Comparing human respiratory adverse effects after acute exposure to particulate matter in conventional and particle-reduced swine building environments.

OBJECTIVES: To evaluate innate immunity responses, lung function and symptoms in volunteers acutely exposed to organic dust in swine buildings after installing particle separators aimed to reduce particulate matter exposure. METHODS: 11 healthy participants were exposed in 2 different facilities, with and without installed particle separators, in a cross-over design including 2-3 weeks wash-out between the 2 exposures. Size, distribution and composition of particulate matter and endotoxins in the air were measured. Lung function (spirometry), bronchial responsiveness, symptoms questionnaire and markers of innate immunity in blood and nasal lavage were measured before and after the 3-hour exposures. RESULTS: The number of particles, in particular fine particles sized 0.3-0.5 µm, was reduced in the particle-separated swine building environment (PSE) compared with that in the conventional building (CE). In the PSE, headache (p=0.03) and increased body temperature (p=0.016) were less pronounced than in the CE. The expression of toll-like receptors (TLR)2 and TLR4 on blood monocytes significantly increased (p=0.016 and 0.017, respectively) while cluster of differentiation (CD)14 on neutrophils decreased (p=0.05) after exposure in the CE, yet with no difference between the 2 exposures. Compared with the conventional environment, exposure to the PSE yielded lower interleukin (IL)-6 (p=0.02) and IL-8 (p=0.04) levels in the upper respiratory tract, as assessed by nasal lavage. CONCLUSIONS: Particulate matter and organic dust in the swine building were reduced after installing particle separators, which, in naïve never exposed volunteers, in turn reduced adverse health effects caused by acute exposure in swine buildings compared with exposure to the conventional swine building environment.

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models.

Constitutive activation of the canonical Wnt signaling pathway, in most cases driven by inactivation of the tumor suppressor APC, is a hallmark of colorectal cancer. Tankyrases are druggable key regulators in these malignancies and are considered as attractive targets for therapeutic interventions, although no inhibitor has been progressed to clinical development yet. We continued our efforts to develop tankyrase inhibitors targeting the nicotinamide pocket with suitable drug-like properties for investigating effects of Wnt pathway inhibition on tumor growth. Herein, the identification of a screening hit series and its optimization through scaffold hopping and SAR exploration is described. The systematic assessment delivered M2912, a compound with an optimal balance between excellent TNKS potency, exquisite PARP selectivity, and a predicted human PK compatible with once daily oral dosing. Modulation of cellular Wnt pathway activity and significant tumor growth inhibition was demonstrated with this compound in colorectal xenograft models in vivo.

Space and time resolved monitoring of airborne particulate matter in proximity of a traffic roundabout in Sweden.

Concerns over exposure to airborne particulate matter (PM) are on the rise. Currently monitoring of PM is done on the basis of interpolating a mass of PM by volume (µg/m(3)) but has the drawback of not taking the chemical nature of PM into account. Here we propose a method of collecting PM at its emission source and employing automated analysis with scanning electron microscopy associated with EDS-analysis together with light scattering to discern the chemical composition, size distribution, and time and space resolved structure of PM emissions in a heavily trafficated roundabout in Sweden. Multivariate methods (PCA, ANOVA) indicate that the technogenic marker Fe follows roadside dust in spreading from the road, and depending on time and location of collection, a statistically significant difference can be seen, adding a useful tool to the repertoiré of detailed PM monitoring and risk assessment of local emission sources.

Visualization of custom-tailored iron oxide nanoparticles chemistry, uptake, and toxicity.

