Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone, FAcilitates Chromatin Transcription (FACT), as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small molecule curaxin compound, CBL0137, markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.
A significant number of prisoners experience mental health problems, and adequate social support is one way that facilitates better mental health. Yet, by being incarcerated, social support, particularly family support, is likely to be strained or even negative. In this study, we examine whether familial support--either positive or negative--in-prison and after release affects mental health outcomes post-release. Using the Serious and Violent Offender Reentry Initiative (SVORI) dataset, we regress post-release mental health on in-prison familial support, post-incarceration familial support, and changes in familial support. We find that while in-prison family support does not affect mental health, post-release familial support does. Also, experiencing an increase in negative familial support is associated with lower post-incarceration mental health. We conclude with a discussion of policies which may facilitate better familial support environments.
Pneumonia remains a global health threat, in part due to expanding categories of susceptible individuals and increasing prevalence of antibiotic resistant pathogens. However, therapeutic stimulation of the lungs’ mucosal defenses by inhaled exposure to a synergistic combination of Toll-like receptor (TLR) agonists known as Pam2-ODN promotes mouse survival of pneumonia caused by a wide array of pathogens. This inducible resistance to pneumonia relies on intact lung epithelial TLR signaling, and inducible protection against viral pathogens has recently been shown to require increased production of epithelial reactive oxygen species (ROS) from multiple epithelial ROS generators. To determine whether similar mechanisms contribute to inducible antibacterial responses, the current work investigates the role of ROS in therapeutically-stimulated protection against Pseudomonas aerugnosa challenges. Inhaled Pam2-ODN treatment one day before infection prevented hemorrhagic lung cytotoxicity and mouse death in a manner that correlated with reduction in bacterial burden. The bacterial killing effect of Pam2-ODN was recapitulated in isolated mouse and human lung epithelial cells, and the protection correlated with inducible epithelial generation of ROS. Scavenging or targeted blockade of ROS production from either dual oxidase or mitochondrial sources resulted in near complete loss of Pam2-ODN-induced bacterial killing, whereas deficiency of induced antimicrobial peptides had little effect. These findings support a central role for multisource epithelial ROS in inducible resistance against a bacterial pathogen and provide mechanistic insights into means to protect vulnerable patients against lethal infections.
Traveler response to the introduction of parking user fees at heavily patronized park-and-ride facilities within the San Francisco Bay Area Rapid Transit (BART) District of California is investigated. After an analysis of systemwide impacts, detailed research at two stations was performed with mail-back surveys, license plate surveys, and focus groups. The primary finding is that introduction of daily parking fees did not cause significant changes in access mode choice, facility location, or line-haul mode of park-and-ride users. New, higher-fee, daily reserved spaces were popular substitutes for monthly reserved spaces. The increased availability of parking spaces shifted arrival times later in the morning at the two stations. Even with user fees, for most trips to regional central business districts the overall cost of using a park-and-ride facility and BART still remained well below the cost of the trip made by automobile only. Overall BART ridership and ridership at those stations where new fees were introduced, remained unchanged.
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