Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the ...lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.
Microplastic research in recent years has shown that small plastic particles are found almost everywhere we look. Besides aquatic and terrestrial environments, this also includes aquatic species ...intended for human consumption and several studies have reported their prevalence in other food products and beverages. The scientific as well as public debate has therefore increasingly focused on human health implications of microplastic exposure. However, there is a big discrepancy between the magnitude of this debate and actual scientific findings, which have merely shown the presence of microplastics in certain products. While plastics can undoubtedly be hazardous to human health due to toxicity of associated chemicals or as a consequence of particle toxicity, the extent to which microplastics in individual food products and beverages contribute to this is debatable. Considering the enormous use of plastic materials in our everyday lives, microplastics from food products and beverages likely only constitute a minor exposure pathway for plastic particles and associated chemicals to humans. But as this is rarely put into perspective, the recent debate has created a skewed picture of human plastic exposure. We risk pulling the focus away from the root of the problem: the way in which we consume, use and dispose of plastics leading to their widespread presence in our everyday life and in the environment. Therefore we urge for a more careful and balanced discussion which includes these aspects.
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•There is data supporting possible chemical and particle toxicity effects of plastic.•The current debate on human health effects of plastics is unbalanced.•There is a disproportionate focus on microplastics in individual food products.•Exposure to additives and microplastics is mainly related to general plastic use.•We urge for a more balanced discussion on human exposure to plastics.
Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been ...initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx‐markers into routine care, because the evidence base is currently limited to specific, individual drug‐gene pairs. The Ubiquitous Pharmacogenomics (U‐PGx) Consortium, which has been funded by the European Commission's Horizon‐2020 program, aims to address this unmet need. In a prospective, block‐randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions PREPARE), pre‐emptive genotyping of a panel of clinically relevant PGx‐markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost‐effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi‐ethnic, and multihealthcare system approach.
Measurements of microplastics in biota and abiotic matrices are key elements of exposure and risk assessments for this emerging environmental pollutant. We investigated the abundance of microplastics ...in field-collected biota, sediment and water. An improved sediment extraction method, based on density separation was developed. For analysis of microplastics in biota we found that an adapted enzymatic digestion protocol using proteinase K performed best, with a 97% recovery of spiked plastic particles and no observed degradation effects on the plastics in subsequent Raman analysis. Field analysis revealed that 8 of 9 tested invertebrate species from the North Sea and 68% of analyzed individuals of brown trout (Salmo trutta) from the Swedish West Coast had microplastics in them. Based on the number of plastic particles per kg d.w. the microplastic concentrations found in mussels were approximately a thousand-fold higher compared to those in sediment and surface water samples from the same location.
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•Recovery of microplastics (MPs) from sediment was improved with olive oil.•Enzymatic digestion for MPs in biota gave a 97% recovery of spiked particles.•MPs were found in 8/9 invertebrate species on the North Sea coast.•MPs were found in 68% of stomach samples of S. trutta from the Swedish west coast.•Mussels had much higher levels of MPs compared to surrounding water and sediment.
Long-term storage of viable mammalian cells is important for applications ranging from in vitro fertilization to cell therapy. Cryopreservation is currently the most common approach, but storage in ...liquid nitrogen is relatively costly and the requirement for low temperatures during shipping is inconvenient. Desiccation is an alternative strategy with the potential to enable viable cell preservation at more convenient storage temperatures without the need for liquid nitrogen. To achieve stability during storage in the dried state it is necessary to remove enough water that the remaining matrix forms a non-crystalline glassy solid. Thus, the glass transition temperature is a key parameter for design of cell desiccation procedures. In this study, we have investigated the effects of moisture content on the glass transition temperature (Tg) of mixtures of sugars (trehalose or raffinose), polymers (polyvinylpyrrolidone or Ficoll), penetrating cryoprotectants (ethylene glycol, propylene glycol, or dimethyl sulfoxide), and phosphate buffered saline (PBS) solutes. Aqueous solutions were dried to different moisture contents by equilibration with saturated salt solutions, or by baking at 95°C. The glass transition temperatures of the dehydrated samples were then measured by differential scanning calorimetry. As expected, Tg increased with decreasing moisture content. For example, in a desiccation medium containing 0.1 M trehalose in PBS, Tg ranged from about 360 K for a completely dry sample to about 220 K at a water mass fraction of 0.4. Addition of polymers to the solutions increased Tg, while addition of penetrating cryoprotectants decreased Tg. Our results provide insight into the relationship between relative humidity, moisture content and glass transition temperature for cell desiccation solutions containing sugars, polymers and penetrating cryoprotectants.
Microplastics were sampled in open surface waters by using a manta trawl and an in-situ filtering pump. A total of 24 trawl samples and 11 pump samples were taken at 12 locations around Sweden. ...Overall, the concentration of microplastic particles was higher in pump samples compared to trawl samples. The median microplastic particle concentration was 0.04 particles per m−3 for manta trawl samples and 0.10 particles per m−3 in pump samples taken with a mesh size of 0.3 mm. The highest concentrations were recorded on the west coast of Sweden. Fibers were found in all samples and were also more frequent in the pump samples. Even higher concentrations of fibers and particles were found on the 0.05 mm pump filters. Using near-infrared hyperspectral imaging the majority of the particles were identified as polyethylene followed by polypropylene.
