Objective: MLN4924, a pharmacological inhibitor of cullin neddylation, resulted in glioma cell apoptosis, deregulation of the S-phase of DNA synthesis and thus, offers great potential for the treatment of brain tumours. However, targeting the neddylation pathway with an MLN4924 treatment stabilized the hypoxia-inducible factor 1A (HIF1A), which is one of the main transcriptional enhancers of the immune checkpoint molecule PDL1 (programmid death ligand-1) in cancer cells. The influence of immune checkpoint molecules on glioma progression has recently been discovered; PDL1 overexpression in gliomas corresponds to a significant shortening of patient survival and a decrease of the anti-tumour immune response. We hypothesize that i) PDL1 is up-regulated in gliomas after treatment with MLN4924 and induces T-cell energy; ii) co-utilization of the PD1/PDL1 blockage with MLN4924 therapy may reduce T-cell energy and may engage MLN4924-induced tumour disruption with the immune response. Methods: PDL1 expression and its immunosuppressive role in gliomas, glioma microenvironments, and after treatments with MLN4924 were assessed by utilizing methods of immunohistochemistry, molecular biology, and biochemistry. Results: We confirmed PDL1 overexpression in clinical brain tumour samples, PDGx and established glioma cell lines, extracellular media from glioma cells, and CSF (cerebrospinal fluid) samples from tumour-bearing mice. Our primary T-cell based assays verified that the up-regulation of PDL1 in tumour cells protects gliomas from T-cell treatment and reduces T-cell activation. We found that a pharmacological inhibitor of cullin neddylation, MLN4924, exhibited strong cytotoxicity towards PDGx and established glioma cell lines, in vitro, with an IC50’s range from 0.2 to 3 uM. However, we observed a significant increase of HIF1A and PDL1 in mRNA and protein levels in all glioma cell lines after treatment with MLN4924. The MLN4924-dependent induction of PDL1 in gliomas resulted in T-cell energy, which was blocked by a blockage of the PD1/PDL1 interaction. Conclusion: We conclude that i) PDL1 up-regulation in gliomas and the glioma microenvironment is an important chemotherapeutic target; ii) MLN4924 therapy, combined with a blockage of the PD1/PDL1 pathway, should be considered as a potential strategy for glioma treatment.

Insurance enrollment is complex for people living with HIV (PLWH) and people at increased risk for HIV, in part, owing to needing to ensure access to adequate provider networks and appropriate formularies. Insurance for PLWH facilitates access to HIV care/treatment and, ultimately, viral suppression, which has the individual benefit of longevity and the public health benefit of decreased HIV transmission. For people at increased risk for HIV, access to insurance facilitates improved access to HIV biomedical prevention, which has the individual benefit of elimination of transmission risk and the public health benefit of decreased HIV transmission. The objective of this study was to explore perceptions of priorities related to plan navigation, barriers and facilitators for enrolling and maintaining insurance coverage, and questions related to regional, state, and federal policies impacting plans provided both on and off the Affordable Care Act (ACA) marketplace. We interviewed a national sample of assisters (n = 40), who specialize in insurance plan selection for these populations. We found that assisters tailor their approaches to HIV-specific and person-specific concerns by navigating challenges related to affordability, formularies, and provider networks. In a complex coverage landscape during a time of uncertainty about the long-term future of the ACA, assisters have mastered the ability to simplify the insurance selection process for a vulnerable population. Assisters have excelled at incorporating insurance literacy education and encouraging client engagement in the process. Assisters play an essential role in the current complicated and fragmented United States' health care delivery system for PLWH and people at increased risk for HIV and could be incorporated into the Ending the HIV Epidemic initiative.

No abstract