarize recent progress in amperometric measurements for monitoring exocytosis in single cells and electrochemical cytometry measurements of vesicular neurotransmitter content in individual vesicles. Important steps have increased our understanding of the different mechanisms of exocytosis. Increasing evidence is firmly establishing that partial release is the primary mechanism of release in multiple cell types.     

Structural insights into peptide self-assembly using photo-induced crosslinking experiments and discontinuous molecular dynamics

Determining the structure of the (oligomeric) intermediates that form during the self-assembly of amyloidogenic peptides is challenging because of their heterogeneous and dynamic nature. Thus, there is need for methodology to analyze the underlying molecular structure of these transient species. In this work, a combination of fluorescence quenching, photo-induced crosslinking (PIC) and molecular dynamics simulation was used to study the assembly of a synthetic amyloid-forming peptide, Aβ_16-22. A PIC amino acid containing a trifluormethyldiazirine (TFMD) group—Fmoc(TFMD)Phe—was incorporated into the sequence (Aβ*_16–22). Electrospray ionization ion-mobility spectrometry mass-spectrometry (ESI-IMS-MS) analysis of the PIC products confirmed that Aβ*_16–22 forms assemblies with the monomers arranged as anti-parallel, in-register β-strands at all time points during the aggregation assay. The assembly process was also monitored separately using fluorescence quenching to profile the fibril assembly reaction. The molecular picture resulting from discontinuous molecule dynamics simulations showed that Aβ_16-22 assembles through a single-step nucleation into a β-sheet fibril in agreement with these experimental observations. This study provides detailed structural insights into the Aβ_16-22 self-assembly processes, paving the way to explore the self-assembly mechanism of larger, more complex peptides, including those whose aggregation is responsible for human disease.     

Engineering Silver-Enriched Copper Core-Shell Electrocatalysts to Enhance the Production of Ethylene and C2+ Chemicals from Carbon Dioxide at Low Cell Potentials

Copper catalysts are widely studied for the electroreduction of carbon dioxide (CO₂) to value-added hydrocarbon products. Controlling the surface composition of copper nanomaterials may provide the electronic and structural properties necessary for carbon-carbon coupling, thus increasing the Faradaic efficiency (FE) towards ethylene and other multi-carbon (C₂₊) products. Synthesis and catalytic study of silver-coated copper nanoparticles (Cu@Ag NPs) for the reduction of CO₂ are presented. Bimetallic CuAg NPs are typically difficult to produce due to the bulk immiscibility between these two metals. Slow injection of the silver precursor, concentrations of organic capping agents, and gas environment proved critical to control the size and metal distribution of the Cu@Ag NPs. The optimized Cu@Ag electrocatalyst exhibited a very low onset cell potential of −2.25 V for ethylene formation, reaching a FE towards C₂₊ products (FE_C2+) of 43% at −2.50 V, which is 1.0 V lower than a reference Cu catalyst to reach a similar FE_C2+. The high ethylene formation at low potentials is attributed to enhanced C C coupling on the Ag enriched shell of the Cu@Ag electrocatalysts. This study offers a new catalyst design towards increasing the efficiency for the electroreduction of CO₂ to value-added chemicals.     

Labeling and Characterization of Phenol-Containing Glycopeptides Using Chemoselective Probes with Isotope Tags

Secondary metabolites are structurally diverse natural products (NPs) and have been widely used for medical applications. Developing new tools to enrich NPs can be a promising solution to isolate novel NPs from the native and complex samples. Here, we developed native and deuterated chemoselective labeling probes to target phenol-containing glycopeptides by the ene-type labeling used in proteomic research. The clickable azido-linker was included for further biotin functionalization to facilitate the enrichment of labeled substrates. Afterward, our chemoselective method, in conjunction with LC-MS and MSn analysis, was demonstrated in bacterial cultures. A vancomycin-related phenol-containing glycopeptide was labeled and characterized by our labeling strategy, showing its potential in glycopeptide discovery in complex environments.     

SnowedOut Atlanta: Examining digital emergence on facebook during a crisis

Individuals in emergencies form spontaneous, emergent groups to respond and recover. With the rise of social media use in crises, academics and professionals must be aware of how groups digitally coordinate emergent response efforts. This paper examines digital emergence through the case of SnowedOut Atlanta, a Facebook group formed during the 2014 ice storms in Atlanta. The posts and actions of the group members are in line with those of traditional emergent groups. For example, group members shared informational, material, and emotional support. The findings also provide implications for practitioners and insight into the communication of such groups. In particular, emergency managers have an opportunity to seek out and partner with these types of groups in future similar events.     

Misconceptions of human factors concepts

Abstract

Like many scientific topics, Human Factors, and Ergonomics concepts are susceptible to being misunderstood by people unfamiliar with the subject matter. Most of the time these misunderstandings are harmless, like when a safety poster within a work setting encourages employees to 'overcome complacency'. This misunderstanding of complacency suggests it is a motivational aspect of human behaviour correctable with encouragement, whereas the human factors approach to overcoming complacency would be to evaluate how task design could diminish the destructive consequences of unexpected changes within a routine setting. No harm comes from the message within the safety poster, other than some wasted ink and paper, but misconceptions among particular audiences can eventually result in dire consequences for the human operator. This paper presents recent evidence that the concepts are being misapplied by casual consumers of human factors, particularly in the aftermath of accidents within complex systems, in ways detrimental to the core mission of improving the well-being of the human operator. Later, because this special issue presents new ways to demonstrate value via return on investment, practical efforts we can take to overcome such misconceptions are suggested.