The Relationship Between Lesion Size and Load to Failure After Stabilization of Simulated Metastatic Lesions of the Proximal Femur

BackgroundAs overall cancer survival continues to improve, the incidence of metastatic lesions to the bone continues to increase. The subsequent skeletal related events that can occur with osseous metastasis can be debilitating. Complete and impending pathologic femur fractures are common with patients often requiring operative fixation. However, the efficacy of an intramedullary nail construct, on providing stability, continue to be debated. Therefore, the purpose of this study was to utilize a synthetic femur model to determine 1) how proximal femur defect size and cortical breach impact femur load to failure (strength) and stiffness, and 2) and how the utilization of an IMN, in a prophylactic fashion, subsequently alters the overall strength and stiffness of the proximal femur.MethodsA total of 21 synthetic femur models were divided into four groups: 1) intact (no defect), 2) 2 cm defect, 3) 2.5 cm defect, and 4) 4 cm defect. An IMN was inserted in half of the femur specimens that had a defect present. This procedure was performed using standard antegrade technique. Specimens were mechanically tested in offset torsion. Force-displacement curves were utilized to determine each constructs load to failure and overall torsional stiffness. The ultimate load to failure and construct stiffness of the synthetic femurs with defects were compared to the intact synthetic femur, while the femurs with the placement of the IMN were directly compared to the synthetic femurs with matching defect size.ResultsThe size of the defect invertedly correlated with the load the failure and overall stiffness. There was no difference in load to failure or overall stiffness when comparing intact models with no defect and the 2 cm defect group (p=0.98, p=0.43). The 2.5 cm, and 4.5 cm defect groups demonstrated significant difference in both load to failure and overall stiffness when compared to intact models with results demonstrating 1313 N (95% CI: 874-1752 N; p<0.001) and 104 N/mm (95% CI: 98-110 N/mm; p=0.03) in the 2.5 cm defect models, and 512 N (95% CI: 390-634 N, p<0.001) and 21 N/mm (95% CI: 9-33 N/mm, p<0.001) in the models with a 4 cm defect. Compared to the groups with defects, the placement an IMN increased overall stiffness in the 2.5 cm defect group (125 N/mm; 95% CI:114-136 N/mm; p=0.003), but not load to failure (p=0.91). In the 4 cm defect group, there was a significant increase in load to failure (1067 N; 95% CI: 835-1300 N; p=0.002) and overall stiffness (57 N/mm; 95% CI:46-69 N/mm; p=0.001).ConclusionProphylactic IMN fixation significantly improved failure load and overall stiffness in the group with the largest cortical defects, but still demonstrated a failure loads less than 50% of the intact model. This investigation suggests that a cortical breach causes a loss of strength that is not completely restored by intramedullary fixation. Level of Evidence: II     

The First Report on Excellent Cycling Stability and Superior Rate Capability of Na3V2(PO4)3 for Sodium Ion Batteries

Sodium ion batteries are attractive for the rapidly emerging large‐scale energy storage market for intermittent renewable resources. Currently a viable cathode material does not exist for practical non‐aqueous sodium ion battery applications. Here we disclose a high performance, durable electrode material based on the 3D NASICON framework. Porous Na₃V₂(PO₄)₃/C was synthesized using a novel solution‐based approach. This material, as a cathode, is capable of delivering an energy storage capacity of ～400 mWh/g vs. sodium metal. Furthermore, at high current rates (10, 20 and 40 C), it displayed remarkable capacity retention. Equally impressive is the long term cycle life. Nearly 50% of the initial capacity was retained after 30,000 charge/discharge cycles at 40 C (4.7 A/g). Notably, coulombic efficiency was 99.68% (average) over the course of cycling. To the best of our knowledge, the combination of high energy density, high power density and ultra long cycle life demonstrated here has never been reported before for sodium ion batteries. We believe our findings will have profound implications for developing large‐scale energy storage systems for renewable energy sources.     

Modulation of G protein-coupled adenosine receptors by strategically functionalized agonists and antagonists immobilized on gold nanoparticles

Gold nanoparticles (AuNPs) allow the tuning of pharmacokinetic and pharmacodynamic properties by active or passive targeting of drugs for cancer and other diseases. We have functionalized gold nanoparticles by tethering specific ligands, agonists and antagonists, of adenosine receptors (ARs) to the gold surface as models for cell surface interactions with G protein-coupled receptors (GPCRs). The AuNP conjugates with chain-extended AR ligands alone (PEGylated nucleosides and nonnucleosides, anchored to the Au via thioctic acid) were found to be insoluble in water due to hydrophobic entities in the ligand. Therefore, we added a second, biologically inactive pendant moiety to increase the water solubility, consisting of a PEGylated chain terminating in a carboxylic or phosphate group. The purity and stability of the immobilized biologically active ligand were examined by ultrafiltration and HPLC. Pharmacological receptor binding studies on these GPCR ligand-derivatized AuNPs (2–5 nm in diameter), performed using membranes of mammalian cells stably expressing human A₁, A_2A, and A₃ARs, showed that the desired selectivity was retained with K _i values (nanomolar) of A₃AR agonist 21b and A_2AAR antagonists 24 and 26a of 14 (A₃), 34 (A_2A), and 69 (A_2A), respectively. The corresponding monomers displayed K _i values of 37, 61, and 1,420 nM, respectively. In conclusion, we have synthesized stable, water-soluble AuNP derivatives of tethered A₃ and A_2AAR ligands that retain the biological properties of their monomeric ligands and are intended for therapeutic and imaging applications. This is the first prototypical application to gold carriers of small molecule (nonpeptide) GPCR ligands, which are under investigation for treatment of cancer and inflammatory diseases.     

Conformation constraint of anilides enabling the discovery of tricyclic lactams as potent MK2 non-ATP competitive inhibitors

Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.     

Heregulin-induced epigenetic regulation of the utrophin-A promoter

Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin is of therapeutic interest since its over-expression can compensate dystrophin's absence. Utrophin is enriched at neuromuscular junctions due to heregulin-mediated utrophin-A promoter activation. We demonstrate that heregulin activated MSK1/2 and phosphorylated histone H3 at serine 10 in cultured C2C12 muscle cells, in an ERK-dependent manner. MSK1/2 inhibition suppressed heregulin-mediated utrophin-A activation. MSK1 over-expression potentiated heregulin-mediated utrophin-A activation and chromatin remodeling at the utrophin-A promoter. These results identify MSK1/2 as key effectors modulating utrophin-A expression as well as identify novel targets for DMD therapy.     

Optical analysis of RE3+ (RE = Nd or Er):B2O3–P2O5–CaF2–ZnO–(Li2O/Na2O/K2O) glasses

Calcium boro fluoro zinc phosphate glasses modified using alkali oxide and doped with Nd³⁺ and Er³⁺ ions with the chemical composition of 69.5 (B₂O₃) + 10 (P₂O₅) + 10 (CaF₂) + 5 (ZnO) + 5 (Na₂O/Li₂O/K₂O) + 0.5 (Er₂O₃/Nd₂O₃) were prepared using a conventional melt quenching technique. The results of X-ray diffraction patterns indicated the amorphous nature of all the prepared glasses. The visible–near-infrared red (NIR) absorption spectra of these glasses were analyzed systematically. The NIR emission spectra of Er³⁺ and Nd³⁺:calcium boro fluoro zinc phosphate glasses showed prominent emission bands at 1536 nm (⁴I_13/2→⁴I_15/2) and 1069 nm (⁴F_3/2→⁴I_11/2) respectively with λ_exci = 514.5 nm (Ar⁺ laser) as the excitation source.