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.     

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.     

Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry

Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the consecutive interaction of the envelope glycoprotein gp120 with CD4 and a coreceptor such as CCR5 or CXCR4. The CCR5 coreceptor is used by the most commonly transmitted HIV-1 strains that often persist throughout the course of infection. Compounds targeting CCR5-mediated entry are a novel class of drugs being developed to treat HIV-1 infection. In this study, we have identified the mechanism of action of two inhibitors of CCR5 function, SCH-350581 (AD101) and SCH-351125 (SCH-C). AD101 is more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines. Both molecules also block the binding of several anti-CCR5 monoclonal antibodies that recognize epitopes in the second extracellular loop of CCR5. Alanine mutagenesis of the transmembrane domain of CCR5 suggests that AD101 and SCH-C bind to overlapping but nonidentical sites within a putative ligand-binding cavity formed by transmembrane helices 1, 2, 3, and 7. We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5.     

Heterologous expression of new antifungal chitinase from wheat

Chitinases (EC 3.2.1.14) have been grouped into seven classes (class I-VII) on the basis of their structural properties. Chitinases expressed during plant-microbe interaction are involved in defense responses of host plant against pathogens. In the present investigation, chitinase gene from wheat has been subcloned and overexpressed in Escherichia coli BL-21 (DE3). Molecular phylogeny analyses of wheat chitinase indicated that it belongs to an acidic form of class VII chitinase (glycosyl hydrolase family 19) and shows 77% identity with other wheat chitinase of class IV and low level identity to other plant chitinases. The three-dimensional structural model of wheat chitinase showed the presence of 10 alpha-helices, 3 beta-strands, 21 loop turns and the presence of 6 cysteine residues that are responsible for the formation of 3 disulphide bridges. The active site residues (Glu94 and Glu103) may be suggested for its antifungal activity. Expression of chitinase (33 kDa) was confirmed by SDS-PAGE and Western hybridization analyses. The yield of purified chitinase was 20 mg/L with chitinase activity of 1.9 U/mg. Purified chitinase exerted a broad-spectrum antifungal activity against Colletotrichum falcatum (red rot of sugarcane) Pestalotia theae (leaf spot of tea), Rhizoctonia solani (sheath blight of rice), Sarocladium oryzae (sheath rot of rice) Alternaria sp. (grain discoloration of rice) and Fusarium sp. (scab of rye). Due to its innate antifungal potential wheat chitinase can be used to enhance fungal-resistance in crop plants.     

Cloning and overexpression of antifungal barley chitinase gene in Escherichia coli

Plant chitinases are pathogenesis-related proteins, which are believed to be involved in plant defense responses to pathogen infection. In this study, chitinase gene from barley was cloned and overexpressed in Escherichia coli. Chitinase (35 kDa) was isolated and purified. Since the protein was produced as insoluble inclusion bodies, the protein was solubilized and refolded. Purified chitinase exerted broad-spectrum antifungal activity against Botrytis cinerea (blight of tobacco), Pestalotia theae (leaf spot of tea), Bipolaris oryzae (brown spot of rice), Alternaria sp. (grain discoloration of rice), Curvularia lunata (leaf spot of clover) and Rhizoctonia solani (sheath blight of rice). Due to the potential of broad-spectrum antifungal activity barley chitinase gene can be used to enhance fungal-resistance in crop plants such as rice, tobacco, tea and clover.     

Discovery of a series of potent arylthiadiazole H(3) antagonists

A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.     

Synthesis and structure-activity relationship (SAR) study of 4-azabenzoxazole analogues as H3 antagonists

The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.     

A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors

A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.