p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis.

The ability of tumor cells to metastasize is increasingly viewed as an interaction between the primary tumor and host tissues. Deletion of the p19/Arf or p53 tumor suppressor genes accelerates malignant progression and metastatic spread of 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced squamous cell carcinomas, providing a model system to address mechanisms of metastasis. Here, we show that benign pre-metastatic papillomas from wild-type mice trigger lymphangiogenesis within draining lymph nodes, whereas there is no growth of primary tumor lymphatic vessels. Lymph node lymphangiogenesis is greatly accelerated in papilloma-bearing p19/Arf- or p53-deficient mice, which coincides with the greater propensity of these tumors to progress to carcinomas and to metastasize. The extent of accumulation of B cells within the tumor-draining lymph nodes of wild-type mice predicted the level of lymph node lymphangiogenesis and metastatic potential. Arf or p53 deficiency strongly accelerated lymph node immune cell accumulation, in a manner that was associated with the extent of lymph node lymphatic sinus growth. This immune cell accumulation and lymph node lymphangiogenesis phenotype identifies host anti-tumor responses that could drive metastatic spread of cancers via the lymphatics

Compressive and Bending Performance of Selectively Laser Melted AlSi10Mg Structures

Selective laser melting (SLM) is a widely used additive manufacturing technique that effectively manufactures complex geometries such as cellular structures. However, challenges such as anisotropy and mechanical property variation are commonly found due to process parameters. In a bid to utilize this method for the commercial production of cellular structures, it is important to understand the behavior of a material under different loading conditions. In this work, the behavior of additively manufactured AlSi10Mg under compression, bending, and tension loads was investigated. Vertical and horizontal build directions are compared for each type of loading. Specimens were manufactured using the reduced build volume (RBV) chamber of the Renishaw AM 250 SLM machine

Inhibition of PI-3K restores nuclear p27(Kip1) expression in a mouse model of Kras-driven lung cancer.

Reduced expression of the CDK inhibitor p27(Kip1) (p27) in human lung cancer correlates with tumor aggressiveness and poor prognosis. However, the regulation of p27 expression and the role of p27 during lung cancer are poorly understood. Urethane-induced lung tumors in mice frequently harbor mutations in the Kras oncogene, and in this study, we use this model to address the regulation of p27 during tumorigenesis. The Ras effector Akt is known to regulate p27 mRNA abundance by phosphorylating and inactivating the FOXO transcription factors. Phosphorylated Akt and FOXO proteins were both increased in lung tumors, correlating with a reduction in p27 mRNA transcript. Akt also directly phosphorylates p27 and regulates its nuclear/cytoplasmic localization. Tumors showed a reduced nuclear/cytoplasmic ratio of p27 protein, together with an increase in phosphorylated Thr197 p27 in the cytoplasmic pool. Treatment of lung tumor-bearing mice with the phosphoinositol-3 kinase inhibitor LY294002 induced a rapid decrease in phosphorylated Akt and phosphorylated p27, concomitant with an increase in nuclear p27. Germline p27 deficiency accelerated both the growth and malignant progression of urethane-induced lung tumors, and did so in a cell autonomous manner, confirming a causal role of p27 in tumor suppression. These results show that p27 is a potent barrier to the growth and malignant progression of Kras-initiated lung tumors. Further, the reduction of nuclear p27 in tumors is mediated by oncogene signaling pathways, which can be reversed by pharmacological agents.Oncogene advance online publication, 3 August 2009; doi:10.1038/onc.2009.226

Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis

The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N‐terminal ubiquitin‐like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin‐binding interface, provide a model for the phosphoubiquitin–parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin‐binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin

Effect of SLM Build Parameters on the Compressive Properties of 304L Stainless Steel

