Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

© 2016 The Author(s) Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies

An Evaluation of Parent Preference for Prompting Procedures

Parent participation in intervention can enhance intervention efficacy and promote generalization of skills across settings. Thus, parents should be trained to implement behavioral interventions. The purpose of the current investigation was to evaluate parent preference for and acceptability of 3 commonly used prompting procedures. We trained parents of children with disabilities to use 3 empirically validated prompting strategies (i.e., least‐to‐most, most‐to‐least, and a progressive‐prompt delay). Once the parent reached the mastery criteria with each prompting procedure, we evaluated his/her preference for each of the procedures using a concurrent‐chains arrangement. We also measured treatment acceptability of all procedures throughout the study. All participants met the mastery criteria for each of the prompting procedures and showed a preference for least‐to‐most prompting. Results suggest parents\u27 acceptability of procedures prior to training were different than posttraining/post‐child practice. In addition, acceptability rating scores obtained at the end of the investigation corresponded to preference of intervention during the concurrent‐chains arrangement. The results demonstrate the benefits of objective measures for studying preference for behavioral, skill‐acquisition procedures

In Vivo Expression of MHC Class I Genes Depends on the Presence of a Downstream Barrier Element

Regulation of MHC class I gene expression is critical to achieve proper immune surveillance. In this work, we identify elements downstream of the MHC class I promoter that are necessary for appropriate in vivo regulation: a novel barrier element that protects the MHC class I gene from silencing and elements within the first two introns that contribute to tissue specific transcription. The barrier element is located in intergenic sequences 3′ to the polyA addition site. It is necessary for stable expression in vivo, but has no effect in transient transfection assays. Accordingly, in both transgenic mice and stably transfected cell lines, truncation of the barrier resulted in transcriptional gene silencing, increased nucleosomal density and decreased histone H3K9/K14 acetylation and H3K4 di-methylation across the gene. Significantly, distinct sequences within the barrier element govern anti-silencing and chromatin modifications. Thus, this novel barrier element functions to maintain transcriptionally permissive chromatin organization and prevent transcriptional silencing of the MHC class I gene, ensuring it is poised to respond to immune signaling

Rapid niche expansion by selection on functional genomic variation after ecosystem recovery

It is well recognized that environmental degradation caused by human activities can result in dramatic losses of species and diversity. However, comparatively little is known about the ability of biodiversity to re-emerge following ecosystem recovery. Here, we show that a European whitefish subspecies, the gangfisch Coregonus lavaretus macrophthalmus, rapidly increased its ecologically functional diversity following the restoration of Lake Constance after anthropogenic eutrophication. In fewer than ten generations, gangfisch evolved a greater range of gill raker numbers (GRNs) to utilize a broader ecological niche. A sparse genetic architecture underlies this variation in GRN. Several co-expressed gene modules and genes showing signals of positive selection were associated with GRN and body shape. These were enriched for biological pathways related to trophic niche expansion in fishes. Our findings demonstrate the potential of functional diversity to expand following habitat restoration, given a fortuitous combination of genetic architecture, genetic diversity and selection

Effect of rehabilitation exercise durations on the dynamic bone repair process by coupling polymer scaffold degradation and bone formation

Implantation of biodegradable scaffold is considered as a promising method to treat bone disorders, but knowledge of the dynamic bone repair process is extremely limited. In this study, based on the representative volume cell of a periodic scaffold, the influence of rehabilitation exercise duration per day on the bone repair was investigated by a computational framework. The framework coupled scaffold degradation and bone remodeling. The scaffold degradation was described by a function of stochastic hydrolysis independent of mechanical stimulation, and the bone formation was remodeled by a function of the mechanical stimulation, i.e., strain energy density. Then, numerical simulations were performed to study the dynamic bone repair process. The results showed that the scaffold degradation and the bone formation in the process were competitive. An optimal exercise duration per day emerged. All exercise durations promoted the bone maturation with a final Young's modulus of 1.9 ± 0.3 GPa. The present study connects clinical rehabilitation and fundamental research, and is helpful to understand the bone repair process and further design bone scaffold for bone tissue engineering

Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production

Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis that brain damage induced changes in the intestinal microbiota. Experimental stroke altered the composition of caecal microbiota, with specific changes in Peptococcaceae and Prevotellaceae correlating with the extent of injury. These effects are mediated by noradrenaline release from the autonomic nervous system with altered caecal mucoprotein production and goblet cell numbers. Traumatic brain injury also caused changes in the gut microbiota, confirming brain injury effects gut microbiota. Changes in intestinal microbiota after brain injury may affect recovery and treatment of patients should appreciate such changes