The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma

Characterization and Depth Profile of Lithium Depletion in Aluminum-Lithium Alloys by Ultrasound

Aluminum-Lithium (Al-Li) alloys have been developed as an alternative to conventional aluminum alloys for use in aerospace and other applications where low-weight, high strength materials are required. The use of Al-Li alloys in military and civil air transport continues to increase [1]. The key benefits of Al-Li alloys, when compared to conventional aluminum alloys, are the lower density and higher elastic modulus. Thus, Al-Li alloys offer enhanced mechanical properties while decreasing overall weight. This is crucial for high performance aircraft, where the higher strength-to-weight ratio can give considerable velocity and maneuverability advantages. It is also of significant benefit for transport aircraft and spacecraft, where reduced weight will increase the range and lift capability, especially if operating at supersonic velocities with large loads. The improved efficiency increases the feasibility of developing a supersonic civil transport that can successfully operate within the economic restrictions of the commercial marketplace.</p

Quantitative power Doppler ultrasonography is a sensitive measure of metacarpophalangeal joint synovial vascularity in rheumatoid arthritis and declines significantly following a 2-week course of oral low-dose corticosteroids.

OBJECTIVE: To investigate the stability over 2 weeks of ultrasonographic assessments of synovial thickness and vascularity in all 10 metacarpophalangeal joints of subjects with rheumatoid arthritis (RA) with a range of disease activities as measured by the validated Disease Activity Score-28 joint score (DAS28-ESR). And in subjects with severe disease activity, to compare the sensitivity of these measurements, acute-phase markers, and vascular endothelial growth factor to change in response to 2 weeks of oral prednisolone (7.5 mg daily). METHODS: A group of 38 subjects with RA were enrolled, 13 (mean DAS28 2.1), 14 (mean DAS28 5.2), and 11 (mean DAS28 5.7) meriting oral corticosteroid treatment. Synovial thickness and vascularity were assessed by ultrasonography at 3 timepoints. Images were ranked by semiquantitative scale. Vascularity was also measured by quantitative determination of the power Doppler area (PDA). RESULTS: In the whole RA cohort, baseline indices of synovial thickness and vascularity correlated with DAS28, as did PDA (r = 0.42, p &lt; 0.05). In the RA groups on stable therapy, synovial thickness and vascularity showed little variation over 2 weeks. In the corticosteroid group, PDA had fold changes of -1.9-fold (p &lt; 0.05) after 1 week and -2.2-fold (p &lt; 0.05) after 2 weeks. These were the largest fold changes of all measured variables. CONCLUSION: Ultrasonographic measures can differentiate disease severity in RA correlating closely with DAS28. Quantitative power Doppler signal was significantly reduced within 1 week of oral prednisolone, a rapid kinetic suggesting that PDA may have value as a sensitive early marker of therapeutic response

Microstructural influence on the work hardening of aluminum-lithium alloy 2090 at cryogenic temperatures

Previous studies indicate that the work hardening characteristics of a Vintage III 2090-T81 12.7-mm (0.5-in.) plate is highly dependent on the through-thickness position. This dependency has been linked to two distinctly different microstructures existing as laminates within the plate. An investigation of the two microstructures by both optical and transmission electron microscopy reveal a difference in the distribution of grains and subgrains. It is believed that these factors affect the work hardening characteristics by governing the manner in which slip is transmitted from grain to grain. The findings are positive as they suggest a practical means by which improvements in work hardening can be obtained through modifications of the microstructure at the polygranular level. 24 refs., 7 figs

Physics-Informed Network Models: a Data Science Approach to Metal Design

Functional graded materials (FGM) allow for reconciliation of conflicting design constraints at different locations in the material. This optimization requires a priori knowledge of how different architectural measures are interdependent and combine to control material performance. In this work, an aluminum FGM was used as a model system to present a new network modeling approach that captures the relationship between design parameters and allows an easy interpretation. The approach, in an un-biased manner, successfully captured the expected relationships and was capable of predicting the hardness as a function of composition