Selective laser melting (SLM) is well suited for the efficient manufacturing of complex structures because of its manufacturing methodology. The optimized process parameters for each alloy has been a cause for debate in recent years. In this study, the hatch angle and build orientation were investigated. 304L stainless steel samples were manufactured using three hatch angles (0◦, 67◦, and 105◦) in three build orientations (x-, y-, and z-direction) and tested in compression. Analysis of variance and Tukey\u27s test were used to evaluate the obtained results. Results showed that the measured compressive yield strength and plastic flow stress varied when the hatch angle and build orientation changed. Samples built in the y-direction exhibited the highest yield strength irrespective of the hatch angle; although, samples manufactured using a hatch angle of 0◦ exhibited the lowest yield strength. Samples manufactured with a hatch angle of 0◦ flowed at the lowest stress at 35% plastic strain. Samples manufactured with hatch angles of 67◦ and 105◦ flowed at statistically the same flow stress at 35% plastic strain. However, samples manufactured with a 67◦ hatch angle deformed non-uniformly. Therefore, it can be concluded that 304L stainless steel parts manufactured using a hatch angle of 105◦ in the y-direction exhibited the best overall compressive behavior

The Impact of Calcium on Chronic Total Occlusion Management.

Coronary artery calcification is prevalent in chronic total occlusions (CTO), particularly in those of longer duration and post-coronary artery bypass. The presence of calcium predicts lower procedural success rates and a higher risk of complications of CTO percutaneous coronary intervention. Adjunctive imaging, including pre-procedural computed tomography and intracoronary imaging, are useful to understand the distribution and morphology of the calcium. Specialised guidewires and microcatheters, as well as penetration, subintimal entry and luminal re-entry techniques, are required to cross calcific CTOs. The use of both atherectomy devices and balloon-based calcium modification tools has been reported during CTO percutaneous coronary intervention, although they are limited by concerns regarding safety and efficacy in the subintimal space

Impact of proctoring on success rates for percutaneous revascularisation of coronary chronic total occlusions.

OBJECTIVE: To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. METHODS: We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. RESULTS: CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p<0.0001). In more complex cases where JCTO≥2, the difference in success was greater (70.7% vs 49.5%, p=0.0003). After proctoring, there was an increase in CTO PCI activity in centres from 2.5% to 3.5%, p<0.0001 (as a proportion of total PCI), and the proportion of very difficult cases with JCTO score ≥3 increased from 15.3% (35/229) to 29.7% (105/354), p<0.0001. CONCLUSIONS: Proctoring resulted in an increase in procedural success for CTO PCI, an increase in complex CTO PCI and an increase in total CTO PCI activity. Proctoring may be a valuable way to improve access to CTO PCI and the likelihood of procedural success

Classification and characterisation of magmatic-hydrothermal tourmaline by combining field observations and microanalytical techniques

Tourmaline from the St. Byron lobe of the Land’s End granite, SW England, was assessed by macroscopic, optical and quantitative microanalytical methods. In total, seven types of tourmaline were distinguished. The seven types reflect different crystallisation environments and stages in the magmatic-hydrothermal transition. Types 1-3 are interpreted to represent a gradual transition from tourmaline crystallising from a silicate melt to precipitation from magmatic aqueous fluids. Types 5-7 crystallised at subsolidus conditions from a different fluid generation than types 1-3. These fluids may be magmatic or mixed with other fluids (e.g., meteoric or formation waters). The Sn-mineralisation in the area is mostly related to the latter fluid generation, and the mineralising potential is reflected by the tourmaline composition.This is an open access article, available to all readers online, published under a creative commons licensing Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. Published under licence by IOP Publishing Lt

Seeing education with northern eyes: University of the Arctic Thematic Network for Teacher Education for Social Justice and Diversity in Education

The University of the Arctic is a virtual organisation of universities, colleges, research institutes and other organisations concerned with education and research in and about the North. Within the organisation, Thematic Networks are the primary means of cooperation between member institutions. Through the Thematic Networks faculty and researchers can facilitate knowledge generation and sharing across the North based on common interests and priorities within this area. This feature article describes the formation of the Thematic Network for Teacher Education for Social Justice and Diversity in Education; its values, themes, goals and activities