Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP ؉/؊ mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP ؉/؊ mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP ؉/؊ mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.

Few therapeutic options exist for the highly aggressive triple negative breast cancers (TNBCs). In this study, we report that a contextual synthetic lethality can be achieved both in vitro and in vivo with combined EGFR and PARP inhibition with lapatinib and ABT-888, respectively. The mechanism involves a transient DNA double strand break repair deficit induced by lapatinib and subsequent activation of the intrinsic pathway of apoptosis. Further dissection of the mechanism reveals that EGFR and BRCA1 can be found in the same protein complex, which is reduced by lapatinib. Interestingly, lapatinib also increases cytosolic BRCA1 and EGFR, away from their nuclear DNA repair substrates. Taken together, these results reveal a novel regulation of homologous recombination repair involving EGFR and BRCA1 interaction and alteration of subcellular localization. Additionally, a contextual synthetic lethality may exist between combined EGFR and PARP inhibitors.

Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

Pre-operative clinical and geriatric assessment tools can help predict the need for discharge to a nursing facility or increased length of stay. Future studies will be required to identify patients suitable for interventions to decrease hospital and post-discharge resource utilization.

No abstract

A tumor is a complex “organ” composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically “normal” tumor stroma contribute to tumor progression and resistance to a wide array of treatment modalities, including radiotherapy. Cancer-associated fibroblasts can promote radioresistance through their secreted factors, contact-mediated signaling, downstream pro-survival signaling pathways, immunomodulatory effects, and cancer stem cell-generating role. The extracellular matrix can govern radiation responsiveness by influencing oxygen availability and controlling the stability and bioavailability of growth factors and cytokines. Immune status regarding the presence of pro- and anti-tumor immune cells can regulate how tumors respond to radiation therapy. Furthermore, stromal cells including endothelial cells and adipocytes can modulate radiosensitivity through their roles in angiogenesis and vasculogenesis, and their secreted adipokines, respectively. Thus, to successfully eradicate cancers, it is important to consider how tumor stroma components interact with and regulate the response to radiation. Detailed knowledge of these interactions will help build a preclinical rationale to support the use of stromal-targeting agents in combination with radiotherapy to increase radiosensitivity.

SeriFascia surgical mesh initially bioresorbed at an ideal rate that supported the transfer of load-bearing responsibility to developing host repair tissue. The results indicate the development of functional native tissue that could potentially minimize any long-term complication associated with presently available mesh implants.

The primary objectives of this study were (a) to measure potential exposures of applicators and assistants to airborne methylene diphenyl diisocyanate (MDI), (b) to measure airborne concentrations of MDI at various distances from the spray foam application, and (c) to measure airborne MDI concentrations as a function of time elapsed since application. Other study objectives were, (a) to compare the results from filter and impinger samples; (b) to determine the particle size distribution in the spray foam aerosol; (c) to determine potential exposures to dichlorofluoroethane; and (d) to measure any off-gassing of MDI after the foam had fully cured. This study was conducted during application of spray polyurethane foam inside five single-family homes under construction in the United States and Canada. Spray foam applicators and assistants may be exposed to airborne MDI concentrations above the OSHA permissible exposure limit. At these concentrations, OSHA recommends appropriate respiratory protection during spray foam application to prevent airborne MDI exposures above established limits and to protect against exposure to dichlorofluoroethane (HCFC-141b). Airborne MDI concentrations decrease rapidly after foam application ceases. The highest airborne concentrations measured after 15 min and 45 min were 0.019 mg/m3 and 0.003 mg/m3, respectively. After 45 min, airborne concentrations were below the limit of quantitation (LOQ) of 0.036-microg per sample. For samples taken 24 hours after completion of foaming, results were also below the LOQ. Approximately two-thirds of the total mass of the airborne particles in the spray foam aerosol was greater than 3.5 microns in diameter. Airborne MDI concentrations determined by filter sampling methods were 6% to 40% lower than those determined by impinger methods.