5-ALA localises to the autophagy compartment and increases its fluorescence upon autophagy enhancement through caloric restriction and spermidine treatment in human glioblastoma.

Glioblastoma Multiforme (GBM) is the most invasive and prevalent Central Nervous System (CNS) malignancy. It is characterised by diffuse infiltrative growth and metabolic dysregulation that impairs the extent of surgical resection (EoR), contributing to its poor prognosis. 5-Aminolevulinic acid (5-ALA) fluorescence-guided surgical resection (FGR) takes advantage of the preferential generation of 5-ALA-derived fluorescence signal in glioma cells, thereby improving visualisation and enhancing the EoR. However, despite 5-ALA FGR is a widely used technique in the surgical management of malignant gliomas, the infiltrative tumour margins usually show only vague or no visible fluorescence and thus a significant amount of residual tumour tissue may hence remain in the resection cavity, subsequently driving tumour recurrence. To investigate the molecular mechanisms that govern the preferential accumulation of 5-ALA in glioma cells, we investigated the precise subcellular localisation of 5-ALA signal using Correlative Light and Electron Microscopy (CLEM) and colocalisation analyses in U118MG glioma cells. Our results revealed strong 5-ALA signal localisation in the autophagy compartment - specifically autolysosomes and lysosomes. Flow cytometry was employed to investigate whether autophagy enhancement through spermidine treatment (SPD) or nutrient deprivation/caloric restriction (CR) would enhance 5-ALA fluorescence signal generation. Indeed, SPD, CR and a combination of SPD/CR treatment significantly increased 5-ALA signal intensity, with a most robust increase in signal intensity observed in the combination treatment of SPD/CR. When using 3-D glioma spheroids to assess the effect of 5-ALA on cellular ultrastructure, we demonstrate that 5-ALA exposure leads to cytoplasmic disruption, vacuolarisation and large-scale mitophagy induction. These findings not only suggest a critical role for the autophagy compartment in 5-ALA engagement and signal generation but also point towards a novel and practically feasible approach to enhance 5-ALA fluorescence signal intensity. The findings may highlight that indeed autophagy control may serve as a promising avenue to promote an improved resection and GBM prognosis.

A unique model for treating chronic hepatitis C in patients with psychiatric disorders, substance abuse, and/or housing instability.

BACKGROUND: Individuals with psychiatric disease, substance abuse, and/or housing instability have a high prevalence of chronic hepatitis C virus (HCV) infection. However, such individuals are often excluded from treatment for HCV infection because of a perceived inability to adhere to the rigorous medication regimen required. METHODS: A pilot program using a multidisciplinary group medical visit model to treat HCV infection in the aforementioned population was created. Medication adherence and virologic response rates were prospectively followed. RESULTS: Approximately 80% of patients were adherent to their HCV infection treatment regimen, as measured by attendance at group medical visits and by medication adherence. A sustained virologic response rate of 55% among individuals with genotype 1 infection and 80% among individuals with genotype 2 or 3 infections was observed. These results compare favorably with those seen in large, randomized controlled trials. Rates of discontinuation and adverse effects were similar to those seen in other studies. CONCLUSIONS: An intensive, multidisciplinary treatment approach toward HCV infection treatment can achieve favorable results even in persons traditionally considered to be "poor treatment candidates." Programs aimed at bringing HCV infection treatment to this population are needed.