Sex differences in the incidence and outcome of human disease are broadly recognized, but in most cases, not sufficiently understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that standard therapy is more effective in female compared to male GBM patients. We then applied a computational algorithm to linked GBM transcriptome and outcome data and identified sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling are the critical determinants of survival for male and female patients, respectively. The clinical utility of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses and that improved outcomes for all patients might be accomplished by tailoring treatment to sex differences in molecular mechanisms.

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Neurotrophins have been shown to promote axonal growth and regeneration after spinal cord injury. The therapeutic utility of neurotrophins may be enhanced by using a controlled delivery system to increase the duration of neurotrophin availability following injury. Such a delivery system can be incorporated into a bioactive scaffold to serve as a physical bridge for regeneration. This study assessed the effect of controlled delivery of neurotrophin-3 (NT-3) from fibrin scaffolds implanted in spinal cord lesions immediately following 2-mm ablation injury in adult rats. Nine days after injury, fibrin scaffolds containing the delivery system and NT-3 (1000 ng/mL) elicited more robust neuronal fiber growth into the lesion than did control scaffolds or saline (1.5- to 3-fold increase). Implantation of fibrin scaffolds resulted in a dramatic reduction of glial scar formation at the white matter border of the lesion. Hindlimb motor function of treated animals did not improve relative to controls at 12 weeks post-injury. Thus, controlled delivery of NT-3 from fibrin scaffolds enhanced the initial regenerative response by increasing neuronal fiber sprouting and cell migration into the lesion, while functional motor recovery was not observed in this model.

The goal of this work was to assess the effect of the controlled delivery of neurotrophin-3 (NT-3) from an affinity-based delivery system in fibrin scaffolds on regeneration following spinal cord injury (SCI). A heparin-based delivery system (HBDS) was used to immobilize NT-3 within fibrin scaffolds via non-covalent interactions. The fibrin scaffolds were implanted in lesions immediately after injury in an adult rat model of SCI (complete ablation of a 2 mm segment of the cord at T9). Delivery of NT-3 was controlled by an affinity-based delivery system that limits drug loss by diffusion and releases the drug via cell-mediated processes. Twelve weeks after injury and treatment, animals treated with fibrin scaffolds and NT-3, with or without the delivery system, did not show functional improvement over saline controls. Substantial cavitation at edges of the lesion was present, and while neuronal fibers were present inside the lesion, traced corticospinal and dorsal sensory tracts did not regenerate into the lesion. Therefore, while previous studies indicate that the controlled delivery of NT-3 from fibrin scaffolds may increase the short term regenerative response, the continued degeneration of the cord, indicative of the severity of the injury, limits the long term regeneration stimulated by this treatment. Chronic or repeated treatments or a less severe injury model may prove useful in assessing the utility of controlled delivery systems for the treatment of spinal cord injury.

SCK nanoparticles having differing core thermal characteristics were designed and evaluated as thermoresponsive drug delivery systems of doxorubicin for the killing of cancerous cells.