The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer

The relationship between the magnitude of systemic inflammatory response and the nutritional/functional parameters in patients with inoperable non-small cell lung cancer were studied. The extent of weight loss, albumin, C-reactive protein, performance status and quality of life was measured in 106 patients with inoperable non-small cell lung cancer (stages III and IV). Survival analysis was performed using the Cox proportional hazard model. The majority of patients were male and almost 80% had elevated circulating C-reactive protein concentrations (>10 mg l−1). On multivariate analysis, age (P=0.012), tumour type (0.002), weight loss (P=0.056), C-reactive protein (P=0.047), Karnofsky performance status (P=0.002) and fatigue (P=0.046) were independent predictors of survival. The patients were grouped according to the magnitude of the C-reactive protein concentrations (⩽10, 11–100 and >100 mg l−1). An increase in the magnitude of the systemic inflammatory response was associated with increased weight loss (P=0.004), reduced albumin concentrations (P=0.001), reduced performance status (P=0.060), increased fatigue (P=0.011) and reduced survival (HR 1.936 95%CI 1.414–2.650, P<0.001). These results indicate that the majority of patients with inoperable non-small cell lung cancer have evidence of a systemic inflammatory response. Furthermore, an increase in the magnitude of the systemic inflammatory response resulted in greater weight loss, poorer performance status, more fatigue and poorer survival

Spacers to improve performance and porosity of graphene based polymer electrolyte fuel cells

Graphene has been suggested as a potential support material to replace commercial carbon black due to its carbon corrosion resistance. However, graphene-based electrodes typically perform poorly in MEA testing due to restacking of the graphitic sheets. In this study we investigate the introduction of carbon black and their effects on the porosity and current density of graphene-based supports

siRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo

Oncogene-specific downregulation mediated by RNA interference (RNAi) is a promising avenue for cancer therapy. In addition to specific gene silencing, in vivo RNAi treatment with short interfering RNAs (siRNAs) can initiate immune activation through innate immune receptors including Toll-like receptors, (TLRs) 7 and 8. Two recent studies have shown that activation of innate immunity by addition of tri-phosphate motifs to oncogene-specific siRNAs, or by co-treatment with CpG oligos, can potentiate siRNA antitumor effects. To date, there are no reports on applying such approach against human papillomavirus (HPV)-driven cancers. Here, we characterized the antitumor effects of non-modified siRNAs that can target a specific oncogene and/or recruit the innate immune system against HPV-driven tumors. Following the characterization of silencing efficacy and TLR7 immunostimulatory potential of 15 siRNAs targeting the HPV type 16 E6/E7 oncogenes, we identified a bifunctional siRNA sequence that displayed both potent gene silencing and active immunostimulation effect. In vivo systemic administration of this siRNA resulted in reduced growth of established TC-1 tumors in C57BL/6 mice. Ablation of TLR7 recruitment via 2′O-methyl modification of the oligo backbone reduced these antitumor effects. Further, a highly immunostimulatory, but non-HPV targeting siRNA was also able to exert antitumoral effects although for less prolonged time compared with the bifunctional siRNA. Collectively, our work demonstrates for the first time that siRNA-induced immunostimulation can have antitumoral effects against HPV-driven tumors in vivo, even independent of gene silencing efficacy

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

background: The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer. methods: The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined. results: A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P&lt;0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P&lt;0.001), and elevated mGPS and NLR (both P&lt;0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%. conclusions: Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer

Lentiviral Engineered Fibroblasts Expressing Codon Optimized COL7A1 Restore Anchoring Fibrils in RDEB

Cells therapies, engineered to secrete replacement proteins, are being developed to ameliorate otherwise debilitating diseases. Recessive dystrophic epidermolysis bullosa (RDEB) is caused by defects of type VII collagen (C7), a protein essential for anchoring fibril formation at the dermal-epidermal junction (DEJ). Whilst allogeneic fibroblasts injected directly into the dermis can mediate transient disease modulation, autologous gene-modified fibroblasts should evade immunological rejection and support sustained delivery of C7 at the DEJ. We demonstrate the feasibility of such an approach using a therapeutic grade, self-inactivating-lentiviral vector, encoding codon optimized COL7A1, to transduce RDEB fibroblasts under conditions suitable for clinical application. Expression and secretion of C7 was confirmed, with transduced cells exhibiting supra-normal levels of protein expression and ex vivo migration of fibroblasts was restored in functional assays. Gene modified RDEB fibroblasts also deposited C7 at the DEJ of human RDEB skin xenografts placed on NOD-scid IL2Rgamma(null) recipients, with reconstruction of human epidermal structure and regeneration of anchoring fibrils at the DEJ. Fibroblast mediated restoration of protein and structural defects in this RDEB model strongly supports proposed therapeutic applications in man

