The off-target distribution of anticancer nanoparticles (NP) to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this NP detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes (LPD) and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate ~70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Further, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well-known to be a major barrier to the delivery of therapeutic NP. Collectively, our results offer a proof of concept for the use of NP to modify TAFs as an effective strategy to treat desmoplastic cancers.

The human brain develops rapidly in the first postnatal year, in which rewired functional brain networks could shape later behavioral and cognitive performance. Resting-state functional magnetic resonances imaging (rs-fMRI) and complex network analysis have been widely used for characterizing the developmental brain functional connectome. Yet, such studies focusing on the first year of postnatal life are still very limited. Leveraging normally developing longitudinal infant rs-fMRI scans from neonate to one year of age, we investigated how brain functional networks develop at a fine temporal scale (every 3 months). Considering challenges in the infant fMRIbased network analysis, we developed a novel algorithm to construct the robust, temporally consistent and modular structure augmented group-level network based on which functional modules were detected at each age. Our study reveals that the brain functional network is gradually subdivided into an increasing number of functional modules accompanied by the strengthened intra-and inter-modular connectivities. Based on the developing modules, we found connector hubs (the high-centrality regions connecting different modules) emerging and increasing, while provincial hubs (the high-centrality regions connecting regions in the same module) diminishing. Further region-wise longitudinal analysis validates that different hubs have distinct developmental trajectories of the intra-and inter-modular connections suggesting different types of role transitions in network, such as non-hubs to hubs or provincial hubs to connector hubs

Adult brains are functionally flexible, a unique characteristic that is thought to contribute to cognitive flexibility. While tools to assess cognitive flexibility during early infancy are lacking, we aimed to assess the spatiotemporal developmental features of “neural flexibility” during the first 2 y of life. Fifty-two typically developing children 0 to 2 y old were longitudinally imaged up to seven times during natural sleep using resting-state functional MRI. Using a sliding window approach, MR-derived neural flexibility, a quantitative measure of the frequency at which brain regions change their allegiance from one functional module to another during a given time period, was used to evaluate the temporal emergence of neural flexibility during early infancy. Results showed that neural flexibility of whole brain, motor, and high-order brain functional networks/regions increased significantly with age, while visual regions exhibited a temporally stable pattern, suggesting spatially and temporally nonuniform developmental features of neural flexibility. Additionally, the neural flexibility of the primary visual network at 3 mo of age was significantly and negatively associated with cognitive ability evaluated at 5/6 y of age. The “flexible club,” comprising brain regions with neural flexibility significantly higher than whole-brain neural flexibility, were consistent with brain regions known to govern cognitive flexibility in adults and exhibited unique characteristics when compared to the functional hub and diverse club regions. Thus, MR-derived neural flexibility has the potential to reveal the underlying neural substrates for developing a cognitively flexible brain during early infancy.

Prenatal opioid exposure has been linked to altered neurodevelopment and visual problems such as strabismus and nystagmus. The neural substrate underlying these alterations is unclear. Resting-state functional connectivity MRI (rsfMRI) is an advanced and well-established technique to evaluate brain networks. Few studies have examined the effects of prenatal opioid exposure on resting-state network connectivity in infancy. In this pilot study, we characterized network connectivity in opioid-exposed infants (n = 19) and controls (n = 20) between 4–8 weeks of age using both a whole-brain connectomic approach and a seed-based approach. Prenatal opioid exposure was associated with differences in distribution of betweenness centrality and connection length, with positive connections unique to each group significantly longer than common connections. The unique connections in the opioid-exposed group were more often inter-network connections while unique connections in controls and connections common to both groups were more often intra-network. The opioid-exposed group had smaller network volumes particularly in the primary visual network, but similar network strength as controls. Network topologies as determined by dice similarity index were different between groups, particularly in visual and executive control networks. These results may provide insight into the neural basis for the developmental and visual problems associated with prenatal opioid exposure.