In-depth mechanistic analysis including high-throughput RNA sequencing in the prediction of functional and structural cardiotoxicants using hiPSC cardiomyocytes.

Background: Cardiotoxicity remains one of the most reported adverse drug reactions that lead to drug attrition during pre-clinical and clinical drug development. Drug-induced cardiotoxicity may develop as a functional change in cardiac electrophysiology (acute alteration of the mechanical function of the myocardium) and/or as a structural change, resulting in loss of viability and morphological damage to cardiac tissue.

Research Design And Methods: Non-clinical models with better predictive value need to be established to improve cardiac safety pharmacology.

The influence of aluminium and copper upon the early aggregatory behaviour and size of Islet amyloid polypeptide under simulated physiological conditions.

Background And Aim: Islet amyloid polypeptide/amylin deposition in the form of amyloid plaques is a common pathological feature observed in the pancreatic tissue of those with Type II Diabetes Mellitus. Its propensity to form amyloid fibrils and the resultant toxicity of this peptide in vivo is influenced by both the concentration and species of metal present in situ. Herein, we examine the influence of Al (III) and Cu (II), applied at equimolar and supra-stoichiometric concentrations on the initial aggregatory behaviour of amylin under near physiological conditions.

Monitoring the early aggregatory behaviour and size of Aβ in the absence & presence of metal ions using dynamic light scattering.

Background And Aim: Aβ is an amyloidogenic peptide found within senile plaques extracted from those who died with a diagnosis of Alzheimer's disease. The potent neurotoxicity of this peptide is related to its propensity to form aggregated conformations in vivo, a process that is influenced by the species and concentration of metal ions present within the local environment. This study examines the impact of different metals upon the early aggregatory behaviour and size of Aβ under simulated physiological conditions.

The measurement and full statistical analysis including Bayesian methods of the aluminium content of infant vaccines.

Background: Aluminium salts are the most common adjuvants in infant vaccines. The aluminium content of a vaccine is provided by the manufacturer and is indicated on the patient information leaflet. There is no independent verification, for example by the European Medicines Agency, of the aluminium content of infant vaccines.

The interaction of aluminium-based adjuvants with THP-1 macrophages in vitro: Implications for cellular survival and systemic translocation.

Within clinical vaccinations, recombinant antigens are routinely entrapped inside or adsorbed onto the surface of aluminium salts in order to increase their immunological potency in vivo. The efficacy of these immunisations is highly dependent upon the recognition and uptake of these complexes by professional phagocytes and their subsequent delivery to the draining lymph nodes for further immunological processing. While monocytes have been shown to internalise aluminium adjuvants and their adsorbates, the role of macrophages in this respect has not been fully established.

The size of micro-crystalline tyrosine (MCT®) influences its recognition and uptake by THP-1 macrophages .

The physicochemical hallmarks of particulate immunopotentiators play a pivotal role with regards to their adjuvanticity . These properties have not been fully characterised in the case of MCT®, an amino acid-based adjuvant used as an alternative to aluminium salts in subcutaneous allergy immunotherapy (SCIT). This study presents a full characterisation of MCT® and in a preliminary capacity reveals how parameters, specifically particle size, might influence the recognition of MCT® by antigen presenting cells (APCs) .

Aggregation of the diabetes-related peptide ProIAPP measured by dynamic light scattering.

Islet amyloid polypeptide (IAPP) or amylin is implicated in the aetiology of diabetes. It is found as amyloid along with its precursor ProIAPP in the islets of Langerhans in the pancreas. Metals have been implicated in amyloidogenesis of both IAPP and ProIAPP.

Unraveling the enigma: elucidating the relationship between the physicochemical properties of aluminium-based adjuvants and their immunological mechanisms of action.

Aluminium salts are by far the most commonly used adjuvants in vaccines. There are only two aluminium salts which are used in clinically-approved vaccines, Alhydrogel and AdjuPhos, while the novel aluminium adjuvant used in Gardasil is a sulphated version of the latter. We have investigated the physicochemical properties of these two aluminium adjuvants and specifically in milieus approximating to both vaccine vehicles and the composition of injection sites.

Intracellular tracing of amyloid vaccines through direct fluorescent labelling.

Alzheimer's disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Aβ as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migratory properties of peripheral blood-borne monocytes and their ability to enter the central nervous system, suggests a beneficial role in mediating tissue damage and neuroinflammation.

From Stock Bottle to Vaccine: Elucidating the Particle Size Distributions of Aluminum Adjuvants Using Dynamic Light Scattering.

The physicochemical properties of aluminum salts are key determinants of their resultant adjuvanticity when administered as part of a vaccine. While there are links between particle size and the efficacy of the immune response, the limited literature directly characterizing the PSD of aluminum adjuvants has stymied the elucidation of such a relationship for these materials. Hence, this comparative study was undertaken to monitor the PSD of aluminum adjuvants throughout the process of vaccine formulation using DLS.

Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations.

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.

Unequivocal identification of intracellular aluminium adjuvant in a monocytic THP-1 cell line.

Aluminium-based adjuvants (ABA) are the predominant adjuvants used in human vaccinations. While a consensus is yet to be reached on the aetiology of the biological activities of ABA several studies have identified shape, crystallinity and size as critical factors affecting their adjuvanticity. In spite of recent advances, the fate of ABA following their administration remains unclear.