•Microplastics (>0.3 mm) were found in 88% of trawl samples and 91% of pump samples, fibers were observed in all samples.•Near-infrared hyperspectral imaging identified most of the particles as polyethylene.•Pump samples had notably higher concentrations of microplastics in 5 out of 11 locations.•Higher concentrations of microplastics and fibers when using a smaller mesh size of 0.05 mm•The highest concentrations were recorded by the pump on the Swedish west coast.
Coherent optical transmission systems have a four-dimensional (4-D) signal space (two quadratures in two polarizations). These four dimensions can be used to create modulation formats that have a ...better power efficiency (higher sensitivity) than the conventional binary phase shift keying/quadrature phase shift keying (BPSK/QPSK) signals. Several examples are given, with some emphasis on a 24-level format and an 8-level format, including descriptions of how they can be realized and expressions for their symbol and bit error probabilities. These formats are, respectively, an extension and a subset of the commonly used 16-level dual-polarization QPSK format. Sphere packing simulations in 2, 3, and 4 dimensions, up to 32 levels, are used to verify their optimality. The numerical results, as the number of levels increases, are shown to agree with lattice-theoretical results. Finally, we point out that the use of these constellations will lead to improved fundamental sensitivity limits for optical communication systems, and they may also be relevant as a way of reducing power demands and/or nonlinear influence.
Several software tools are available that facilitate the use of the NONMEM software and extend its functionality. This tutorial shows how three commonly used and freely available tools, Pirana, PsN, ...and Xpose, form a tightly integrated workbench for modeling and simulation with NONMEM. During the tutorial, we provide some guidance on what diagnostics we consider most useful in pharmacokinetic model development and how to construct them using these tools.
CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e50; doi:10.1038/psp.2013.24; advance online publication 26 June 2013
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•Surface oxide speciation on metal NPs possible to assess using an electrochemical tool.•Electrochemical activity closely linked to metal release and cytotoxic response.•Particle ...sedimentation is a source of error in intended NP dose in cell viability tests.•Cell viability largely linked to surface oxide activity and corrosion
Most metal nanoparticles (NPs), except noble metal NPs, rapidly form a thin surface oxide in ambient conditions. The protective properties of these oxides improve or worsen depending on the environment, e.g., the human lung. Several properties, including the chemical/electrochemical stability and defect density, determine the capacity of these surface oxides to hinder the bulk metal from further oxidation (corrosion). The aim of this study was to investigate whether electrochemical surface oxide characterization of non-functionalized base metal NPs of different characteristics (Al, Mn and Cu) can assist in understanding their bioaccessibility (metal release) in cell media (DMEM+) and their cytotoxic properties following exposure in lung epithelial (A549) cells. The composition and valence states of surface oxides of metal NPs and their electrochemical activity were investigated using an electrochemical technique based on a graphite paste electrode to perform cyclic voltammetry in buffer solutions and open circuit potential measurements in DMEM+. The electrochemical surface oxide characterization was complemented and verified by Raman spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The open circuit potential trends in DMEM+ correlated well with metal release results in the same solution, and provided information on the kinetics of oxide dissolution in the case of Cu NPs. Extensive particle agglomeration in cell medium (DMEM+) was observed by means of photon-cross correlation spectroscopy for all metal NPs, with sedimentation taking place very quickly. As a consequence, measurements of the real dose of added non-functionalized metal NPs to cell cultures for cytotoxicity testing from a sonicated stock solution were shown necessary. The cytotoxic response was found to be strongly correlated to changes in physico-chemical and electrochemical properties of the surface oxides of the metal NPs, the most potent being Cu NPs, followed by Mn NPs. No cytotoxicity was observed for Al NPs. The electrochemical surface oxide characterization corresponded well with other tools commonly used for nanotoxicological characterization and provided additional information.
Owing to the development and adoption of a variety of methods for sampling and identifying microplastics, there is now data showing the presence of microplastics in surface waters from all over the ...world. The difference between the methods, however, hampers comparisons, and to date, most studies are qualitative rather than quantitative. In order to allow for a quantitative comparison of microplastics abundance, it is crucial to understand the differences between sampling methods. Therefore, a manta trawl and an in situ filtering pump were compared during realistic, but controlled, field tests. Identical microplastic analyses of all replicates allowed the differences between the methods with respect to (1) precision, (2) concentrations, and (3) composition to be assessed. The results show that the pump gave higher accuracy with respect to volume than the trawl. The trawl, however, sampled higher concentrations, which appeared to be due to a more efficient sampling of particles on the sea surface microlayer, such as expanded polystyrene and air-filled microspheres. The trawl also sampled a higher volume, which decreased statistical counting uncertainties. A key finding in this study was that, regardless of sampling method, it is critical that a sufficiently high volume is sampled to provide enough particles for statistical evaluation. Due to the patchiness of this type of contaminant, our data indicate that a minimum of 26 particles per sample should be recorded to allow for concentration comparisons and to avoid false null values. The necessary amount of replicates to detect temporal or spatial differences is also discussed. For compositional differences and size distributions, even higher particle counts would be necessary. Quantitative measurements and comparisons would also require an unbiased approach towards both visual and spectroscopic identification. To facilitate the development of such methods, a visual protocol that can be further developed to fit different needs is introduced and discussed. Some of the challenges encountered while using FTIR microspectroscopic particle identification are also critically discussed in relation to specific compositions found.
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