The Multifarious Role of Microglia in Brain Metastasis

The immune landscape in brain metastasis is a very heterogeneous framework. Amongst a broad plethora of cells within the tumor microenvironment, the presence of activated microglia has been perfectly described. The innate role of microglial cells is to detect and eliminate any insults that may disturb the regular behavior of the brain. As part of its defensive role, it releases pro- and anti-inflammatory cytokines that aim to modulate the inflammatory scenario at the metastatic foci. However, the long term effects that these cells may exert on the metastatic progression is not clear. One of the biggest challenges in the field is to distinguish between brain resident microglial cells and infiltrated bone-marrow derived macrophages. Part of this issue is the fact that both cell types share similar phenotypes. Current studies are based on the modulation of the immune response against cancer cells (immunotherapy). However, most of current clinical trials and newly developed drugs focus on the adaptive immune response (e.g., immune blockade check-points). Additionally, the unique structure of the central nervous system with the presence of the blood-brain barrier have hindered a significant advance in novel therapies against brain metastasis. In this manuscript, we describe current advances in characterization of tumor-associated microglia and macrophages, the importance of microglia during the anti-cancerous response, and the future direction for the development of new strategies against this complex disease

Clustering as an example of optimizing arbitrarily chosen objective functions

This paper is a reflection upon a common practice of solving various types of learning problems by optimizing arbitrarily chosen criteria in the hope that they are well correlated with the criterion actually used for assessment of the results. This issue has been investigated using clustering as an example, hence a unified view of clustering as an optimization problem is first proposed, stemming from the belief that typical design choices in clustering, like the number of clusters or similarity measure can be, and often are suboptimal, also from the point of view of clustering quality measures later used for algorithm comparison and ranking. In order to illustrate our point we propose a generalized clustering framework and provide a proof-of-concept using standard benchmark datasets and two popular clustering methods for comparison

A Situation Analysis of Ley Pasture Utilisation in the Western Downs and Maranoa Regions of S Queensland, Australia

Previous studies have shown that the uptake of ley pasture systems in S Queensland\u27s grain growing region has been slow when compared with mixed farming systems in S Australia. This is despite their demonstrated benefits to subsequent crops, livestock production and the environment. A survey was conducted that aimed to determine the level of utilisation of ley pastures in the Western Downs and Maranoa regions of S Queensland, and the possible constraints to their adoption, and benefits arising from their use. The survey also aimed to determine the commonly used pasture species, the reasons for their use and their contribution to the livestock component of mixed farms

A Situation Analysis of Ley Pasture Utilisation in the Western Downs and Maranoa Regions of S Queensland, Australia

Previous studies have shown that the uptake of ley pasture systems in S Queensland\u27s grain growing region has been slow when compared with mixed farming systems in S Australia. This is despite their demonstrated benefits to subsequent crops, livestock production and the environment. A survey was conducted that aimed to determine the level of utilisation of ley pastures in the Western Downs and Maranoa regions of S Queensland, and the possible constraints to their adoption, and benefits arising from their use. The survey also aimed to determine the commonly used pasture species, the reasons for their use and their contribution to the livestock component of mixed farms

Functional role of endothelial adhesion molecules in the early stages of brain metastasis

BACKGROUND: Cellular adhesion molecules (CAMs), which are normally associated with leukocyte trafficking, have also been shown to play an essential role in tumor metastasis to non-CNS sites. However, the role played by CAMs in brain metastasis is largely unexplored. It is known that leukocyte recruitment to the brain is very atypical and that mechanisms of disease in peripheral tissues cannot be extrapolated to the brain. Here, we have established the spatiotemporal expression of 12 key CAMs in the initial phases of tumor seeding in 2 different models of brain metastasis. METHODS: BALB/c or SCID mice were injected intracardially (10(5) cells/100 μL phosphate-buffered saline with either 4T1-GFP or MDA231BR-GFP cells, respectively (n = 4–6/group), and expression of the CAMs was determined by immunohistochemistry and immunofluorescence colocalisation. RESULTS: Endothelial expression of E-selectin, VCAM-1, ALCAM, ICAM-1, VLA-4, and β(4) integrin was markedly increased early in tumor seeding. At the same time, the natural ligands to these adhesion molecules were highly expressed on the metastatic tumor cells both in vitro and in vivo. Two of these ligands showed particularly high tumor cell expression (ALCAM and VLA-4), and consequently their functional role in tumor seeding was determined. Antibody neutralization of either ALCAM or VLA-4 significantly reduced tumor seeding within the brain (>60% decrease in tumor number/mm(2) brain; P < .05–0.01). CONCLUSIONS: These findings suggest that ALCAM/ALCAM and VLA-4/VCAM-1 interactions play an important functional role in the early stages of metastasis seeding in the brain. Moreover, this work identifies a specific subset of ligand-receptor interactions that may yield new therapeutic and diagnostic targets for brain metastasis

