AXIN2

Scientists are testing a novel technology to treat endodontic diseases more effectively through tissue regeneration instead of root canal therapy. Because the technology promotes formation of the type of stem cells that can differentiate into dentin (tooth), bone, cartilage or fat, it has huge potential for the field of regenerative medicine beyond the tissues in the teeth. It could be used to grow bones in other parts of the body. Want to avoid a root canal? In the future, you might be able to opt for tissue regeneration instead. ADA Forsyth scientists are testing a novel technology to treat endodontic diseases (diseases of the soft tissue or pulp in your teeth) more effectively. The study, "RvE1 Promotes Axin2+Cell Regeneration and Reduces Bacterial Invasion," which appeared in The Journal of Dental Research, demonstrates regenerative properties of resolvins, specifically Resolvin E1 (RvE1), when applied to dental pulp. Resolvins are part of a greater class of Specialized Proresolving Mediators (SPMs). This class of molecule is naturally produced by the body and is exquisitely effective in the control of excess inflammation associated with disease. "Pulpitis (inflammation of dental pulp) is a very common oral health disease that can become a serious health condition if not treated properly," said Dr. Thomas Van Dyke, Vice President at the Center for Clinical and Translational Research at ADA Forsyth, and a senior scientist leading the study. "Root canal therapy (RCT) is effective, but it does have some problems since you are removing significant portions of dentin, and the tooth dries out leading to a greater risk of fracture down the road. Our goal is to come up with a method for regenerating the pulp, instead of filling the root canal with inert material." Inflammation of this tissue is usually caused by damage to the tooth through injury, cavities or cracking, and the resulting infection can quickly kill the pulp and cause secondary problems if not treated. The study applied RvE1 to different levels of infected and damaged pulp to explore its regenerative and anti-inflammatory capacities. There were two major findings. First, they showed RvE1 is very effective at promoting pulp regeneration when used in direct pulp-capping of vital or living pulp (replicating conditions of reversible pulpitis). They were also able to identify the specific mechanism supporting tissue regeneration. Second, the scientists found that placing RvE1 on exposed and severely infected and necrotic pulp did not facilitate regeneration. However, this treatment did effectively slow down the rate of infection and treat the inflammation, preventing the periapical lesions (abscesses) that typically occur with this type of infection. Previous publications have shown that if the infected root canal is cleaned before RvE1 treatment, regeneration of the pulp does occur. While this study focused on this technology in treating endodontic disease, the potential therapeutic impact is far reaching. Dr. Van Dyke explained, "because application of RvE1 to dental pulp promotes formation of the type of stem cells that can differentiate into dentin (tooth), bone, cartilage or fat, this technology has huge potential for the field of regenerative medicine beyond the tissues in the teeth. It could be used to grow bones in other parts of the body, for instance." The study was funded by Alvin Krakow Harvard/Forsyth Research Fund (Y. Wu), and USPHS grant DE025020 from the National Institute of Dental and Craniofacial Research (NIDCR) (T.E. Van Dyke). Study authors include Yu-Chiao Wu, Ning Yu, Carla Alvarez Rivas, Nika Mehrnia, and Alpdogan Kantarci.

Researchers have identified several genetic variants associated with increased risk of cancer in children with non-chromosomal birth defects, such as congenital heart disease and defects of the central nervous system. While the risk of developing cancer is not as high as children with chromosomal birth defects, it is significantly higher than children with no birth defects at all, and the findings may provide a basis for early detection in these understudied patients. Researchers from Children's Hospital of Philadelphia (CHOP) have identified several genetic variants associated with increased risk of cancer in children with non-chromosomal birth defects, such as congenital heart disease and defects of the central nervous system. While the risk of developing cancer is not as high as children with chromosomal birth defects, it is significantly higher than children with no birth defects at all, and the findings may provide a basis for early detection in these understudied patients. The findings were recently published in the journal Biomarker Research. Children with birth defects are more likely to develop cancer, and that increased risk of cancer persists into adulthood. Prior studies have demonstrated that children with chromosomal birth defects, such as Down syndrome and Klinefelter syndrome, are more than 11 times more likely to be diagnosed with cancer than children without any birth defects. However, children with non-chromosomal birth defects are up to 2.5 times more likely to be diagnosed with cancer than those without birth defects. With birth defects of any kind occurring in 1 in every 33 births in the United States each year, that increased risk implicates a significant number of children. The underlying genetics of non-chromosomal birth defects have not been studied in great detail. Researchers at the Center for Applied Genomics (CAG) at CHOP wanted to determine what molecular mechanisms were at play and potentially identify genetic clues that could lead to early identification of cancer in these patients. "We assembled one of the largest pediatric oncology and birth defects projects in children as part of the Gabriella Miller Kids First program project, which helps to uncover new insights into childhood cancer and structural birth defects," said Hakon Hakonarson, MD, PhD, director of the CAG at CHOP and senior author of the study. "With this partnership, we sought to identify functional molecular pathways based on mutations we identified as part of this study." In this study, researchers used data obtained from whole genome sequencing of blood samples from 1,653 individuals without chromosomal abnormalities that were acquired from the Kids First Data Resource Center. These samples included 541 birth defect probands -- the first person in a family to receive genetic counseling or testing for hereditary risk of a disease -- with at least one type of malignant tumor, 767 birth defect probands without malignant tumors, and 345 healthy family members who are parents or siblings of the aforementioned probands. Additionally, once variants were identified, whole genome sequencing data from 40 birth defect probands from outside the data resource center, including 25 patients with at least one type of cancer, were used to further validate the study. The study identified thousands of variants of interest, including 119 genes with at least two variants in coding regions -- regions of the gene that will eventually be transcribed and translated into proteins to carry out essential functions -- and 478 genes with at least 20 variants in their non-coding regions. Five genes in particular -- AXIN2, BMP1, CR1, ERBB2, and RYR1 - are associated with birth defects and increased risk of cancer. Additionally, the researchers built a deep learning model to assess the variants of interest identified in the Kids First cohort when compared with the 40 validation samples and found that they had achieved approximately 75% accuracy, with even greater accuracy for variants that were associated with non-coding regions. Further detailed analysis of this data could identify genes and noncoding mutations that not only result in specific birth defects but also identify which types of cancer they are more prone to and whether the risk is more pronounced in childhood or adulthood. "While more research is needed to delve into the variants of interest we identified, this study represents a critical step toward the earlier detection of cancer children with non-chromosomal birth defects," Hakonarson said. The sequencing data was provided through the Gabriella Miller Kids First Pediatric Research Program consortium (Kids First), supported by the Common Fund of the Office of the Director of the National Institutes of Health. The study was supported by Institutional Development Funds from CHOP to the CAG.