Madison Butler

Subthalamic nucleus (STN) deep brain stimulation (DBS) is well-established for improving appendicular motor signs but its effect on axial motor signs is less clear. Additionally, the location of active electrode contact within the STN has been shown to differentially affect motor outcomes. We investigate the effect of STN DBS and the role of active electrode contact location on axial motor outcomes. Axial scores were assessed in 70 patients with advanced PD between 6 and 12 months after bilateral STN DBS. Repeated measures one-way ANOVA was performed to compare the mean axial motor scores between different medication and stimulation treatment conditions. Multiple linear regression was performed to determine the association between electrode contact location and axial motor score. The mean duration of follow-up was 7.37 ± 2.49 months. The mean total axial score was improved with STN DBS compared to the OFF MED-OFF STIM condition (6.36 ± 4.50 vs. 8.91 ± 5.49, p < 0.0001). A more dorsal electrode contact location on the right was associated with increased (worsened) total axial score (slope = 0.407, p = 0.0047). Total axial score was also lower (improved) in the anterior ventral STN region but not the posterior ventral STN region on the right. STN DBS improves total axial score and several axial subscores in patients with PD 6–12 months postoperatively. A more ventral electrode contact location on the right was associated with improved axial score. Additional research is warranted to determine if this is the optimal stimulation location to improve axial signs in other DBS cohorts.

Glioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CA^mut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients. We used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CA^mut from each of 3 mutated domains and induced their expression in NHA with (NHA^RAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CA^mut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro. PIK3CA^mut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHA^RAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHA^RAS tumorigenesis in vivo. PIK3CA^mut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHA^RAS harboring ABD or helical mutations. PIK3CA^mut promoted differential gliomagenesis based on the mutated domain. While PIK3CA^mut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CA^mut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.