Targeting NKG2D ligands in glioblastoma with a bispecific T-cell engager is augmented with conventional therapy and enhances oncolytic virotherapy of glioma stem-like cells.

Background: Glioblastoma (GBM) almost invariably becomes resistant towards conventional treatment of radiotherapy and temozolomide (TMZ) chemotherapy, partly due to subpopulations of intrinsically resistant glioma stem-like cells (GSC). The oncolytic herpes simplex virus-1 G207 is a promising approach for GBM virotherapy although its efficacy in patients with GBM is often limited. Natural killer group 2 member D ligands (NKG2DLs) are minimally expressed by healthy cells but are upregulated by the DNA damage response (DDR) and in malignant cells with chronic DDR signaling, resulting in innate immune activation.

Chemogenomic library design strategies for precision oncology, applied to phenotypic profiling of glioblastoma patient cells.

Designing a targeted screening library of bioactive small molecules is a challenging task since most compounds modulate their effects through multiple protein targets with varying degrees of potency and selectivity. We implemented analytic procedures for designing anticancer compound libraries adjusted for library size, cellular activity, chemical diversity and availability, and target selectivity. The resulting compound collections cover a wide range of protein targets and biological pathways implicated in various cancers, making them widely applicable to precision oncology.

Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia.

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal.

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons.

Pyroglutamate-modified amyloid-β (pE-Aβ) is a highly neurotoxic amyloid-β (Aβ) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aβ oligomerization and alters the interactions of Aβ with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established. We report here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1-42)).

PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning.

Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases.

C-terminal peptides modelling constitutive PrPC processing demonstrate ameliorated toxicity predisposition consequent to α-cleavage.

Misfolding of PrPC (cellular prion protein) to β-strand-rich conformations constitutes a key event in prion disease pathogenesis. PrPC can undergo either of two constitutive endoproteolytic events known as α- and β-cleavage, yielding C-terminal fragments known as C1 and C2 respectively. It is unclear whether C-terminal fragments generated through α- and β-cleavage, especially C2, influence pathogenesis directly.

Oligomers, fact or artefact? SDS-PAGE induces dimerization of β-amyloid in human brain samples.

The formation of low-order oligomers of β-amyloid (Aβ) within the brain is widely believed to be a central component of Alzheimer's disease (AD) pathogenesis. However, despite advances in high-throughput and high-resolution techniques such as xMAP and mass spectrometry (MS), investigations into these oligomeric species have remained reliant on low-resolution Western blots and enzyme-linked immunosorbent assays. The current investigation compared Aβ profiles within human cortical tissue using sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced laser desorption/ionization time-of-flight MS and found that whilst there was significant correlation across the techniques regarding levels of monomeric Aβ, only SDS-PAGE was capable of detecting dimeric isoforms of Aβ.

Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.

Alzheimer's Disease (AD) is complicated by pro-oxidant intraneuronal Fe(2+) elevation as well as extracellular Zn(2+) accumulation within amyloid plaque. We found that the AD β-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn(2+). Like ceruloplasmin, APP catalytically oxidizes Fe(2+), loads Fe(3+) into transferrin, and has a major interaction with ferroportin in HEK293T cells (that lack ceruloplasmin) and in human cortical tissue.

Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity.

Previous studies suggest membrane binding is a key determinant of amyloid β (Aβ) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of Aβ42 (D-Aβ42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type Aβ42 (L-Aβ42).

Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease.

Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy.

Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer's disease amyloid-beta peptide.

The Amyloid beta peptide (Abeta) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline associated with the disease. Cu2+ ions can induce the de novo aggregation of the Abeta peptide into non-amyloidogenic aggregates and the production of a toxic species. The mechanism by which Cu2+ mediates the change from amyloid material toward Cu2+ induced aggregates is poorly defined.