Isolation and characterization of patient-derived CNS metastasis-associated stromal cell lines.

The functional role of human derived stromal cells in the tumor microenviornment of CNS metastases (CM) remain understudied. The purpose of the current study was to isolate and characterize stromal cells of the tumor microenvironment in CM. Four different patient-derived cell lines (PDCs) of stromal and one PDC of tumorigenic origin were generated from breast or lung CM. PDCs were analyzed by DNA/RNA sequencing, DNA methylation profiling, and immunophenotypic assays. The stromal derived PDCs were termed CNS metastasis-associated stromal cells (cMASCs). Functional analysis of cMASCs was tested by co-implanting them with tumorigenic cells in mice. cMASCs displayed normal genotypes compared with tumorigenic cell lines. RNA-seq and DNA methylation analyses demonstrated that cMASCs highly resembled each other, suggesting a common cell of origin. Additionally, cMASCs revealed gene expression signatures associated with cancer associated fibroblasts (CAFs), epithelial to mesenchymal transition, mesenchymal stem cells and expressed high levels of collagen. Functionally, cMASCs restricted tumor growth, and induced desmoplasia in vivo, suggesting that cMASCs may promote a protective host response to impede tumor growth. In summary, we demonstrated the isolation, molecular characterization and functional role of human derived cMASCs, a subpopulation of cells in the microenvironment of CM that have tumor inhibitory functions.

Pre-diagnosis physical activity habits are associated with age of diagnosis in Parkinson's disease.

INTRODUCTION: Studies suggest that exercise may be neuroprotective when implemented before the clinical presentation of Parkinson's disease (PD). Levels of brain-derived neurotrophic factor (BDNF), theorized to play a role in neuroprotection, are affected by its genotype and exercise. Here we explore this previously unstudied interaction on age at diagnosis and severity of symptoms. METHODS: 76 participants with PD submitted buccal cells to determine BDNF genotype, completed the modified Lifetime Physical Activity Questionnaire to determine exercise habits, and were assessed using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale III (MDS-UPDRS-III) and the Mini-Balance Evaluations Test (MBT). For aim 1 (age at diagnosis), 60 participants (age = 69.6 ±â€¯7.4; males = 45, females = 15) were analyzed. For aim 2 (severity of symptoms), 54 participants (age = 70.0 ±â€¯7.6; males = 41, females = 13) were analyzed. RESULTS: The final hierarchical regression model for age at diagnosis produced an R2 = 0.146, p = .033; however, the only significant variable in the final model was average moderate physical activity from ages 20s to 40s (p = .009). The regression for MDS-UPDRS III was not significant; however, the regression for MBT was, p = .0499. In the final model, 23.1% of the variance was explained. Years since diagnosis (p = .014) and average vigorous physical activity from ages 20s to 40s (p = .047) were the only predictors in the final model. CONCLUSIONS: While a strong interaction between BDNF genotype and lifetime physical activity was not observed, our results suggest that lifetime exercise may be neuroprotective in PD. Specifically, higher amounts of moderate PA were associated with an older age at diagnosis.

Integrated genomic and epigenomic analysis of breast cancer brain metastasis.

The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.