Abstract MEK inhibitors (MEKi) PD0325901 and AZD6244 (Selumetinib) are drugs currently under clinical investigation for cancer treatment, however the Ras–MAPK pathway is also an important mediator of ...normal bone cell differentiation and function. In this study we examined the effects of these compounds on endochondral processes using both in vitro and in vivo models. Treatment with PD0325901 or AZD6244 significantly increased Runx2 and Alkaline phosphate gene expression in calvarial osteoblasts and decreased TRAP + cells in induced osteoclast cultures. To test the effects of these drugs on bone healing, C57/Bl6 mice underwent a closed tibial fracture and were treated with PD0325901 or AZD6244 at 10 mg/kg/day. Animals were culled at day 10 and at day 21 post-fracture for analysis of the fracture callus and the femoral growth plate in the contralateral leg. MEKi treatment markedly increased cartilage volume in the soft callus at day 10 post-fracture (+ 60% PD0325901, + 20% AZD6244) and continued treatment led to a delay in cartilage remodeling. At the growth plate, we observed an increase in the height of the hypertrophic zone relative to the proliferative zone of + 78% in PD0325901 treated mice. Osteoclast surface was significantly decreased both at the terminal end of the growth plate and within the fracture calluses of MEKi treated animals. The mechanistic effects of MEKi on genes encoding cartilage matrix proteins and catabolic enzymes were examined in articular chondrocyte cultures. PD0325901 or AZD6244 led to increased matrix protein expression ( Col2a1 and Acan ) and decreased expression of catabolic factors ( Mmp13 and Adamts-5 ). Taken together, these data support the hypothesis that MEKi treatment can impact chondrocyte hypertrophy, matrix resorption, and fracture healing. These compounds can also affect bone architecture by expanding the hypertrophic zone of the growth plate and reducing osteoclast surface systemically.
Congenital tibial dysplasia is a severe pediatric condition that classically results in a persistent pseudarthrosis. A majority of these cases are associated with neurofibromatosis type I (NF1), a ...genetic disorder in which inactivation of the NF1 gene leads to overactivity of the Ras-MEK-MAPK (mitogen-activated protein kinase) signaling pathway. We therefore hypothesized that pharmaceutical inhibition of MEK-MAPK may be a beneficial therapeutic strategy.
In vitro methods were used to demonstrate a role for the MEK inhibitor PD0325901 in promoting osteogenic differentiation in Nf1
calvarial osteoblasts. Local applications of rhBMP-2 and/or PD0325901 were then tested in a mouse model of NF1 tibial pseudarthrosis featuring localized double inactivation of the Nf1 gene in a fracture. Mice received no treatment, PD0325901 (10 mg/kg/day from two days before fracture to ten days after fracture), rhBMP-2 (10 μg), or a combination of rhBMP-2 and PD0325901.
Animals treated with the delivery vehicle alone, PD0325901, rhBMP-2, or the PD0325901 + rhBMP-2 combination showed union rates of 0%, 8%, 69% (p < 0.01), or 80% (p < 0.01), respectively, at twenty-one days after fracture. Mice treated with the rhBMP-2 + PD0325901 combination displayed a callus volume sixfold greater than the vehicle controls and twofold greater than the group receiving rhBMP-2 alone. Although MEK inhibition combined with rhBMP-2 led to increases in bone formation and union, the proportion of fibrous tissue in the callus was not significantly reduced.
The data suggest that MEK inhibition can promote bone formation in combination with rhBMP-2 in the context of an NF1 pseudarthrosis. However, PD0325901 did not promote substantive bone anabolism in the absence of an exogenous anabolic stimulus and did not suppress fibrosis.
This study examines a signaling pathway-based approach to treating poor bone healing in a model of NF1 pseudarthrosis.
Analyzing surface forces for myriad geometric structures facilitates the design of properties in interacting interfacial systems. Along these lines, we demonstrate a generalized technique that can be ...utilized to evaluate the orientation dependence of a particle interacting with multiple finite or semi‐infinite objects. Specifically, the surface element integration technique is modified to account for surface elements of a particle not directly adjacent to the object with which it is interacting; this facilitates the analysis of objects with finite shape and with arbitrary orientations. Furthermore, as a technology‐relevant proof‐of‐concept demonstration, the influence of van der Waals (vdW) forces on the performance and reliability of microstructured systems used for the collection of trace particles is reported. The importance of the location of the particle contact with the microstructure and the independence of vdW forces generated by each microstructure is demonstrated using the developed computational approach. Thus, the methodology presented here can ultimately be utilized for a variety of interfacial forces generated by nontrivial systems with heterogeneous properties in order to provide design motifs in a low‐cost, high‐throughput manner.
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Cohesive Hamaker constants of solid materials are measured via optical and dielectric properties (i.e., Lifshitz theory), inverse gas chromatography (IGC), and contact angle ...measurements. To date, however, a comparison across these measurement techniques for common energetic materials has not been reported. This has been due to the inability of the community to produce samples of energetic materials that are readily compatible with contact angle measurements. Here we overcome this limitation by using physical vapor deposition to produce thin films of five common energetic materials, and the contact angle measurement approach is applied to estimate the cohesive Hamaker constants and surface energy components of the materials. The cohesive Hamaker constants range from 85zJ to 135zJ across the different films. When these Hamaker constants are compared to prior work using Lifshitz theory and nonpolar probe IGC, the relative magnitudes can be ordered as follows: contact angle>Lifshitz>IGC. Furthermore, the dispersive surface energy components estimated here are in good agreement with those estimated by IGC. Due to these results, researchers and technologists will now have access to a comprehensive database of adhesion constants which describe the behavior of these energetic materials over a range of settings.
Highlights • Evaluated contact sampling trap effectiveness for detecting trace residues. • Analyzed mechanical properties of traps and surfaces common in security settings. • Developed computational ...approach to deformation of thin, rough films.
Background and Importance: Since Trousseau’s initial publication, the development of thromboembolic events related to malignancy has been well established. The pathophysiology of this is understood ...to be through activation of the coagulation cascade through neoplastic cells themselves or the therapy initiated (chemotherapy or surgery). To date, there have been a variety of studies, such as the OASIS-CANCER trial, which highlight the relationship of hypercoagulability to ischemic stroke. Despite these efforts, clear evidence is lacking for the utilization of antiplatelet or anticoagulation therapy in the secondary prevention of stroke following mechanical thrombectomy in patients with suspected or confirmed malignancy. Clinical Presentation: A 71-year-old female with a history of immune thrombocytopenia, diabetes mellitus, and hypertension who was undergoing an evaluation for a lung nodule, later determined to be adenocarcinoma of the lung, underwent three successful mechanical thrombectomies for acute ischemic stroke with large vessel occlusion over a one month period. This patient had improved National Institutes of Health Stroke Scale (NIHSS) scores following each of her thrombectomies. However, her history of immune thrombocytopenia and underlying malignancy complicated her discharge medication regimen following each of her thrombectomies and may have contributed to her repeat strokes. Conclusion: Clear guidance is lacking regarding the utilization of antiplatelet and anticoagulation therapy in patients with suspected or confirmed malignancy following mechanical thrombectomy. Review of the literature suggests that controlling a patient’s hypercoagulability may lead to improved clinical outcomes, but further clinical trials are warranted.
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