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Concept: Toxicity

332

Autism spectrum disorder (ASD) is defined by standardized criteria of qualitative impairments in social interaction, qualitative impairments in communication, and restricted and stereotyped patterns of behavior, interests, and activities. A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills, which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth. To date, the etiology of ASD remains under debate, however, many studies suggest toxicity, especially from mercury (Hg), in individuals diagnosed with an ASD. The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal (49.55% Hg by weight) in childhood vaccines by conducting a two-phased (hypothesis generating/hypothesis testing) study with documented exposure to varying levels of Thimerosal from vaccinations.

Concepts: Immune system, Vaccine, Vaccination, Greek loanwords, Autism, Mercury, Toxicity, Autism spectrum

244

Background The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. Methods Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. Results At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. Conclusions As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

Concepts: Clinical trial, Cancer, Cancer staging, Clinical research, Placebo, Group theory, Toxicity

244

Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al(3+) in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain.

Concepts: Immune system, Electron, Cell, Immunology, Microscope, Particle size distribution, Toxicity, Particulates

178

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer’s disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer’s disease. Despite the importance of plaques to Alzheimer’s disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer’s disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer’s disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer’s disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer’s disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer’s disease pathogenesis.

Concepts: Alzheimer's disease, Neuron, Polymer chemistry, Monomer, Acetylcholine, Toxicity, Oligomer, Neurofibrillary tangle

170

Access to safe drinking water is a human right, crucial to combat inequalities, reduce poverty and allow sustainable development. In many areas of the world, however, this right is not guaranteed, in part because of the lack of easily deployable diagnostic tools. Low-cost and simple methods to test water supplies onsite can protect vulnerable communities from the impact of contaminants in drinking water. Ideally such devices would also be easy to dispose of so as to leave no trace, or have a detrimental effect on the environment. To this aim, we here report the first paper microbial fuel cell (pMFC) fabricated by screen-printing biodegradable carbon-based electrodes onto a single sheet of paper, and demonstrate its use as a shock sensor for bioactive compounds (e.g. formaldehyde) in water. We also show a simple route to enhance the sensor performance by folding back-to-back two pMFCs electrically connected in parallel. This promising proof of concept work can lead to a revolutionizing way of testing water at point of use, which is not only green, easy-to-operate and rapid, but is also affordable to all.

Concepts: Water, Electrochemistry, Toxicity, Electrolysis, Sustainability, Water quality, Fuel cell, Microbial fuel cell

170

Our previous studies have confirmed that the crude tentacle-only extract (cTOE) from the jellyfish Cyanea capillata (Cyaneidae) exhibits hemolytic and cardiovascular toxicities simultaneously. So, it is quite difficult to discern the underlying active component responsible for heart injury caused by cTOE. The inactivation of the hemolytic toxicity from cTOE accompanied with a removal of plenty of precipitates would facilitate the separation of cardiovascular component and the investigation of its cardiovascular injury mechanism. In our research, after the treatment of one-step alkaline denaturation followed by twice dialysis, the protein concentration of the treated tentacle-only extract (tTOE) was about 1/3 of cTOE, and SDS-PAGE showed smaller numbers and lower density of protein bands in tTOE. The hemolytic toxicity of tTOE was completely lost while its cardiovascular toxicity was well retained. The observations of cardiac function, histopathology and ultrastructural pathology all support tTOE with significant cardiovascular toxicity. Blood gas indexes and electrolytes changed far less by tTOE than those by cTOE, though still with significant difference from normal. In summary, the cardiovascular toxicity of cTOE can exist independently of the hemolytic toxicity and tTOE can be employed as a better venom sample for further purification and mechanism research on the jellyfish cardiovascular toxic proteins.

Concepts: Protein, Blood, Heart, Toxicity, Jellyfish, Lion's mane jellyfish, Cyaneidae, Semaeostomeae

150

Peptide mediated gain-of-toxic function is central to pathology in Alzheimer’s, Parkinson’s and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here we focus on islet amyloid polypeptide (IAPP) mediated loss-of-insulin secreting cells in patients with diabetes. Newly developed methods enable structure-function enquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two classes of poration occur; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilising non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalisable approach for enquiry applicable to other partially ordered protein assemblies.

Concepts: Alzheimer's disease, Protein, Cell, Cell biology, Peptide, Amylin, Cytotoxicity, Toxicity

150

Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.

Concepts: Agriculture, Nanotechnology, Sol-gel, Cytotoxicity, Sulfur, Toxicity, Mycology, Fungicides

142

Concentration addition (CA) was proposed as a reasonable default approach for the ecological risk assessment of chemical mixtures. However, CA cannot predict the toxicity of mixture at some effect zones if not all components have definite effective concentrations at the given effect, such as some compounds induce hormesis. In this paper, we developed a new method for the toxicity prediction of various types of binary mixtures, an interpolation method based on the Delaunay triangulation (DT) and Voronoi tessellation (VT) as well as the training set of direct equipartition ray design (EquRay) mixtures, simply IDVequ. At first, the EquRay was employed to design the basic concentration compositions of five binary mixture rays. The toxic effects of single components and mixture rays at different times and various concentrations were determined by the time-dependent microplate toxicity analysis. Secondly, the concentration-toxicity data of the pure components and various mixture rays were acted as a training set. The DT triangles and VT polygons were constructed by various vertices of concentrations in the training set. The toxicities of unknown mixtures were predicted by the linear interpolation and natural neighbor interpolation of vertices. The IDVequ successfully predicted the toxicities of various types of binary mixtures.

Concepts: Chemical substance, Mixture, Chemical compound, Toxicity, Computational geometry, Delaunay triangulation, Voronoi diagram, CGAL

138

Chlorhexidine gluconate (CHX) and benzalkonium chloride (BZK) formulations are frequently used as antiseptics in healthcare and consumer products. Burkholderia cepacia complex (BCC) contamination of pharmaceutical products could be due to the use of contaminated water in the manufacturing process, over-diluted antiseptic solutions in the product, and the use of outdated products, which in turn, reduces the antimicrobial activity of CHX and BZK. To establish a “safe use” period following opening containers of CHX and BZK, we measured the antimicrobial effects of CHX (2 ~ 10 µg/ml) and BZK (10 ~ 50 µg/ml) at sub-lethal concentrations on six strains of Burkholderia cenocepacia using chemical and microbiological assays. CHX (2, 4 and 10 µg/ml) and BZK (10, 20 and 50 µg/ml) stored for 42 days at 23°C showed almost the same concentration and toxicity compared to freshly prepared CHX and BZK on B. cenocepacia strains. When 5 µg/ml CHX and 20 µg/ml BZK were spiked with six B. cenocepacia strains with different inoculum sizes (10⁰ ~ 10⁵CFU/mL), their toxic effects were not changed for 28 days. B. cenocepacia strains in diluted CHX and BZK were detectable at concentration up to 10² CFU/mL after incubation for 28 days at 23°C. Although abiotic and biotic changes in the toxicity of both antiseptics were not observed, our results indicate that B. cenocepacia strains could remain viable in CHX and BZK for 28 days, which in turn, indicates the importance of control measures to monitor BCC contamination in pharmaceutical products.

Concepts: Microbiology, Antiseptic, Toxicity, Disinfectant, Burkholderia, Burkholderiales, Mouthwash, Antiseptics