Irena Carmichael

Oligodendrocytes (OLs) myelinate central nervous system (CNS) axons and provide metabolic support to maintain axonal integrity. Thyroid hormone (TH) is a mitogen for oligodendroglial precursor cells (OPCs) maturation into myelinating OLs. Cellular uptake of TH is mediated by monocarboxylate transporter 8 (MCT8; encoded by slc16a2 ), and its dysfunction results in intracellular triiodothyronine (T3) deprivation, leading to hypomyelination and myelin degeneration during neuroinflammation. We showed that MCT8 expression is maintained in OPCs residing within the sub–ventricular zone (SVZ) throughout CNS development, suggesting a role during OL development. We identified MCT8 deficiency during neuroinflammatory and cuprizone demyelination models, as well as in secondary progressive multiple sclerosis (SPMS). These conditions were associated with dysregulated AKT–mTOR–PANK2 signaling and abrogated Co Enzyme A and lipid synthesis pathways in the CNS during myelin degeneration. Hence, neuroprotection during SPMS maybe achieved by overcoming MCT8 deficiencies in OLs.

Despite advancement in skin engineering, native skin grafting remains the gold standard in clinical settings. We have previously demonstrated that a platelet-derived hydrogel (PG) can act as a scaffold to engineer a semi-mature bilaminar human skin equivalent (PG-HSE). In this study, PG-HSE was grafted on full thickness wounds in athymic mice. PG-HSE was compared with native skin autografts and a clinically proven bilaminar skin graft that utilises a single layer NovoSorb^® polyurethane biodegradable temporising matrix (plus plasma) as the scaffold (BTM-HSE). The graft analysis revealed PG-HSE-grafted wounds were fully epidermised in two weeks and the level of inflammatory markers, CXCl1, CXCl2, IL1β, and IL-6 transcripts, in grafts were at similar levels to their levels in autografts. This coincided with higher expression of COL1A2, COL3A1, and COL5A1 transcripts in PG-HSE grafts, compared to autografts and BTM-HSE grafts. Moreover, a higher deposition of both Col I and Col III was detected in the PG-HSE graft wound bed, when compared to the BTM-HSE graft wound bed. Conversely, BTM-HSE grafts showed a higher level of integrins, ITGA2, ITGA3, ITGA5, ITGA6, ITGAV, and ITGB1, at the RNA level, suggesting a stronger cell–scaffold interaction. In summary, we have shown although both PG and single layer BTM foam (plus plasma) are effective scaffolds for skin engineering, some key aspects of wound repair, including a reduction in inflammation and an increase in collagen deposition, are achieved with the platelet-derived hydrogel. The long-term effect of these scaffolds on wound scarring remains to be investigated.

Over the last three decades changes in the treatment paradigm for newly diagnosed multiple myeloma (MM) have led to a significant increase in overall survival. Despite this, the majority of patients relapse after one or more lines of treatment while acquiring resistance to available therapies. Panobinostat, a pan-histone deacetylase inhibitor, was approved by the FDA in 2015 for patients with relapsed MM but how to incorporate panobinostat most effectively into everyday practice remains unclear. Dysregulation of the Wnt canonical pathway, and its key mediator β-catenin, has been shown to be important for the evolution of MM and the acquisition of drug resistance, making it a potentially attractive therapeutic target. Despite concerns regarding the safety of Wnt pathway inhibitors, we have recently shown that the β-catenin inhibitor Tegavivint is deliverable and effective in in vivo models of MM. In this study we show that the combination of low concentrations of panobinostat and Tegavivint have significant in vitro and in vivo anti-MM effects including in the context of proteasome inhibitor resistance, by targeting both aerobic glycolysis and mitochondrial respiration and the down-regulation of down-stream β-catenin targets including myc, cyclinD1, and cyclinD2. The significant anti-MM effect of this novel combination warrants further evaluation for the treatment of MM patients with relapsed and/or refractory MM.