Nanoparticles of iron oxide generated by wearing of vehicles have been modelled with a tailored solution of size-uniform engineered magnetite particles produced by the Bradley reaction, a solvothermal metal-organic approach rendering hydrophilic particles. The latter does not bear any pronounced surface charge in analogy with that originating from anthropogenic sources in the environment. Physicochemical properties of the nanoparticles were thoroughly characterized by a wide range of methods, including XPD, TEM, SEM, DLS and spectroscopic techniques. The magnetite nanoparticles were found to be sensitive for transformation into maghemite under ambient conditions. This process was clearly revealed by Raman spectroscopy for high surface energy magnetite particles containing minor impurities of the hydromaghemite phase and was followed by quantitative measurements with EXAFS spectroscopy. In order to assess the toxicological effects of the produced nanoparticles in humans, with and without surface modification with ATP (a model of bio-corona formed in alveolar liquid), a pathway of potential uptake and clearance was modelled with a sequence of in vitro studies using A549 lung epithelial cells, lymphocyte 221-B cells, and 293T embryonal kidney cells, respectively. Raman microscopy unambiguously showed that magnetite nanoparticles are internalized within the A549 cells after 24 h co-incubation, and that the ATP ligand is retained on the nanoparticles throughout the uptake process. The toxicity of the nanoparticles was estimated using confocal fluorescence microscopy and indicated no principal difference for unmodified and modified particles, but revealed considerably different biochemical responses. The IL-8 cytokine response was found to be significantly lower for the magnetite nanoparticles compared to TiO(2), while an enhancement of ROS was observed, which was further increased for the ATP-modified nanoparticles, implicating involvement of the ATP signalling pathway in the epithelium.

New tabletop SEM-EDS-based approach for cost-efficient monitoring of airborne particulate matter.

Recent developments in scanning electron microscopy (SEM) have produced tabletop instruments capable of reasonable imaging resolution at less cost compared to conventional equipment. Combining the SEM with energy dispersive spectroscopy (EDS) allows the possibility of elemental analysis through detection of X-rays emitted from interaction between individual particles and the SEM electron beam, revealing their atomic composition. It's well known that exposure to inhalable particulate matter (PM) poses health risks and routine monitoring of the chemical content of these has been realized. Exposure information is of a general character but by combining the chemical build-up of monitored particles and knowledge of their inherent health effects will allow better risk assessment. An analysis technique using a tabletop SEM with EDS is demonstrated on particles collected onto nucleopore filters from urban, industrial and rural areas. Detailed characterization of the instruments analysis capabilities as applied to PM are described.

Solution-engineered palladium nanoparticles: model for health effect studies of automotive particulate pollution.

Palladium (Pd) nanoparticles are recognized as components of airborne automotive pollution produced by abrasion of catalyst materials in the car exhaust system. Here we produced dispersions of hydrophilic spherical Pd nanoparticles (Pd-NP) of uniform shape and size (10.4 ± 2.7 nm) in one step by Bradley's reaction (solvothermal decomposition in an alcohol or ketone solvent) as a model particle for experimental studies of the Pd particles in air pollution. The same approach provided mixtures of Pd-NP and nanoparticles of non-redox-active metal oxides, such as Al(2)O(3). Particle aggregation in applied media was studied by DLS and nanoparticle tracking analysis. The putative health effects of the produced Pd nanoparticles and nanocomposite mixtures were evaluated in vitro, using human primary bronchial epithelial cells (PBEC) and a human alveolar carcinoma cell line (A549). Viability of these cells was tracked by vital dye exclusion, and apoptosis was also assessed. In addition, we monitored the release of IL-8 and PGE(2) in response to noncytotoxic doses of the nanoparticles. Our studies demonstrate cellular uptake of Pd nanoparticles only in PBEC, as determined by TEM, with pronounced and dose-dependent effects on cellular secretion of soluble biomarkers in both cell types and a decreased responsiveness of human epithelial cells to the pro-inflammatory cytokine TNF-α. When cells were incubated with higher doses of the Pd nanoparticles, apoptosis induction and caspase activation were apparent in PBEC but not in A549 cells. These studies demonstrate the feasibility of using engineered Pd nanoparticles to assess the health effects of airborne automotive pollution.