Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.

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Fasciotomy of the forearm is a well-described technique for the treatment of compartment syndrome in adults; however, it has not been discussed with sufficient details in the setting of neonatal compartment syndrome. When performing a fasciotomy, it is imperative to decompress all compartments within the forearm to limit the ischemic damage and prevent the progression of the disease. Although it is common to utilize both volar and dorsal incisions to release these compartments, we describe a method that potentially allows for total decompression through a single volar incision with minimal to no morbidity. This novel technique provides sufficient soft-tissue exposure while improving upon the cosmesis that results from a traditional approach.

Background: Favorable rates of meaningful recovery (≥M3/S3) of processed nerve allografts (PNAs) for mixed and motor nerve injuries have been reported, but there are few reports of patients having complete PNA failure (M0/S0). The purpose of this study was to describe the outcomes, including rate of complete failures, in a case series of patients who underwent PNA for peripheral mixed nerve reconstructions. Methods: A retrospective review of outcomes between May 2018 to September 2020 was performed. Consecutive patients who underwent nerve reconstruction (>15 mm) with PNA for a peripheral mixed nerve injury of the upper or lower extremity were eligible. Those who returned to clinic for a 10-month postoperative visit were included in this study. The primary outcome was whether the patient was defined as having a complete failure (M0/S0). Results: A total of 22 patients underwent a PNA during the time period; 14 patients participated in follow-up and were included (average age: 34.7 years) with a mean follow-up of 11.9 months. The average gap length was 46.4 mm (range 15–110 mm). At their 10-month postoperative visit, no patients had any motor or sensory improvement; all patients were deemed as having complete failure. Four patients underwent or were planned for subsequent revision surgery. Conclusions: In this study, we demonstrated a high number of complete failures, with all 14 included patients sustaining a complete failure (100% failure rate) at a minimum 10-month follow-up visit. Failure in this case series was not observed to affect one nerve type, location, or be related to preoperative injury size.

The 70 kDa and 90 kDa heat shock proteins Hsp70 and Hsp90 are two abundant and highly conserved ATP-dependent molecular chaperones that participate in the maintenance of cellular homeostasis. In Escherichia coli, Hsp90 (Hsp90Ec) and Hsp70 (DnaK) directly interact and collaborate in protein remodeling. Previous work has produced a model of the direct interaction of both chaperones. The locations of the residues involved have been confirmed and the model has been validated. In this study, we investigate the allosteric communication between Hsp90Ec and DnaK and how the chaperones couple their conformational cycles. Using elastic network models (ENM), normal mode analysis (NMA), and a structural perturbation method (SPM) of asymmetric and symmetric DnaK-Hsp90Ec, we extract biologically relevant vibrations and identify residues involved in allosteric signaling. When one DnaK is bound, the dominant normal modes favor biological motions that orient a substrate protein bound to DnaK within the substrate/client binding site of Hsp90Ec and release the substrate from the DnaK substrate binding domain. The presence of one DnaK molecule stabilizes the entire Hsp90Ec protomer to which it is bound. Conversely, the symmetric model of DnaK binding results in steric clashes of DnaK molecules and suggests that the Hsp90Ec and DnaK chaperone cycles operate independently. Together, this data supports an asymmetric binding of DnaK to Hsp90Ec.