ABSTRACT
OBJECTIVES: To alert policy makers early about emerging health technologies that could significantly impact the healthcare system at the clinical, financial and organizational levels, the Agency for Care Effectiveness (ACE) in Singapore established a horizon scanning system (HSS) in 2019. This paper describes the development of the ACE HSS and showcases its application with cell and gene therapy products as the first example. METHODS: A literature review of existing HSS methods, including the processes of the EuroScan International Network and other overseas horizon scanning agencies, was done to inform the development of our horizon scanning framework. The framework was first applied to the new and emerging cell and gene therapies. RESULTS: Identification sources, filtration and prioritization criteria, and horizon scanning outputs for the HSS were developed in alignment to international best practices, with recommendations for technology uptake represented by a traffic light system. For the first horizon scanning exercise on cell and gene therapies, forty therapies passed the filtration step, of which eight were prioritized for further assessment. The few early reports developed were used to inform and prepare the healthcare system for their potential introduction, particularly in terms of the need to develop health and funding policies. CONCLUSIONS: Early assessment of prioritized topics has provided support for strategic efforts within the Ministry of Health. Given that ACE's horizon scanning program is still in its infancy, the framework will continue to evolve to ensure relevance to our stakeholders so that it remains fit for purpose for our healthcare system.
ABSTRACT
Axonal injury is a common feature of central nervous system insults. Upregulation of amyloid precursor protein (APP) is observed following central nervous system neurotrauma and is regarded as a marker of central nervous system axonal injury. However, the underlying mechanism by which APP mediates neuronal death remains to be elucidated. Here, we used mouse optic nerve axotomy (ONA) to model central nervous system axonal injury replicating aspects of retinal ganglion cell (RGC) death in optic neuropathies. APP and APP intracellular domain (AICD) were upregulated in retina after ONA and APP knockout reduced Tuj1+ RGC loss. Pathway analysis of microarray data combined with chromatin immunoprecipitation and a luciferase reporter assay demonstrated that AICD interacts with the JNK3 gene locus and regulates JNK3 expression. Moreover, JNK3 was found to be upregulated after ONA and to contribute to Tuj1+ RGC death. APP knockout reduced the ONA-induced enhanced expression of JNK3 and phosphorylated JNK (pJNK). Gamma-secretase inhibitors prevented production of AICD, reduced JNK3 and pJNK expression similarly, and protected Tuj1+ RGCs from ONA-induced cell death. Together these data indicate that ONA induces APP expression and that gamma-secretase cleavage of APP releases AICD, which upregulates JNK3 leading to RGC death. This pathway may be a novel target for neuronal protection in optic neuropathies and other forms of neurotrauma.
Subject(s)
Amyloid beta-Protein Precursor/biosynthesis , Gene Expression Regulation, Enzymologic , Mitogen-Activated Protein Kinase 10/biosynthesis , Optic Nerve Diseases/metabolism , Optic Nerve/metabolism , Retinal Ganglion Cells/metabolism , Up-Regulation , Amyloid beta-Protein Precursor/genetics , Animals , Axotomy , Mice , Mice, Mutant Strains , Mitogen-Activated Protein Kinase 10/genetics , Optic Nerve/pathology , Optic Nerve Diseases/genetics , Optic Nerve Diseases/pathology , Retinal Ganglion Cells/pathologyABSTRACT
A novel selection approach is presented to screen phage display peptide libraries against sets of receptors that share specificity for the same ligand. This strategy was applied to the discovery of glycomimetic peptides. Through these screens, a number of peptide clones were discovered that bind the lectins used in the screen, in a sugar competitive manner. In addition, the majority of the selected peptides demonstrate sugar type mimicry consistent with lectin specificity. Docking studies were conducted to establish whether the mimetic peptides bind to the lectin ConA at the sugar binding site or to a nearby, alternative site shown to bind to YPY-containing peptides previously discovered from single-target screens. Of the three cyclic peptides subjected to computational docking, CNTPLTSRC had the highest predicted affinity and CSRILTAAC demonstrated specificity for the sugar binding site comparable to the natural ligand itself.
Subject(s)
Binding Sites , Carbohydrate Metabolism , Carbohydrates/chemistry , Peptide Library , Peptides/chemistry , Peptides/metabolism , Amino Acid Sequence , Biomimetics , Computer Simulation , Lectins/chemistry , Lectins/metabolism , Ligands , Models, Molecular , Protein BindingABSTRACT
Stem cell-based technologies have the potential to help cure a number of cell degenerative diseases. Combinatorial and high throughput screening techniques could provide tools to control and manipulate the self-renewal and differentiation of stem cells. This review chronicles historic and recent progress in the stem cell field involving both pluripotent and multipotent cells, and it highlights relevant cellular signal transduction pathways. This review further describes screens using libraries of soluble, small-molecule ligands, and arrays of molecules immobilized onto surfaces while proposing future trends in similar studies. It is hoped that by reviewing both the stem cell and the relevant high throughput screening literature, this paper can act as a resource to the combinatorial science community.
