BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair.

The cellular and humoral responses that orchestrate fracture healing are still elusive. Here we report that bone morphogenic protein 2 (BMP2)-dependent fracture healing occurs through a tight control of chemokine C-X-C motif-ligand-12 (CXCL12) cellular, spatial, and temporal expression. We found that the fracture repair process elicited an early site-specific response of CXCL12(+)-BMP2(+) endosteal cells and osteocytes that was not present in unfractured bones and gradually decreased as healing progressed.

PTEN deficiency mediates a reciprocal response to IGFI and mTOR inhibition.

Unlabelled: Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified.

Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors.

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response.

Treatment of childhood kaposiform hemangioendothelioma with sirolimus.

Sirolimus (Rapamune), a mammalian target of Rapamycin (mTOR) inhibitor, which has been used extensively in children following solid organ transplantation, has been demonstrated to have anti-angiogenic activity in pre-clinical models. Limited experience suggests that it may have application to the treatment of vascular lesions. We describe our experience with a 1-year-old female with a kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon who had rapid and dramatic response to sirolimus (0.

Inhibition of IGF-I receptor signaling in combination with rapamycin or temsirolimus increases MYC-N phosphorylation.

Background: It has been previously shown that blockade of the type 1 insulin-like growth factor receptor (IGF1R) signaling combined with mTOR inhibition decreased neuroblastoma proliferation in vitro. MYC-N inactivation occurs through phosphorylation by downstream elements of the IGF1R signaling pathway. It was hypothesized that inhibition of IGF1R signaling would increase the inactivation of MYC-N.