DISCOVERY AND ELUCIDATION OF THE FGFR3-TACC3 RECURRENT FUSION IN GLIOBLASTOMA

Fusion genes occur due to chromosomal instability where two previously separate genes rearrange and fuse together, forming a hybrid gene. The first fusions were reported in leukemias; however, with the advent of more powerful sequencing technologies, fusions have recently been reported in several solid tumors. Using next-generation deep sequencing approaches, we discovered a fusion gene connecting the fibroblast growth factor receptor 3 (FGFR3) gene to the transforming coiled-coil containing protein 3 (TACC3) gene in glioblastoma multiforme. The fusion occurred in 8.3% of patient samples, but not in low grade or normal samples. FGFR3-TACC3 produced an in-frame fusion protein that promoted an oncogenic phenotype both in vitro and in vivo. While the fusion was overexpressed and contained the majority of the FGFR3 gene, levels of wild-type FGFR3 were very low. We attributed this effect to the ability of the fusion to bypass miR-99a regulation, by losing the 3’ UTR of FGFR3 upon formation of the fusion. The fusion activated ERK and STAT3 signaling, and was more sensitive to FGFR, ERK, and STAT3 inhibitors, while more resistant to treatment with frontline chemotherapy agent, temozolomide

Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer

Social Cohesion Among Sex Workers and Client Condom Refusal in a Canadian Setting: Implications for Structural and Community-Led Interventions

Community empowerment can be a powerful determinant of HIV risk among sex workers (SWs). This study modeled the impact of social cohesion on client condom refusal among SWs in Vancouver. Longitudinal data were drawn from a prospective cohort of SWs (2010–2013). Lippman and colleagues’ Social Cohesion Scale measured SWs’ connectedness (i.e., perception of mutual aid, trust, support). Multivariable logistic regression examined the independent effect of social cohesion on client condom refusal. Of 654 SWs, 22 % reported baseline client condom refusal and 34 % over 3 years. The baseline median social cohesion score was 24 (IQR 20–29, range 4–45). In the final confounding model, for every one-point increase in the social cohesion score, average odds of condom refusal decreased by 3 % (AOR 0.97; 95 % CI 0.95–0.99). Community empowerment can have a direct protective effect on HIV risk. These findings highlight the need for a legal framework that enables collectivization and SW-led efforts in the HIV response