Growth inhibition associated with disruption of the actin cytoskeleton by Latrunculin A in rhabdomyosarcoma cells.

Functional genomic screening of KRAS-driven mouse sarcomas was previously employed to identify proliferation-relevant genes. Genes identified included Ubiquitin-conjugating enzyme E2 (Ube2c), Centromere Protein E (Cenpe), Hyaluronan Synthase 2 (Has2), and CAMP Responsive Element Binding Protein 3 Like 2 (Creb3l2). This study examines the expression and chemical inhibition of these candidate genes, identifying variable levels of protein expression and significant contributions to rhabdomyosarcoma (RMS) cell proliferation.

Enduring and Sex-specific Changes in Hippocampal Gene Expression after a Subchronic Immune Challenge.

Major illnesses, including heart attack and sepsis, can cause cognitive impairments, depression, and progressive memory decline that persist long after recovery from the original illness. In rodent models of sepsis or subchronic immune challenge, memory deficits also persist for weeks or months, even in the absence of ongoing neuroimmune activation. This raises the question of what mechanisms in the brain mediate such persistent changes in neural function.

Memory deficits in males and females long after subchronic immune challenge.

Memory impairments and cognitive decline persist long after recovery from major illness or injury, and correlate with increased risk of later dementia. Here we developed a subchronic peripheral immune challenge model to examine delayed and persistent memory impairments in females and in males. We show that intermittent injections of either lipopolysaccharides or Poly I:C cause memory decline in both sexes that are evident eight weeks after the immune challenge.

Neuroimmune Activation Drives Multiple Brain States.

Neuroimmune signaling is increasingly identified as a critical component of neuronal processes underlying memory, emotion and cognition. The interactions of microglia and astrocytes with neurons and synapses, and the individual cytokines and immune signaling molecules that mediate these interactions are a current focus of much research. Here, we discuss neuroimmune activation as a mechanism triggering different states that modulate cognitive and affective processes to allow for appropriate behavior during and after illness or injury.

Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma.

Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a.

Hedgehog-driven myogenic tumors recapitulate skeletal muscle cellular heterogeneity.

Hedgehog (Hh) pathway activation in R26-SmoM2;CAGGS-CreER mice, which carry a tamoxifen-inducible activated Smoothened allele (SmoM2), results in numerous microscopic tumor foci in mouse skeletal muscle. These tumors exhibit a highly differentiated myogenic phenotype and resemble human fetal rhabdomyomas. This study sought to apply previously established strategies to isolate lineally distinct populations of normal mouse myofiber-associated cells in order to examine cellular heterogeneity in SmoM2 tumors.

Isolation of progenitors that exhibit myogenic/osteogenic bipotency in vitro by fluorescence-activated cell sorting from human fetal muscle.

Fluorescence-activated cell sorting (FACS) strategies to purify distinct cell types from the pool of fetal human myofiber-associated (hMFA) cells were developed. We demonstrate that cells expressing the satellite cell marker PAX7 are highly enriched within the subset of CD45(-)CD11b(-)GlyA(-)CD31(-)CD34(-)CD56(int)ITGA7(hi) hMFA cells. These CD45(-)CD11b(-)GlyA(-)CD31(-)CD34(-)CD56(int)ITGA7(hi) cells lack adipogenic capacity but exhibit robust, bipotent myogenic and osteogenic activity in vitro and engraft myofibers when transplanted into mouse muscle.