Brg1 Regulates Hoxa9-Mediated Proliferation and Gene Expression in Acute Myeloid Leukemia

Honors (Bachelor's)Cell and Molecular BiologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/98944/1/snagara.pd

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy

Mapping inequalities in exclusive breastfeeding in low- and middle-income countries, 2000–2018

Exclusive breastfeeding (EBF)—giving infants only breast-milk for the first 6 months of life—is a component of optimal breastfeeding practices effective in preventing child morbidity and mortality. EBF practices are known to vary by population and comparable subnational estimates of prevalence and progress across low- and middle-income countries (LMICs) are required for planning policy and interventions. Here we present a geospatial analysis of EBF prevalence estimates from 2000 to 2018 across 94 LMICs mapped to policy-relevant administrative units (for example, districts), quantify subnational inequalities and their changes over time, and estimate probabilities of meeting the World Health Organization’s Global Nutrition Target (WHO GNT) of ≥70% EBF prevalence by 2030. While six LMICs are projected to meet the WHO GNT of ≥70% EBF prevalence at a national scale, only three are predicted to meet the target in all their district-level units by 2030

Additional file 4: of Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Table S2. Significant differentially expressed genes between normal cortical microglia, DIPG-associated macrophages, and aGBM-associated macrophages. (XLSX 75 kb

Additional file 6: of Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Figure S4. DIPG cells do not express significant levels of cytokines (a-b) FPKMs of cytokine (left), chemokine (middle) and other factors (right) expressed by patient-derived DIPG cell cultures (a) or in bulk primary DIPG tissue (b) Horizontal line represents FPKM = 5 (c) Violin plots of single-cell DIPG expression of cytokines, chemokines, and other factors from primary DIPG biopsy tissue. Horizontal line represents log(tpm + 1) = 1. (TIF 1442 kb

Additional file 3: of Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Figure S2. Isolated microglia/macrophages are enriched for myeloid genes. FPKMs binned across sample type for isolated DIPG (blue), aGBM (red), and pediatric cortical microglia/macrophages (green). There is minimal or absent expression of genes associated with other major cortical cell types (astrocytes, neurons, OPCs, oligodendrocytes, and endothelial cells). (TIF 948 kb

Additional file 1: of Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Table S1. Patient characteristics of early post-mortem DIPG autopsy cases. (XLSX 55 kb

Additional file 2: of Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Figure S1. Primary DIPG samples do not consistently demonstrate differential CD45 high/low populations (a-b) Representative FACS plots of primary DIPG tissue samples showing an example of an indistinguishable CD45 high/low sample (a) and a distinguishable CD45 high/low population (b). Samples were gated for size, singularity, and viability prior to these plots. (TIF 585 kb