A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations

Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown. © 2013 Wiley Periodicals, Inc

The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation

<p>Abstract</p> <p>Background</p> <p>Activated microglia are a feature of the host response to neurodegeneration in Parkinson's disease (PD) and are thought to contribute to disease progression. Recent evidence suggests that extracellular α-synuclein (eSNCA) may play an important role in the pathogenesis of PD and that this may be mediated by a microglial response.</p> <p>Methods</p> <p>We wished to discover whether the host response to eSNCA would be sufficient to induce significant cytokine production. <it>In vitro </it>cultured BV-2 microglia were used to determine the basic inflammatory response to eSNCA. <it>In vivo</it>, 8-week old Biozzi mice were subjected to a single intranigral injection of either 3 μg SNCA, lipopolysaccharide (LPS) or serum protein (BSA) and allowed to recover for 24 hours. A second cohort of animals were peripherally challenged with LPS (0.5 mg/kg) 6 hours prior to tissue collection. Inflammation was studied by quantitative real-time PCR for a number of pro-inflammatory genes and immunohistochemistry for microglial activation, endothelial activation and cell death.</p> <p>Results</p> <p><it>In vitro </it>data showed a robust microglial response to SNCA, including a positive NFĸB response and the production of pro-inflammatory cytokines. Direct injection of SNCA into the substantia nigra resulted in the upregulation of mRNA expression of proinflammatory cytokines, the expression of endothelial markers of inflammation and microglial activation. However, these results were significantly different to those obtained after direct injection of LPS. By contrast, when the animals were injected intracerebrally with SNCA and subsequently challenged with systemic LPS, the level of production of IL-1β in the substantia nigra became comparable to that induced by the direct injection of LPS into the brain. The injection of albumin into the nigra with a peripheral LPS challenge did not provoke the production of a significant inflammatory response. Direct injection of LPS into the substantia nigra also induces cell death in a more robust manner than direct injection of either SNCA or BSA.</p> <p>Conclusion</p> <p>These results suggest that the presence of eSNCA protein 'primes' microglia, making them susceptible to environmental proinflammatory challenge. For this reason, we hypothesise that where 'inflammation' contributes to the disease progression in PD, it does so in a punctuate manner (on-off) as a result of systemic events.</p

Flip Graphs of Degree-Bounded (Pseudo-)Triangulations

We study flip graphs of triangulations whose maximum vertex degree is bounded by a constant $k$. In particular, we consider triangulations of sets of $n$ points in convex position in the plane and prove that their flip graph is connected if and only if $k > 6$; the diameter of the flip graph is $O(n^2)$. We also show that, for general point sets, flip graphs of pointed pseudo-triangulations can be disconnected for $k \leq 9$, and flip graphs of triangulations can be disconnected for any $k$. Additionally, we consider a relaxed version of the original problem. We allow the violation of the degree bound $k$ by a small constant. Any two triangulations with maximum degree at most $k$ of a convex point set are connected in the flip graph by a path of length $O(n \log n)$, where every intermediate triangulation has maximum degree at most $k+4$.Comment: 13 pages, 12 figures, acknowledgments update

Cretaceous age, composition, and microstructure of pseudotachylyte in the Otago Schist, New Zealand

At Tucker Hill, in Central Otago, New Zealand, a series of pseudotachylyte veins are hosted in quartzofeldspathic schist. Chilled margins, microlites, flow banding, and the crystallisation of mineral phases absent from the host rock provide unequivocal evidence for melting during pseudotachylyte formation. Whole rock analyses of pseudotachylyte reveal c. 3 enrichment of K2O, Ba, and Rb, and similar depletion of Na2O, CaO, Sr, and Eu, as compared to host schist. Formation age of pseudotachylyte is 95.9±1.8 Ma as measured by total fusion 40Ar/39Ar analyses. Stepwise heating of pseudotachylyte matrix yields an excellently defined 40Ar/39Ar plateau age of 96.0±0.3 Ma. These well-defined ages are attributed to the presence of potassium feldspar, low abundance of inherited lithic material from the host rock, and few fluid inclusions containing extraneous Ar. We propose that formation of these pseudotachylyte veins was related to Cretaceous extensional uplift and exhumation of the Otago Schist