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration and COX-2 expression and survival in patients with transitional cell carcinoma of the urinary bladder

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration, and COX-2 expression and survival was examined in patients with transitional cell carcinoma of the urinary bladder (n=103). Sixty-one patients had superficial disease and 42 patients had invasive disease. Cancer-specific survival was shorter in those patients with invasive compared with superficial bladder cancer (P<0.001). On univariate analysis, stratified by stage, increased Ki-67 labelling index (P<0.05), increased COX-2 expression (P<0.05), C-reactive protein (P<0.05) and adjuvant therapy (P<0.01) were associated with poorer cancer-specific survival. On multivariate analysis of these significant factors, stratified by stage, only C-reactive protein (HR 2.89, 95% CI 1.42–5.91, P=0.004) and adjuvant therapy (HR 0.29, 95% CI 0.14–0.62, P=0.001) were independently associated with poorer cancer-specific survival. These results would suggest that tumour-based factors such as grade, COX-2 expression or T-lymphocytic infiltration are subordinate to systemic factors such as C-reactive protein in determining survival in patients with transitional cell carcinoma of the urinary bladder

The merger that led to the formation of the Milky Way's inner stellar halo and thick disk

The assembly process of our Galaxy can be retrieved using the motions and chemistry of individual stars. Chemo-dynamical studies of the nearby halo have long hinted at the presence of multiple components such as streams, clumps, duality and correlations between the stars' chemical abundances and orbital parameters. More recently, the analysis of two large stellar surveys have revealed the presence of a well-populated chemical elemental abundance sequence, of two distinct sequences in the colour-magnitude diagram, and of a prominent slightly retrograde kinematic structure all in the nearby halo, which may trace an important accretion event experienced by the Galaxy. Here report an analysis of the kinematics, chemistry, age and spatial distribution of stars in a relatively large volume around the Sun that are mainly linked to two major Galactic components, the thick disk and the stellar halo. We demonstrate that the inner halo is dominated by debris from an object which at infall was slightly more massive than the Small Magellanic Cloud, and which we refer to as Gaia-Enceladus. The stars originating in Gaia-Enceladus cover nearly the full sky, their motions reveal the presence of streams and slightly retrograde and elongated trajectories. Hundreds of RR Lyrae stars and thirteen globular clusters following a consistent age-metallicity relation can be associated to Gaia-Enceladus on the basis of their orbits. With an estimated 4:1 mass-ratio, the merger with Gaia-Enceladus must have led to the dynamical heating of the precursor of the Galactic thick disk and therefore contributed to the formation of this component approximately 10 Gyr ago. These findings are in line with simulations of galaxy formation, which predict that the inner stellar halo should be dominated by debris from just a few massive progenitors.Comment: 19 pages, 8 figures. Published in Nature in the issue of Nov. 1st, 2018. This is the authors' version before final edit

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

The distribution of pond snail communities across a landscape: separating out the influence of spatial position from local habitat quality for ponds in south-east Northumberland, UK

Ponds support a rich biodiversity because the heterogeneity of individual ponds creates, at the landscape scale, a diversity of habitats for wildlife. The distribution of pond animals and plants will be influenced by both the local conditions within a pond and the spatial distribution of ponds across the landscape. Separating out the local from the spatial is difficult because the two are often linked. Pond snails are likely to be affected by both local conditions, e.g. water hardness, and spatial patterns, e.g. distance between ponds, but studies of snail communities struggle distinguishing between the two. In this study, communities of snails were recorded from 52 ponds in a biogeographically coherent landscape in north-east England. The distribution of snail communities was compared to local environments characterised by the macrophyte communities within each pond and to the spatial pattern of ponds throughout the landscape. Mantel tests were used to partial out the local versus the landscape respective influences. Snail communities became more similar in ponds that were closer together and in ponds with similar macrophyte communities as both the local and the landscape scale were important for this group of animals. Data were collected from several types of ponds, including those created on nature reserves specifically for wildlife, old field ponds (at least 150 years old) primarily created for watering livestock and subsidence ponds outside protected areas or amongst coastal dunes. No one pond type supported all the species. Larger, deeper ponds on nature reserves had the highest numbers of species within individual ponds but shallow, temporary sites on farm land supported a distinct temporary water fauna. The conservation of pond snails in this region requires a diversity of pond types rather than one idealised type and ponds scattered throughout the area at a variety of sites, not just concentrated on nature reserves